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Patents and the Pipeline: Is Access Under Threat?

By Jonathan Berger

September 2011

Table of Contents


Introduction

Access to the pipeline, particularly in developing countries that are home to a disproportionate share of the global population of people with HIV, will by no means be guaranteed. Numerous barriers may stand in the way of timely access, including but not limited to slow drug registration processes, inefficient domestic procurement policies, and problematic supply chain management practices. But, as was the case with access to treatment in the developing world in the late 1990s and early 2000s,1 the single biggest barrier to access may indeed be the high prices of new drugs.

Central to the affordability of medicines is the existence of adequate generic competition. This, in turn, is dependent on a number of intellectual property-related factors, including the patent status of the drug in countries with significant generic pharmaceutical manufacturing capacity (in particular India), the patent status of the drug in the country in whose market generic competition is required, and/or the licensing policy of the relevant patent holder. Some detail on the licensing policies of companies with products in the pipeline is provided below. But before that, this section considers the global context that affects the nature of domestic patent laws.


Threats to Countries' Ability to Manufacture and Supply Affordable Drugs

Since amending its laws in 2005 to ensure compliance with the World Trade Organization (WTO) Agreement on Trade-related Aspects of Intellectual Property Rights (TRIPS),2 India has been subjected to numerous threats to its ability to manufacture and supply affordable generic finished products and active pharmaceutical ingredients (APIs). The rapidly changing nature of the Indian generics industry has been accompanied by the rising grant of product patents, with new products for the first time in decades not being subjected to generic competition; this includes many new-generation antiretroviral (ARV) medicines.

While India took great care in ensuring that its amended laws take advantage of a range of public health safeguards and flexibilities in TRIPS, something that many developing countries such as South Africa have thus far failed to do, the post-TRIPS era is one in which access has unquestionably been curtailed. Put differently, an international patent regime that does not require minimum levels of patent protection for all pharmaceutical products would mean more people having access. But instead of a move in this direction, "the policy space to produce or import generic versions of patented medicines [within the context of TRIPS] is shrinking in some developing countries." As 't Hoen et al. explain:

Stringent intellectual property provisions exceeding TRIPS requirements ("TRIPS-plus") have been negotiated into free trade agreements between industrialized and developing countries, and/or investment and WTO accession agreements. Measures, such as patent term extensions, data exclusivity, patentregistration linkage and border enforcement requirements, can all delay access to generics by lengthening, strengthening or broadening monopolies on medicines. In addition, some agreements contain measures that confuse legitimate generics with counterfeit medicines; such policies can undermine public health by restricting access to affordable, quality-assured generic medicines. Countries that enter into agreements that undermine access to medicines are arguably violating their international human rights obligations.3

In recent years and months, India has been under pressure from the European Union (EU) to conclude a free trade agreement (FTA) that, if adopted in the form proposed by the EU, would substantially undermine India's already-constrained ability to produce affordable medicines.4 At the June 2011 UN High-Level Meeting on HIV and AIDS, India formally announced that it will not accept data exclusivity -- a provision that has the potential to limit access to medicines, and that is not required by TRIPS -- as part of the FTA it is currently negotiating with the EU.

But other problematic provisions that threaten access remain on the EU's negotiating agenda.

According to Médecins Sans Frontières (MSF), "Europe is still pushing provisions on the enforcement of intellectual property that are of great concern for procurers and suppliers of medicines ... [that put them] at risk of litigation or court orders that prevent [them] from delivering medicines to patients". In addition, the EU is also proposing an investment chapter that "includes measures to protect the commercial interests of foreign companies investing in India ... [by giving them] the right to bypass Indian courts and sue the Indian government in secret international arbitration panels that do not balance public health against private profit."5


Licensing Policies

While the global context and resultant domestic patent laws are central to determining whether medicines are affordable, so too is the conduct of exclusive rights holders (whether patent holders or exclusive licensees) and their approach to licensing. One option available to companies is the Medicines Patent Pool,6 which was established in the late 2000s and is expected to work as follows:7

Patent holders will make licenses available through the Pool that will allow others to produce low-cost generic versions of patented ARVs for use in developing countries. It will be important that the licenses cover as many developing countries as possible, both to maximize public health benefit and to ensure economies of scale in generic drug production. The licenses are also intended to facilitate the development of FDCs and other formulations adapted for use in resource-poor settings, such as special formulations for treating children, by ensuring that patents do not block generic companies or product development initiatives from carrying out follow-on R&D.

Companies that receive licenses from the Pool will pay royalties on their sales to the patent holders. The Pool will be a systematic and predictable way of making voluntary licences available, offering legal certainty to all parties involved. No change in international or national law is required for the Pool to work; what is required is a change in mindset from the patent holders, without whose collaboration this initiative cannot succeed. In other words, the Patent Pool will work only if patent holders are willing to collaborate to make their intellectual property available to the Pool.

On 12 July 2011, the Medicines Patent Pool announced its first agreement with a pharmaceutical company - Gilead Sciences.8 Whilst the agreement will result in expanded access to the company's products, including those currently in the pipeline, numerous of its provisions have drawn criticism: for example, the agreement excludes a number of developing countries with high HIV burdens and places limits on API sourcing. Given the voluntary nature of the Pool, it is unsurprising that the agreement does not go far enough.

A second option is adopting access-friendly patent enforcement and/or licensing policies. In the next section we consider whether companies with key products in the pipeline have addressed this issue, and if so, how. These companies are:


Abbott Laboratories

Abbott has consistently refused to license any company to produce generic versions of its fixed-dose combination lopinavir/ritonavir (LPV/r); it is, however, prepared not to enforce its patent on the soft-gel formulation of ritonavir (RTV) in South Africa.9 That said, there is currently no patent barrier to the production of generic LPV/r or RTV in India;10 importation from India depends solely on the patent status of the relevant product in the importing country and whether a compulsory licence for importation has been issued in that country (in the event that the relevant product is indeed under patent protection).


BI

According to its policy paper on HIV/AIDS, BI does not enforce its patents on nevirapine and tipranavir in the following countries: low-income countries as defined by the World Bank;11 least-developed countries (LDCs) as defined by the United Nations Development Programme;12 and all African countries that are not classified as low-income or LDCs.

This policy, which applies to immediate-release and extended-release versions of nevirapine, means that companies in eligible countries -- without the need for any legislative or administrative action -- may lawfully manufacture generic products. They may also export products to and/or import them from other eligible countries.

Of concern, however, is that the policy does not cover middle-income countries outside of sub-Saharan Africa, including those such as Brazil, China, India, and Thailand with significant generic pharmaceutical manufacturing capacity. This limits the ability of the eligible countries to import generic finished products and APIs, with manufacturers based in countries such as Kenya and South Africa being almost completely reliant on the importation of APIs.

BMS

BMS does not enforce the exclusive marketing rights it holds on didanosine (ddI), stavudine (d4T) and atazanavir (ATV) in sub-Saharan Africa. Since 2001, it has entered into 11 "immunity-from-suit" agreements in respect of ddI and d4T; it has committed to entering into similar agreements with requesting companies in respect of ATV. In 2006, BMS granted royalty-free licenses to, and entered into technology transfer agreements with, two companies -- one in South Africa and the other in India -- regarding the production of generic ATV and its sale in sub-Saharan Africa.

On the one hand, this approach is an improvement on BI's: it has resulted in the licensing of an Indian generics company -- a member of the Clinton Health Access Initiative (CHAI) consortium -- with significant manufacturing capacity in respect of quality finished products and APIs. On the other, the limitation on the number of licensees has implications for competition and pricing; the best international prices for ATV still remain too high.

BMS's publicly stated position on intellectual property suggests that the company is open to following this approach in respect of pipeline products such as BMS-663068.


Gilead Sciences

Following the introduction in 2005 of patent protection on pharmaceutical products in India, Gilead began to enter into non-exclusive licensing agreements with a range of generics companies for the manufacture and sale of tenofovir disoproxil fumarate (TDF) and the fixed-dose combination (FDC) of TDF and emtricitabine (FTC).13 These agreements, which were concluded prior to any final decisions of the authorities in India regarding the relevant patent applications, apply both to finished products and APIs. As of April 2011, Gilead had licensed 14 companies: 13 in India and one in South Africa.14

The agreements permit the licensees to manufacture generic TDF and TDF/FTC in India and to sell finished products in India and an additional 94 countries,15 including a range of middle-income countries such as Thailand, Moldova, and various states in Central America and the Caribbean. Licensees are entitled to buy APIs from -- and sell them to -- each other, as well as to obtain APIs from Gilead's own supplier. All licensees are required to pay Gilead a five percent royalty on the sale of finished products.

The agreement between Gilead and the Medicines Patent Pool, details of which were released on 12 July 2011, follows a similar approach in respect of the company's pipeline products: elvitegravir (EVG); cobicistat (COBI); and the FDC of TDF/FTC/EVG/COBI ("Quad"). Under the terms of the agreement, Indian generics companies will be licensed by the Pool to produce and sell APIs (to each other) and finished products (to a list of countries). Licensees may also sell to countries in which compulsory licences for import have been issued.

In addition to the 95 countries already covered by earlier agreements, licensees will be able to sell finished TDF and TDF/FTC products in 16 more countries, including 7 in the Caribbean and Latin America, 4 in Eastern Europe and Central Asia, and 4 in the Pacific. But the geographic scope of the pipeline products is more restricted: 12 of the 111 countries are excluded from the COBI licence, with 3 of these countries also being excluded from the EVG and Quad licences.


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Merck & Co.

Merck does not appear to have any coherent approach to licensing. That said, the company has -- in response to legal action -- licensed numerous companies for the production of generic efavirenz (EFV) products in, and/or the importation of EFV products into, South Africa. In addition, government-issued compulsory licenses in Thailand and Brazil have paved the way for the introduction of affordable generic EFV products. In India, there are no product patents on the drug and consequently at least six Indian companies are producing it currently.16,17

According to the MSF Access Campaign, Merck and the Institute for Research in Molecular Biology (IRBM)18 applied for patents on raltegravir (RAL) in a number of developing countries with generic drug manufacturing capacity, such as Brazil, China, India, and South Africa. IRBM was granted a patent on RAL in India in December 2007, which will expire only in 2022. Unless and until Merck is effectively compelled to license RAL to manufacturers in India and/or other developing countries with generic drug manufacturing capacity, access to RAL products will remain out of reach for the majority of those living with HIV in developing countries.


ViiV Healthcare

ViiV's voluntary licensing policy, in terms of which royalty-free licences are offered to generics companies to manufacture and sell all its current products and those in the pipeline, covers 69 countries: all LDCs, low-income countries, and sub-Saharan African countries. This policy also extends to the integrase inhibitor dolutegravir, currently being developed jointly by ViiV and Shionogi. As is the case with the BI policy, ViiV's does not cover middle-income countries outside of sub-Saharan Africa, including those with significant generic pharmaceutical manufacturing capacity; this limits the ability of the listed countries to import generic finished products and APIs.


Tibotec

Tibotec's Global Access Programme (GAP) -- which first addressed access to darunavir (DRV) and etravirine (ETV) -- was initially focused on sub-Saharan Africa and LDCs. This has been expanded with rilpivirine (RLV): prior to the drug's licensure in the United States, Tibotec granted multiple non-exclusive licences to generics companies (including two in India and one in South Africa) to manufacture, market, and distribute finished products. The Indian companies -- of which there are now four -- have the right to market in sub-Saharan Africa, LDCs, and India; South Africa's Aspen is limited to sub-Saharan Africa.

The agreements extend to the development, manufacturing, and distribution of two FDCs containing RPV: TDF/3TC/RPV and TDF/FTC/RPV. No agreement has yet been reached in respect of the relevant API: generic production of the single agent and/or the FDCs will require the purchase of the RPV API from Tibotec.


Tobira Therapeutics

Tobira is a private company that was founded only in 2006. On 22 June 2011, it announced that it had started a phase IIb clinical trial for the CCR5/CCR2 inhibitor cenicriviroc (TBR-652); the drug, therefore, still has two to three years of clinical development left to assess safety and efficacy in support of regulatory authority approval. Tobira has indicated that its access policies will be determined only after substantial completion of this clinical work.


References

  1. See Ellen 't Hoen et al., Driving a decade of change: HIV/AIDS, patents and access to medicines for all, Journal of the International AIDS Society. 2011 March 27;14:15.
  2. For more information on the impact of TRIPS on access to medicines, see 't Hoen et al., ibid.
  3. Ibid.
  4. India is not alone. Other countries -- such as South Africa and its partners in the Southern African Customs Union, Mozambique and Angola -- may have faced similar pressures. In this regard, see www.section27.org.za/2011/03/16/proposed-economic-partnershipagreement-with-the-eu-raises-concerns-about-access-to-medicines.
  5. See www.msfaccess.org/media-room/press-releases/press-release-detail/?tx_ttnews[tt_news]=1700&cHash=2f6721d292.
  6. See www.medicinespatentpool.org/.
  7. Numerous companies are currently in negotiations with the Patent Pool. For further detail in this regard, see www.medicinespatentpool.org/LICENSING/Company-Engagement.
  8. See International Treatment Preparedness Coalition and Initiative for Medicines, Access & Knowledge Briefing Paper, "The Implications of the Medicines Patent Pool and Gilead Licenses on Access to Treatment", accessed 11 August 2011 at http://www.i-mak.org/publications/. But also see Krista Cox, Medicines Patent Pool agreement with Gilead contains flexibilities including termination provisions and severability of licenses, accessed 11 August 2011.
  9. This waiver of rights applies only to the production of the soft-gel capsule version of RTV for sale and use in South Africa.
  10. According to the MSF Access Campaign, Abbott applied for several patents on the solid dosage formulation and polymorphic forms of LPV/r and its constituent parts. A number of these applications were opposed by civil society organizations and generics companies. Opposition to the LPV/r soft-gel formulation patent application resulted in it being withdrawn; on 30 December 2010, the Indian Patent Office decided that LPV/r does not merit a patent under Indian law. For further information in this regard, see http://utw.msfaccess.org/drugs/lopinavir-ritonavir and http://msf-utw.tumblr.com/post/2624553835/india-rejects-patent-for-aids-drug-lopinavir-ritonavir.
  11. See http://data.worldbank.org/about/country-classifications/country-and-lending-groups#Low_income.
  12. See www.un.org/wcm/content/site/ldc/home/Background/quick_facts.
  13. The history of Gilead's Global Access Program (GAP) is available at www.gilead.com/pdf/GAPHistory.pdf.
  14. Gilead's initial agreement with South Africa's Aspen Pharmacare was for the production and distribution of co-branded Viread and Truvada in Africa, using APIs from Gilead's supplier. In November 2007, Gilead and Aspen entered into a full licensing agreement with terms and conditions similar to those granted to the Indian licensees.
  15. The full list of companies is available at www.gilead.com/access_partnerships#distribution.
  16. MSF 2011. Untangling the web of antiretroviral price reductions. 2011 edition. Accessed 23 June 2011.
  17. According to the MSF Access Campaign, there are concerns regarding the potential impact of a patent for the process of preparing form 1 of crystalline EFV that was granted in India in June 2005 -- it appears to protect a key process for manufacturing the drug. Opposition to that patent is ongoing.
  18. IRBM, which is based in Pomezia in Italy, is one of Merck's research sites.




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