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Secondary Patenting of Branded Pharmaceuticals: A Case Study of How Patents on Two HIV Drugs Could be Extended for Decades
Abstract
Pharmaceutical manufacturers rely on patents to protect their intellectual property and often seek to extend market exclusivity for their products to maximize their return on investment. One method is by obtaining patents on features other than the original active drug ingredient, including secondary patents on alternate formulations of the drug or on methods of administration. This article examines how secondary patents can extend market exclusivity and thus delay generic competition, using as an example two key antiretroviral drugs for the management of HIV: ritonavir (Norvir) and lopinavir/ritonavir (Kaletra). We identified 108 patents, which together could delay generic competition until at least 2028-twelve years after the expiration of the patents on the drugs' base compounds and thirty-nine years after the first patents on ritonavir were filed. Some of the secondary patents that were reviewed were found to be of questionable inventiveness. We argue that increased transparency for existing patents, stricter patentability standards, and increased opportunities to challenge patent applications and patents could reduce inappropriate market exclusivity extensions on brand-name drugs and open the door to lower-cost generics.
... The marketing of enantiopure compounds with questionable advantages over the original drug is just one example of an evergreening strategy [8]. Other evergreening techniques include patenting combination formulations , structural analogues, active metabolic types, and slowrelease forms [9]. The specific impact of these second-generation products, or ''follow-on'' drugs, on overall healthcare costs has not been well studied. ...
... While the patent system's main purpose is to incentivise innovation, it is sometimes used (or abused) to stifle competition. A recently published study identified 108 patents for two antiretroviral drugs (ritonavir and lopinavir/ritonavir) that could delay competition with generics until at least 2028, well beyond the usual 20-y period [9]. Some of these patents were judged by Amin et al. [9] to shelter ''innovations'' of very limited value. ...
... A recently published study identified 108 patents for two antiretroviral drugs (ritonavir and lopinavir/ritonavir) that could delay competition with generics until at least 2028, well beyond the usual 20-y period [9]. Some of these patents were judged by Amin et al. [9] to shelter ''innovations'' of very limited value. A similar argument may be made for some of the follow-on drugs examined in this study. ...
Drug manufacturers have developed "evergreening" strategies to compete with generic medication after patent termination. These include marketing of slightly modified follow-on drugs. We aimed to estimate the financial impact of these drugs on overall healthcare costs and also to examine the impact of listing these drugs in hospital restrictive drug formularies (RDFs) on the healthcare system as a whole ("spillover effect").
We used hospital and community pharmacy invoice office data in the Swiss canton of Geneva to calculate utilisation of eight follow-on drugs in defined daily doses between 2000 and 2008. "Extra costs" were calculated for three different scenarios assuming replacement with the corresponding generic equivalent for prescriptions of (1) all brand (i.e., initially patented) drugs, (2) all follow-on drugs, or (3) brand and follow-on drugs. To examine the financial spillover effect we calculated a monthly follow-on drug market share in defined daily doses for medications prescribed by hospital physicians but dispensed in community pharmacies, in comparison to drugs prescribed by non-hospital physicians in the community. Estimated "extra costs" over the study period were €15.9 (95% CI 15.5; 16.2) million for scenario 1, €14.4 (95% CI 14.1; 14.7) million for scenario 2, and €30.3 (95% CI 29.8; 30.8) million for scenario 3. The impact of strictly switching all patients using proton-pump inhibitors to esomeprazole at admission resulted in a spillover "extra cost" of €330,300 (95% CI 276,100; 383,800), whereas strictly switching to generic cetirizine resulted in savings of €7,700 (95% CI 4,100; 11,100). Overall we estimated that the RDF resulted in "extra costs" of €503,600 (95% CI 444,500; 563,100).
Evergreening strategies have been successful in maintaining market share in Geneva, offsetting competition by generics and cost containment policies. Hospitals may be contributing to increased overall healthcare costs by listing follow-on drugs in their RDF. Therefore, healthcare providers and policy makers should be aware of the impact of evergreening strategies. Please see later in the article for the Editors' Summary.
... Secondary patents: After drug development, patents are filed on other aspects of active ingredients such as different dosage forms, formulations, and production methods 6,7 . ...
... The effect of this monopoly can be very severe in pharmaceutical sector, more so in the case of lifesaving drugs. 6,7,10,11,12,13 . ...
... Although a criticism like non-agreement to TRIPS came in the NOVARTIS case with regard to GLIVEC, the Honorable Court cleared its stand on "evergreening" and discouraged such strategies. 7,9 Time-consuming work process: High workload compared to patent office of other countries and less workforce are implicated in the delay in the patent process. 2 ...
... This may be particularly valuable for generics producers that want to develop proprietary drugs by modifying existing active ingredients as a lower risk strategy. For example, consider a new formulation that allows administering an active ingredient in form of a temperature-stable pill instead of a temperature-sensitive soft-gel version [7]. It is clear that the pill has no added therapeutic benefit over the soft-gel version; at the same time the pill represents an improvement over the soft-gel in terms of ease of drug storage and administration. ...
... The mean masks considerable variation. For example, [7] found for their case study of two HIV drugs that secondary patents extend patent protection up to 12 years beyond the lifetime of the original primary patents. Although this number might overstate the effective extension of a drug's patent protection because [7] include patent applications (as opposed to grants) as well as granted patents not listed in the Orange Book (which may be a lot less effective in preventing generic entry). ...
... For example, [7] found for their case study of two HIV drugs that secondary patents extend patent protection up to 12 years beyond the lifetime of the original primary patents. Although this number might overstate the effective extension of a drug's patent protection because [7] include patent applications (as opposed to grants) as well as granted patents not listed in the Orange Book (which may be a lot less effective in preventing generic entry). Another example is Sanofi Aventis's ARAVA arthritis drug in Australia. ...
We analyze the patent filing strategies of foreign pharmaceutical companies in Chile distinguishing between "primary" (active ingredient) and "secondary" patents (patents on modified compounds, formulations, dosages, particular medical uses, etc.). There is prior evidence that secondary patents are used by pharmaceutical originator companies in the U.S. and Europe to extend patent protection on drugs in length and breadth. Using a novel dataset that comprises all drugs registered in Chile between 1991 and 2010 as well as the corresponding patents and trademarks, we find evidence that foreign originator companies pursue similar strategies in Chile. We find a primary to secondary patents ratio of 1:4 at the drug-level, which is comparable to the available evidence for Europe; most secondary patents are filed over several years following the original primary patent and after the protected active ingredient has obtained market approval in Chile. This points toward effective patent term extensions through secondary patents. Secondary patents dominate "older" therapeutic classes like anti-ulcer and anti-depressants. In contrast, newer areas like anti-virals and anti-neoplastics (anti-cancer) have a much larger share of primary patents.
... Evergreening presents a particular problem in countries with low patentability standards, such as Australia and the US. 8,9 US researchers examined patents granted for two HIV drugs (ritonavir and lopinavir/ritonavir) and found that Abbott owned 82 secondary patents and had a further 26 pending applications in the US, all of which involved small variations on the original patents for these drugs. 9 They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. ...
... 8,9 US researchers examined patents granted for two HIV drugs (ritonavir and lopinavir/ritonavir) and found that Abbott owned 82 secondary patents and had a further 26 pending applications in the US, all of which involved small variations on the original patents for these drugs. 9 They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. 9 This problem is largely due to low standards for patent grant, together with barriers to the challenge and revocation of questionable patents. ...
... 9 They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. 9 This problem is largely due to low standards for patent grant, together with barriers to the challenge and revocation of questionable patents. ...
Intellectual property (IP) protections proposed by the United States for the Trans-Pacific Partnership Agreement (TPPA) have sparked widespread alarm about the potential negative impact on access to affordable medicines. The most recently leaked draft of the IP chapter shows some shifts in the US position, presumably in response to ongoing resistance from other countries. While some problematic provisions identified in earlier drafts have been removed or mitigated, major concerns remain unresolved. Three of the greatest concerns for Australia in the recent draft include provisions that would further entrench secondary patenting and evergreening, lock in extensions to patent terms and extend monopoly rights over clinical trial data for certain medicines. Data from the 2013 Pharmaceutical Patents Review, and from various submissions made to it, show that pharmaceutical monopoly protections already cost Australian taxpayers hundreds of millions of dollars each year. Provisions still being considered for the TPPA would further entrench and extend costly monopolies, with serious implications for the budget bottom line and the sustainability of the Pharmaceutical Benefits Scheme.
... Evergreening presents a particular problem in countries with low patentability standards, such as Australia and the US. 8,9 US researchers examined patents granted for two HIV drugs (ritonavir and lopinavir/ritonavir) and found that Abbott owned 82 secondary patents and had a further 26 pending applications in the US, all of which involved small variations on the original patents for these drugs. 9 They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. ...
... 8,9 US researchers examined patents granted for two HIV drugs (ritonavir and lopinavir/ritonavir) and found that Abbott owned 82 secondary patents and had a further 26 pending applications in the US, all of which involved small variations on the original patents for these drugs. 9 They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. 9 This problem is largely due to low standards for patent grant, together with barriers to the challenge and revocation of questionable patents. ...
... 9 They found that these evergreening patents could delay generic competition for 19 years beyond the date from which generic entry would have been anticipated. 9 This problem is largely due to low standards for patent grant, together with barriers to the challenge and revocation of questionable patents. ...
Intellectual property (IP) protections proposed by the United States for the Trans-Pacific Partnership Agreement (TPPA) have sparked widespread alarm about the potential negative impact on access to affordable medicines. The most recently leaked draft of the IP chapter shows some shifts in the US position, presumably in response to ongoing resistance from other countries. While some problematic provisions identified in earlier drafts have been removed or mitigated, major concerns remain unresolved. Three of the greatest concerns for Australia in the recent draft include provisions that would further entrench secondary patenting and evergreening, lock in extensions to patent terms and extend monopoly rights over clinical trial data for certain medicines. Data from the 2013 Pharmaceutical Patents Review, and from various submissions made to it, show that pharmaceutical monopoly protections already cost Australian taxpayers hundreds of millions of dollars each year. Provisions still being considered for the TPPA would further entrench and extend costly monopolies, with serious implications for the budget bottom line and the sustainability of the Pharmaceutical Benefits Scheme. © 2015, Australasian Medical Publishing Co. Ltd. All rights reserved.
... It is therefore important to monitor the fundamental matter of where manufacturers have filed patents on MLEM products globally [10,11]. There have been many medicine patents landscape studies with relatively narrow focus upon one or more specific medicines [12][13][14][15][16][17][18], upon a limited sample of purposefully-chosen developing countries, and upon specific types of patents on aspects of the medicines that are more likely to block generic competition (e.g., compound patents). Fewer have taken broader scope, surveying relatively larger sets of medicines and developing countries to provide an overview of the landscape [19,20]. ...
... While this concerns an admittedly small subset of the MLEM, these patented medicines are of serious global public health interest in specific cases (e.g., curative treatments for hepatitis C) and should not be minimized [48]. Narrowly focused patent studies are useful for further evaluating these potential problem areas on a case-by-case basis [12][13][14][15][16][17][18]. ...
Background
This article is based upon data gathered during a study conducted in partnership with the World Intellectual Property Organization on the patent status of products appearing on the World Health Organization’s 2013 Model List of Essential Medicines (MLEM). It is a statistical analysis aimed at answering: in which developing countries are patents on essential medicines being filed?
Methods
Patent data were collected by linking those listed in the United States and Canada’s medicine patent registers to corresponding patents in developing countries using two international patent databases (INPADOC and Derwent) via a commerical-grade patent search platform (Thomson Innovation). The respective supplier companies were then contacted to correct and verify our data. We next tallied the number of MLEM patents per developing country. Spearman correlations were done to assess bivariate relationships between variables, and a multivariate regression model was developed to explain the number of MLEM patents in each country using SPSS 23.0.
Results
A subset of 20 of the 375 (5%) products on the 2013 MLEM fit our inclusion criteria. The patent estate reports (i.e., the global list of patents for a given drug) varied greatly in their number with a median of 48 patents (interquartile range [IQR]: 26-76). Their geographic reach had a median of 15% of the developing countries sampled (IQR: 8-28%). The number of developing countries covered appeared to increase with the age of the patent estate (r = .433, p = 0.028). The number of MLEM patents per country was significantly positively associated with human development index (HDI), gross domestic income (GDI) per capita, total healthcare expenditure per capita, population size, the Rule of Law Index, and average education level. Population size, GDI per capita, and healthcare expenditure (in % of national expenditure) were predictors of the number of MLEM patents in countries (p = 0.001, p = 0.001, p = 0.009, respectively). Population size was the most important predictor (β = 0.59), followed by income (GDI per capita) (β = 0.32), and healthcare expenditure (β = 0.15). Holding the other factors constant, (i) 14.3 million more people, (ii) $833.33 more per capita (GDI), or (iii) 0.88% more of national spending on healthcare resulted in 1 additional essential medicine patent.
Conclusion
Population was a powerful predictor of the number of patent filings in developing countries along with GDI and healthcare expenditure. The age and historical context of the patent estate may make a difference in the number of patents and countries covered. Broad surveillance and benchmarking of the global medicine patent landscape is valuable for detecting significant shifts that may occur over time. With improved international medicine patent transparency by companies and data available through third parties, such studies will be increasingly feasible.
Electronic supplementary material
The online version of this article (doi:10.1186/s12992-017-0262-4) contains supplementary material, which is available to authorized users.
... Each of these steps can generate additional patent applications. As a result, for any given medication, it is common to see tens of patents covering the base compound as well as diverse molecular forms, formulations and uses (Howard 2007;Amin and Kesselheim 2012). ...
... Third, in many developing countries, the introduction of pharmaceutical patenting, and the ensuing proliferation of pharmaceutical patents, may simply overwhelm the capacities of local legal systems to properly handle litigation. A final issue is search costs: not knowing how many patents exist on a given drug creates uncertainty, and conducting searches on patent landscapes in developing countries is particularly difficult (Amin and Kesselheim 2012). For all of these reasons, once patents are granted, they may be particularly difficult to overturn in developing countries. ...
This article compares national approaches toward secondary pharmaceutical patents. Because secondary patents can extend periods of exclusivity and delay generic competition, they can raise prices and reduce access to medicines. Little is known about what measures countries have enacted policies to address applications for secondary pharmaceutical patents, how they function, and whether, in practice, these measures limit secondary patents. We analyze the cases of India and Brazil. We assemble data on pharmaceutical patent applications filed in the two countries, code each application to identify which constitute secondary applications, and examine outcomes for each application in both countries. The data indicate that Brazil is less likely to grant applications than India, but in both countries the measures designed to limit secondary patents are having little direct effect. This suggests, on the one hand, that critics of these policies, such as the transnational pharmaceutical sector and foreign governments, may be more worried than they
should be. On the other hand, champions of the policies, such as NGOs and international organizations, may have cause for concern that laws on the books are not having the expected impact on patent outcomes in practice. Our findings also suggest that, at the drug level, the effects of countries’ approaches toward secondary patents need to be understood in the context of their broader approaches toward TRIPS implementation, including when and how they introduced pharmaceutical patents in the 1990s and 2000s.
... The other refers either to small structural modifications to the original molecule or combinations of active or non-active ingredients in a novel pharmaceutical entity. This second strategy is also referred to as "evergreening", and expands the duration of a monopoly, without improving the drug itself [56]. Both strategies prolong patents and are pursued for commercial ends, impacting generic competition and access to drugs. ...
Background:
This study examines the dynamics of the eculizumab patenting, orphan designation, and marketing authorization process in different countries and regulatory systems and analyzes drug revenues since its first marketing authorization.
Methods:
A retrospective case study was conducted. Multiple information sources were used to: determine the status of eculizumab patents; examine the designation of orphan drug status by US, European, Japanese, and Brazilian regulatory authorities to determine registration status and approved clinical indications; estimate the prevalence of associated clinical conditions; investigate the history of the drug manufacturer, Alexion Pharmaceuticals, Inc., and its financialized business model; and examine global eculizumab sales revenues since its first marketing authorization.
Results:
Our search yielded 32 patent families divided into 98 applications. The first patent granted was filed in 1995 by Alexion Pharmaceuticals, Inc. in the US. Eculizumab has always been as an orphan drug, except in the Brazilian regulatory agency. All clinical indications approved thus far refer to rare diseases (e.g., paroxysmal nocturnal hemoglobinuria syndrome, atypical hemolytic-uremic syndrome, refractory and generalized myasthenia gravis, and neuromyelitis optica spectrum disorder). Alexion's revenues amounted to more than US$25 billion between 2007 and 2019, showing a growing trend. Eculizumab led sales from the beginning, being the only product in the company's portfolio until 2015. In 2019, the drug accounted for 79.1% of all revenues.
Discussion:
Our findings show that a strategy focused on obtaining orphan drug designation, expanding therapeutic indications and the geographic range of marketing approvals, extending monopoly periods, and prioritizing public procurement niches has enhanced revenues and helped the company achieve leadership in a highly specific and profitable market.
... Patents claiming a FDC are classified as secondary patents. A secondary patent claims features, other than the original active drug ingredient, including combinations and other formulations and methods of administration [15,16]. In this case, the sponsor company is able to add patent time to the combination of individual products included in the FDC, for which patents may be expired or close to expire. ...
Introduction:
Fixed-dose combinations (FDC) contain two or more active ingredients. The effective patent and exclusivity life of FDC compared to single active ingredient has not been assessed.
Objectives:
Trends in FDA approved FDC in the period 1980-2012 and time lag between approval of FDC and single active ingredients in the combination were assessed, and the effective patent and exclusivity life of FDC was compared with their single active ingredients.
Materials and methods:
New molecular entities (NMEs), new therapeutic biologics license applications (BLAs) and FDC data were collected from the FDA Orange Book and Drugs@FDA. Analysis included FDC containing one or more NMEs or BLAs at first FDA approval (NMEs-FDC) and only already marketed drugs (Non-NMEs-FDC). Descriptive, Kruskal-Wallis and Wilcoxon Rank Sum analyses were performed.
Results:
During the study period, the FDA approved 28 NMEs-FDC (3.5% of NMEs) and 117 non-NMEs-FDC. FDC approvals increased from 12 in the 1980s to 59 in the 2000s. Non-NMEs-FDC entered the market at a median of 5.43 years (interquartile range 1.74, 10.31) after first FDA approval of single active ingredients in the combination. The Non-NMEs-FDC entered the market at a median of 2.33 years (-7.55, 2.39) before approval of generic single active ingredient. Non-NME-FDC added a median of 9.70 (2.75, 16.24) years to the patent and exclusivity life of the single active ingredients in the combination.
Conclusion:
FDC approvals significantly increased over the last twenty years. Pharmaceutical companies market FDC drugs shortly before the generic versions of the single ingredients enter the market extending the patent and exclusivity life of drugs included in the combination.
... These deals allow both originator and generic companies to profit, when supply to LICs is either non-existent or limited to the wealthy. " Evergreening " refers to a proliferation of secondary patenting around the most successful medicines (Amin and Kesslheim, 2012; Christie et al., 2013), which may further reduce the ability of generics to enter the market. Any reduction in the possibility of generics entering the market has a dramatic effect on LICs, as they would produce medicines at lower prices, increasing their affordability. ...
Individuals in low-income countries (“LICs”) often lack access to appropriate medicines. The multi-disciplinary nature of this problem requires a holistic approach. Whereas, other writings on the topic tend to focus on one or a small number of issues, often from the perspective of a single discipline, this paper seeks to consider the major issues from a multi-disciplinary perspective. It first considers mechanisms for improving the availability of medicines in LICs, through grants, prizes, treaties, advance market commitments, priority review and product development partnerships to incentivize and fund R&D for neglected diseases. The paper then assesses mechanisms for improving affordability of medicines in LICs, such as differential pricing mechanisms, monopsonies, patent law flexibilities and human rights obligations. Next, the paper reviews mechanisms for improving the efficacy of medicines in LICs, including authentication, criminalization, international and national enforcement and communication and education. Finally, the paper examines mechanisms for improving the obtainability of medicines in LICs, through low-cost intervention, task-shifting, efficient regulation, grass-roots service provision and education. The paper concludes by identifying areas warranting further research.
... These patents or applications involved categories of compositions/formulations, processes, treatment methods and/or general patents. They found 28 patents/applications which "did not specifically mention either lopinavir or ritonavir but that could still serve as roadblocks to generic competition" (Amin andKesselheim 2012: 2289). ...
Evergreening is a strategy employed by pharmaceutical companies to extend patent protection around their branded medicines beyond 25 years. It involves claiming modifications to the original active pharmaceutical ingredient (API) as separate "inventions" to extend the period during which pharmaceutically equivalent products are denied market entry. Evergreening refers only to patents taken out by the company owning the original API. Similar improvement/modification patents taken out by other entities are referred to as secondary patents. Such delayed or reduced competition translates into an increase in the cost of healthcare.Brand pharmaceutical companies, of course, argue that these "lifecycle management" patents provide improved health outcomes to the community. They meet the (low) patentability thresholds of novelty, inventiveness and utility. Critics argue that the claimed improved health outcomes are usually either very small or non-existent. If the improved health outcome is negligible the evergreening patents incur a social cost rather than providing a social benefit, as the healthcare costs associated with delayed generic entry are large. This paper complements the existing empirical evidence by providing an in-depth analysis of a small number of Australian cases where evergreening of brand medicines has occurred. With two exceptions, the cases discussed here involve litigation. Evidence from court cases is useful in identifying rules that encourage or delay generic entry. For some cases PBS data allow partial estimates of the costs of evergreening. Analysis of the case material identifies types of evergreening patents and their market effects. This highlights some key issues in the impact of evergreening on market competition and healthcare costs and points to areas of patent and health policy that need reform. The paper also looks at the role of trademarks in evergreening by establishing branding distinctions. These are used by sales forces to encourage prescribing doctors to shift from the original branded medicine to the evergreened branded medicine, reinforcing any existing brand loyalty while developing new loyalty in the evergreened brand and extracting a price premium beyond the original patent period. For virtually identical patented drugs, PBS data allow the identification of "prescribing shifts." Drug companies have large marketing budgets and use these to "educate" decision-makers in the prescribing process. Consequent prescribing shifts, between closely similar medicines with very similar patient-health outcomes, indicate the returns to these marketing outlays. There are substantial challenges in using official patent databases to identify secondary patents. These are discussed as background to the case selection for this study.
... The consequences of weak standards of patentability can be quite significant. For example, there are over 800 different families of patents on the antiretroviral booster, ritonavir [12], and its period of exclusivity had been extended for decades [13]. Such extended periods of exclusivity can have significant cost implications [14]. ...
Brook Baker describes the potential harms to global health from the Trans Pacific Partnership Agreement and its failure to balance the interests of patients and the public with those of industry.
... 19 Evergreening patents are the sub-set of secondary patents owned by the company producing the new active pharmaceutical ingredient (API). Amin and Kesselheim (2012) identified the evergreening patents associated with two important HIV medicines, ritonavir and lopinavir. The original ritonavir patent was filed in the USA in 1995, granted in 1996 and expires on 25 April 2015. ...
In the Trans Pacific partnership Agreement (TPPA) negotiations, the United States has proposed expanded patent protections that will likely impact the affordability of medicines in TPPA partners. This includes antiretroviral (ARV) medicines used in the treatment of HIV/AIDS. Vietnam has the lowest GDP per capita of the 12 countries participating in the TPPA negotiations. Using the current Vietnamese patent regime as our base case, we analyse the potential impact of alternative patent regimes on access to ARVs in Vietnam. The two other scenarios investigated are a patent regime making full use of TRIPS flexibilities, and a regime based on the US proposals in the 2014 leaked draft of the TPPA intellectual property chapter. Using World Health Organization (WHO) treatment guidelines, we identified the most commonly used chemical entities and combinations used in the treatment of HIV. We examined patent data sets to discover patents that had been registered for these medicines and used information from examination of these patents to identify which might be granted under alternative patent regimes. We then drew on the empirical literature to estimate prices under the three patent scenarios. The current ARV budget was used as a constraint, with the consequence that the results focus on the impact of alternative patent regimes on access to treatment. Our results indicate 82% of the HIV population eligible for treatment would receive ARVs under a full TRIPS flexibility scenario, while only 30% of Vietnam's eligible HIV patients would have access to ARVs under the US 2014 TPPA proposals – more than halving the proportion treated compared to the current 68% receiving treatment. Similar price impacts can be expected for other countries participating in the TPPA, though these are less economically vulnerable than Vietnam.
... These 'secondary' patents simply protect peripheral features of the product (such as a tablet's coating), metabolites or alternative crystalline forms of the product, or methods of use (such as a method of treating disease). In the pharmaceutical sector, this practice is called 'life-cycle management;' it is also sometimes referred to as 'evergreening.' 19 Enactment of laws which have the effect of increasing the effective patent life, lowering of patentability standards, extension of patent protection to ineligible subject matter due to industrial compulsion etc., also have strengthened the monopolistic powers and resulted in the escalation of price of pharmaceutical products. Various methods are used to extend effective patent life in the developed countries due to the extensive lobbying by drug developers. ...
... Ouellette found an average of 3.5 patents per drug [24], and Hemphill and Sampat found an average of 2.7 patents per drug [6], based on a count of patents listed in the Orange Book under the U.S Hatch-Waxman linkage regime [25]. The European Commission's Pharmaceutical Sector Inquiry, using data reported to it by drug originators, found an average of 99 actual or potential patents per drug in its sample [26] [27], while Amin and Kesselheim identified 82 granted US patents covering a sample of two drugs – an average of 41 patents per drug [28]. The patent count methods used in those two studies most closely resembles our method, and their findings regarding overall patent frequency by drug are also close to our findings. ...
Australia, like most countries, faces high and rapidly-rising drug costs. There are longstanding concerns about pharmaceutical companies inappropriately extending their monopoly position by "evergreening" blockbuster drugs, through misuse of the patent system. There is, however, very little empirical information about this behaviour. We fill the gap by analysing all of the patents associated with 15 of the costliest drugs in Australia over the last 20 years. Specifically, we search the patent register to identify all the granted patents that cover the active pharmaceutical ingredient of the high-cost drugs. Then, we classify the patents by type, and identify their owners. We find a mean of 49 patents associated with each drug. Three-quarters of these patents are owned by companies other than the drug's originator. Surprisingly, the majority of all patents are owned by companies that do not have a record of developing top-selling drugs. Our findings show that a multitude of players seek monopoly control over innovations to blockbuster drugs. Consequently, attempts to control drug costs by mitigating misuse of the patent system are likely to miss the mark if they focus only on the patenting activities of originators.
... Industry representatives suggest that process patents may play an important role in life-cycle management strategies [7]. A recent analysis of secondary patents on two antiretroviral drugs reports a large number of unlisted patents, including but not limited to process patents [27]. One factor that our analysis does not incorporate is litigation. ...
While there has been much discussion by policymakers and stakeholders about the effects of "secondary patents" on the pharmaceutical industry, there is no empirical evidence on their prevalence or determinants. Characterizing the landscape of secondary patents is important in light of recent court decisions in the U.S. that may make them more difficult to obtain, and for developing countries considering restrictions on secondary patents.
We read the claims of the 1304 Orange Book listed patents on all new molecular entities approved in the U.S. between 1988 and 2005, and coded the patents as including chemical compound claims (claims covering the active molecule itself) and/or one of several types of secondary claims. We distinguish between patents with any secondary claims, and those with only secondary claims and no chemical compound claims ("independent" secondary patents). We find that secondary claims are common in the pharmaceutical industry. We also show that independent secondary patents tend to be filed and issued later than chemical compound patents, and are also more likely to be filed after the drug is approved. When present, independent formulation patents add an average of 6.5 years of patent life (95% C.I.: 5.9 to 7.3 years), independent method of use patents add 7.4 years (95% C.I.: 6.4 to 8.4 years), and independent patents on polymorphs, isomers, prodrug, ester, and/or salt claims add 6.3 years (95% C.I.: 5.3 to 7.3 years). We also provide evidence that late-filed independent secondary patents are more common for higher sales drugs.
Policies and court decisions affecting secondary patenting are likely to have a significant impact on the pharmaceutical industry. Secondary patents provide substantial additional patent life in the pharmaceutical industry, at least nominally. Evidence that they are also more common for best-selling drugs is consistent with accounts of active "life cycle management" or "evergreening" of patent portfolios in the industry.
... Так, по данным литературы, были рассмотрены 108 патентов на препараты «Норвир» (ритонавир), «Калетра» (лопинавир/ритонавир). Авторы отмечают, что некоторые из них не соответствовали критерию патентоспособности изобретения -изобретательский уровень [5]. Поэтому соглашение TRIPS рекомендует ужесточить практику выдачи патентов на лекарственные средства, исключить возможность патентования изобретений, не соответствующих критериям новизны, изобретательского уровня (например, незначительные изменения состава, дозы). ...
... These 'secondary' patents simply protect peripheral features of the product (such as a tablet's coating), metabolites or alternative crystalline forms of the product, or methods of use (such as a method of treating disease). In the pharmaceutical sector, this practice is called 'life-cycle management;' it is also sometimes referred to as 'evergreening.' 19 Enactment of laws which have the effect of increasing the effective patent life, lowering of patentability standards, extension of patent protection to ineligible subject matter due to industrial compulsion etc., also have strengthened the monopolistic powers and resulted in the escalation of price of pharmaceutical products. Various methods are used to extend effective patent life in the developed countries due to the extensive lobbying by drug developers. ...
Patents and data exclusivity affect health care costs even in developed countries and health care costs are rapidly increasing in those countries. Pharmaceutical product prices form substantial portion of health care costs and strong intellectual property protection is one of the major reasons for high health care costs. High drug prices affect patient access to medicines and thereby universal healthcare coverage. Left to market forces universal health care coverage, which is a fundamental obligation of states will remain an unaccomplished goal.
... Prevention Innovation Extraction Adaption Fig. 2 Overview of the four generic strategic pathways [Source: modelled after Raasch (2006)] improvement of the primary patent and would permit the innovator-company to maintain the market share, even if the generic producers try to enter the market by contesting the validity of the primary patent. Amin and Kesselheim (2012) reported that a large cluster of secondary patents related to HIV medication (ritonavir) could delay generic competition 12 years after the expiration of the patents on the drug's base compound. The Sector Inquiry by European Commission has revealed that there is a trend for companies to continuously file patent applications as the expiry date of the primary patent approaches, whereby the ratio of primary to secondary patents is 1:7. ...
Extending the period of the market exclusivity and responding properly to the recent agglomeration of patent expiries are pivotal to the success of pharmaceutical companies. Declining R&D productivity, rising costs of commercialization, near-term patent expirations for many top-selling drugs are forcing companies to adopt new systems to introduce innovative products to market and to focus on strategies that increase the returns from the existing product portfolio. This systematic review explores various strategic and tactical management approaches by synthesizing the relevant literature and practical examples on patent expiration strategies. It further discusses how the mix of competition policies and strategic instruments can be used to maintain declining revenue streams from the blockbuster business model of the pharmaceutical industry. The review provides a comprehensive overview of the research on various strategies, offers both theoretical and practical guidelines for strategy transformation that companies can use to prolong the market exclusivity, and identifies knowledge gaps that needed to be addressed in order to improve efficiency in policy design.
... Overflows are a significant issue for this industry, particularly with regard to its often uneasy relationship with markets in low-income countries. For some time, the pharmaceutical industry has been accused of producing and pricing goods and services to benefit lucrative markets in high-income countries rather than addressing diseases prevalent in low-income countries (Amin & Kesselheim, 2012). Neyland and Simakova (2015, p. 139) have called these conditions diseases 'without a profitable market', and Moon, Bermudez and t'Hoen (2012, n.p.) have spoken of a 'broken R&D system' in relation to global access to medicines. ...
How do actors innovate markets in cases of perceived market failures? This paper’s aim is to examine what happens when a market is innovated or, as we call it, ‘redevised’ in situations where public and commercial interests significantly diverge. Market devices can serve an important function in such attempts to innovate markets: they are material and/or social arrangements that are put into place to shape the market in question in certain ways. But can such devices really transform a market from within? To examine this question we trace the history of the Geneva Medicines Patent Pool, a civil society initiative introduced to change pharmaceutical firms’ licensing and collaboration practices in the market for HIV/AIDS medicines. Our empirical results indicate that redevising a market in response to market failures can shift the market’s frames and contribute to altering its practices, but that this is a pragmatic and often lengthy process that is never fully predictable in advance. By attending to the intended and unintended consequences - or misfires - of redevising a market, our study raises important questions around acting in and on the market, market innovation’s’ ontological impact, zooming in and zooming out when studying redevising, and attending to the temporality of market innovation.
... The study identified 108 patents related to two HIV medicines (ritonavir (Norvir) and lopinavir/ritonavir (Kaletra)) whose impact could delay generic competition until at least 2028. This is a twelve years additional period after the expiration of the patents on the drugs' base compounds and thirty-nine years after the first patents on ritonavir were filed (Amin andKesselheim 2012: 2286). ...
The current outbreak of COVID-19 pandemic traces its roots back many decades and is worsened by a number of ill-conceived strategies and policies. The current patent protection regime and its suitability in dealing with the current COVID-19 pandemic need to be questioned. Strengthened intellectual property protection manifested by the rise of TRIPS-Plus standards is having a negative impact on the affordability and accessibility of medicines. Dealing with the current pandemic urgently demands serious reform and collective efforts.
... For instance, to fight against 'evergreening', the Indian IPR framework wards off patents for new forms or uses of existing pharmaceutical products that are simply minor modifications of existing products, unless they demonstrate improved efficacy (Rajkumar & Kesselheim, 2013). Other developing countries, such as Argentina and the Philippines, have amended their IPR regulations to restrict the patentability of certain categories of pharmaceutical inventions (e.g., polymorphs, formulations, and additional uses of existing compounds) to avoid granting undeserved patents that can be detrimental to access to lifesaving medicines (Amin & Kesselheim, 2012). ...
While Trade-Related Aspects of Intellectual Property Rights (TRIPS) was expected to hike up prices of patented medicines, there was no consensus on its likely final impact on access, because the agreement housed instruments to address this challenge. For instance, compulsory licensing, through the facilitation of price reductions, was considered to be an important countermeasure. However, little is known about the extent to which compulsory licensing has actually been effective in reducing prices of much-needed patented drugs. To fill this gap, this paper undertakes a systematic-review of the existing evidence on the impact of compulsory licensing on drug prices. Retrieval and analysis of 51 observations of pre- and post-compulsory licensing prices indicate that a compulsory licensing event is likely to reduce the price of a patented drug, albeit with some caveats. Moreover, compulsory licensing procurement from the international market is likely to be more effective in reducing drug prices than contracts to local companies. These findings are reconfirmed in the race to improve access to Remdesivir for hospitalized COVID-19 patients. Clearly, the future incidence and impact of compulsory licensing will depend on further possible procedural refinements to ease its implementation, the development of technological and manufacturing capabilities in developing countries, and the importance of biologics among life-saving drugs.
... The strongest predictors of patent challenges are a longer patent term and the presence of evergreening patents (themselves correlated), suggesting that patent challenges are a response to evergreening. Adding to these macro-level studies, Amin and Kesselheim (2012) investigate evergreening patents over two HIV drugs, both owned by Abbott (ritonavir and lopinavir). They identified 82 granted patents and 26 applications covering compositions and formulations, processes, treatment methods and/or general patents. ...
... As previously discussed, unlike TRIPS, which provides that patents be protected for 20 years from the filing date, the CPTPP -as is common in PTAs promoted by the USA 88 -also includes patent extension, a provision granting term adjustment to compensate for unreasonable delays in the patent granting procedure and, in relation 81 WIPO (2011). 82 Amin and Kesselheim (2012), pp. 2286-2294. ...
The Comprehensive and Progressive Agreement for Trans-Pacific Partnership (CPTPP or TPP11) is a trade agreement between Australia, Brunei Darussalam, Canada, Chile, Japan, Malaysia, Mexico, New Zealand, Peru, Singapore and Vietnam. CPTPP negotiations started after the Trans-Pacific Partnership Agreement reached a stalemate due to the withdrawal of the United States on 23 January 2017. This paper’s aim is to provide an appraisal of some sensitive provisions of the CPTPP, and their impact on access to affordable medicines. As access to medicines is mainly related to the protection of intellectual property rights and in particular patents, a first part of the paper will focus on the international regulatory framework for patents, considering the main international conventions, the TRIPS Agreement and its relation with preferential trade agreements. The narration will then focus on the provision of the CPTPP relating to patents and pharmaceuticals, and those relating to investment. The discussion will revolve around whether said provisions significantly depart from the framework set by TRIPS, for instance, including TRIPS-plus provisions, notably criticised for their adverse repercussions on the fundamental right to health. As regards the provisions in the investment chapter, the analysis will focus on whether the wording of said chapter is equipped to strike a balance between protection of foreign investors and health regulation. A conclusion will follow, summarising the main findings of the paper.
... Methods of use patents are widely employed in the US to try to forestall generic competition on brand-name drugs. For example, one review of patents relating to the HIV protease inhibitor combination ritonavir/lopinavir in the US found 210 patents and applications relating to peripheral aspects of the product, including 31 covering methods of use [17]. Such patents, obtained at various points after the drugs were in development, had the potential to delay generic competition on the drug for more than 12 years after the expiration of the original patent on the active ingredient. ...
The Trans-Pacific Partnership (TPP) Agreement is a proposed free trade agreement between the US and 11 other countries in Asia and South America covering many consumer goods, including prescription medicines. This review describes how the TPP could affect international laws governing intellectual property rights for prescription drugs, focusing on patents and exclusivity protections for test data, including their effect on reimbursement decisions by national health care authorities responsible for health priority setting. We conclude that the TPP could affect low-income patients' access to medicines in signatory countries. © 2016 American Medical Association. All Rights Reserved. ISSN 2376-6980.
... In countries where secondary patents are permitted, it is common for pharmaceutical products to be protected by a large array of patents in addition to the patent on the original active pharmaceutical ingredient. For example, in the United States, researchers found a total of 108 patents (granted or applied for) associated with two key HIV drugs (ritonavir and lopinavir/ritonavir), many of which were of minimal inventiveness (Amin and Kesselheim, 2012). These patents were expected to prolong the monopolies on these drugs for 12 years beyond the expiry of the patents on the original pharmaceutical products. ...
The final text of the Trans Pacific Partnership Agreement (TPP), agreed between the 12 negotiating countries in 2016, included a suite of intellectual property provisions intended to expand and extend pharmaceutical company exclusivities on medicines. It drew wide criticism for including such provisions in an agreement that involved developing countries (Vietnam, Peru, Malaysia, Mexico, Chile and Brunei Darussalam) because of the effect on delaying the introduction of low-cost generics. While developing nations negotiated transition periods for implementing some obligations, all parties would have eventually been expected to meet the same standards had the TPP come into force. While the TPP has stalled following US withdrawal, there are moves by some of the remaining countries to reinvigorate the agreement without the United States. The proponents may seek to retain as much as possible of the original text in the hope that the United States will re-join the accord in future. This article presents a comparative analysis of the impact the final 2016 TPP intellectual property chapter could be expected to have (if implemented in its current form) on the intellectual property laws and regulatory regimes for medicines in the TPP countries. Drawing on the published literature, it traces the likely impact on access to medicines. It focuses particularly on the differential impact on regulatory frameworks for developed and developing nations (in terms of whether or not legislative action would have been required to implement the agreement). The article also explores the political and economic dynamics that contributed to these differential outcomes.
... Such incremental inventions may be regarded as examples of gaming the system by acquiring extended or new patent monopolies not justified by the minor level of inventive contribution or the possibly negligible added benefit to the public. Such opportunistic practices are commonly referred to as 'evergreening' (Amin and Kesselheim, 2012). The industry of course sees them as perfectly justifiable. ...
This article reviews current trends in patent claims regarding personalised, stratified and precision medicine. These trends are not particularly well understood by policymakers, even less by the public, and are quite recent. Consequently, their implications for the public interest have hardly been thought out. Some see personalised and other secondary drug patent claims as promoting better targeted treatment. Others are inclined to see them as manifestations of ‘evergreening’ whereby companies are, in some cases quite cynically, trying to extend market monopolies in old products or creating new monopolies based on supposedly improved versions of such earlier drugs. The article claims that the relaxation of ‘novelty’ is a privilege unavailable to inventions in other fields and that on balance the patent system does privilege this industry and that no adequate case has yet been made thus far to prove the public benefits overall.
... Based on a study conducted by Amin et al from the two Human Immunodeficiency Virus (HIV) drugs that has been granted with patents (ritonavir and lopinavir/ritonavir) in the US, there are 82 secondary patents granted and 26 pending applications, which mostly involved only minor variation from primary patents. 34 This scenario clearly proves the significance of multinational companies utilizing "evergreening" practice to gain longer patent extension on brand-name drugs. By doing this, an additional 20 years of secondary patent can be obtained in addition to the original patent of 20 years. ...
This article aims to discuss the main consequences of the implementation of the Trans-Pacific Partnership Agreement (TTPA) in the pharmaceutical sector in regard to public health, focusing on the accessibility and affordability of medicines. This paper also looks at the likely impact of the TPP agreement on access to affordable medicines. The potential effects of provisions in the final text are explored based on the context of developed and developing countries. A meta-synthesis study design was used. The thematic analysis technique was used to generate themes and a decision tree of the TTPA meta-synthesis. PubMed, EBSCOhost, Ovid, and Scopus databases from inception until the first week of January 2016 were used. Only peer-reviewed journals that discussed TPPA’s impact on the pharmaceutical sector were included. Data were extracted by 2 reviewers and then verified by 3 senior researchers. The extracted data were imported into Excel spreadsheets and coded line by line. Codes were organized into descriptive themes. The identified themes were cross-checked against original articles to ensure consistency. A total of 85 full articles and reports were reviewed and, finally, 32 of them were used in the meta-synthesis. Two central themes to the TTPA emerged: intellectual property rights and transparency. Five subthemes were identified under intellectual property rights: patent subject matter (representing scope of patentability), patent term adjustment for patent office delays (representing patent term extension), protection of undisclosed test or other data (representing data exclusivity), protection of undisclosed test or other data (representing patent linkage), and compulsory licensing. Meanwhile, transparency and anti-corruption-procedural fairness, which presents restriction of coverage program and reimbursement, were identified as the subthemes of transparency. Findings indicate that the TPPA could potentially hinder the affordability and accessibility of medicine, which could increase risks to public health.
... 19 Evergreening patents are the sub-set of secondary patents owned by the company producing the new active pharmaceutical ingredient (API). Amin and Kesselheim (2012) identified the evergreening patents associated with two important HIV medicines, ritonavir and lopinavir. The original ritonavir patent was filed in the USA in 1995, granted in 1996 and expires on 25 April 2015. ...
... The strongest predictors of patent challenges are a longer patent term and the presence of evergreening patents (themselves correlated), suggesting that patent challenges are a response to evergreening. Adding to these macro-level studies, Amin and Kesselheim (2012) investigate evergreening patents over two HIV drugs, both owned by Abbott (ritonavir and lopinavir). They identified 82 granted patents and 26 applications covering compositions and formulations, processes, treatment methods and/or general patents. ...
Litigated pharmaceutical patents are a valuable source of data on how much inventiveness is required for a patent grant and what are the costs of patents. Although innovation is central to economic growth and the competitiveness of firms, there are few data about either the cost of granted patents or the quantum of inventiveness required for a patent. Two cases of litigated pharmaceutical patents allow investigation of two types of secondary ‘evergreening’ patents—new formulations and closely related chemical variants. Both lead to higher Pharmaceutical Benefits Scheme outlays, and in some cases, these can be substantial. There are clear policy implications.
... The other refers either to small structural modifications to the original molecule or combinations of active or non-active ingredients in a novel pharmaceutical entity. This second strategy is also referred to as "evergreening", and expands the duration of a monopoly, without improving the drug itself [56]. Both strategies prolong patents and are pursued for commercial ends, impacting generic competition and access to drugs. ...
O campo das imagens medicas e uma das areas da medicina onde o desenvolvimento e a incorporacao de novas tecnologias a pratica clinica e aos sistemas de saude tem sido particularmente significativo. Essa tese tem por objeto o estudo do progresso tecnico relacionado a tres tecnologias de imagem introduzidas no cuidado a saude nos ultimos trinta anos: a tomografia computadorizada, a imagem por ressonancia magnetica e a tomografia por emissao de positrons. Sua proposta foi caracterizar a trajetoria de desenvolvimento destas tecnologias de imagem, buscando reconhecer os diferentes fatores e mecanismos envolvidos na dinamica deste processo. Para tal, utilizou-se de um conjunto de ferramentas oriundas do campo da economia da inovacao - os conceitos de paradigma e trajetoria tecnologica, de design dominante e de sistemas tecnologicos - que trabalham com a visao de multideterminacao do desenvolvimento tecnologico, reconhecendo as inter-relacoes entre varios condicionantes como o progresso cientifico, as necessidades clinicas, o mercado e as politicas publicas. O conhecimento dos fatores e mecanismos intervenientes no desenvolvimento dessas tecnologias traz elementos que permitem uma melhor compreensao do processo de inovacao tecnologica no setor de imagens. Elas podem auxiliar na avaliacao de propostas de intervencao e na formulacao de politicas referentes a estes equipamentos, seja no que diz respeito a politicas industriais, seja no que se refere a decisoes internas ao sistema de saude relacionadas com o acesso, uso e financiamento destas tecnologias e procedimentos. (Au). Doutor -- Universidade do Estado do Rio de Janeiro. Instituto de Medicina Social, Rio de Janeiro, 2002.
In the United States, effective market exclusivity for a prescription drug is the time between US Food and Drug Administration (FDA) approval and the availability of the first generic version. Market exclusivity incorporates the minimum regulatory exclusivity periods granted to all FDA-approved drugs (eg, 5 years for new small-molecule drugs as set by the Hatch-Waxman Act of 1984), the remaining time on the original patent covering the active ingredient in the drug, the existence of so-called secondary patents covering peripheral aspects of drugs such as metabolites or alternative formulations,¹ and other factors that affect generic entry, such as generic manufacturers’ prospects of profit-making in the market and legal settlements between manufacturers of brand-name and generic drugs regarding disputed patents. Recent research has shown that prescription brand-name drugs that eventually face generic competition have, on average, an effective market exclusivity period of 12.4 years.² We assessed how the market exclusivity period varied among drugs for different therapeutic areas and for other characteristics of top-selling prescription medications.
Understandings of the public interest underpin many law reform processes. The public interest is not a fully definable term and so reform bodies have to engage with a range of articulations of that interest. The negotiation of the different articulations, however, has not been explored empirically before. This article reports on a study of the claims to the public interest in a public Australian inquiry into potential abuses of the patent system by pharmaceutical companies. More specifically, submissions to the Pharmaceutical Patents Review are analysed and the results show “oligopolistic” tensions between competing views of the public interest—and with these views claiming primacy over more technical understandings of the issues. This lack of a single “public interest” allows dominant players to frame the debate to reflect their interests; and the tension between these players means that the debate, and the underlying problem, has not been subject to a resolution.
Drug repurposing (i.e., finding novel indications for established substances) has received increasing attention in industry recently. One challenge of repositioned drugs is obtaining effective patent protection, especially if the ‘novel’ indications have already been claimed by competitors within the same drug class. Here, I report the case of patents relating to phosphodiesterase type 5 (PDE5) inhibitors. Patentees of later-filed patents on novel indications (even when they could not observe prior patenting of their direct competitors) filed patents for which patent examiners did not see the prior-filed patents of the competitors as relevant prior art, whereas these follower patent applications often failed because of other reasons
This paper discusses the problem of strategic accumulation of patents in the pharmaceutical industry. In the academic legal discussion, this strategy is often confused with the notion of patent thickets. It will be argued, however, that these two strategies, although sharing similar features, are, nevertheless, distant issues and therefore require different analysis. The paper will first discuss the notion of patent thickets in complex technologies, including their definition, factors that contribute to their growth, examples of patent thickets and how the problem of patent thickets in complex technologies is currently being resolved. The subsequent part will analyse the specific strategy of pharmaceutical companies identified by the European Commission as “patent thickets” in its Pharmaceutical Sector Inquiry. It is argued that this strategy of pharmaceutical companies is not, in fact, “patent thickets” according to the classical, traditional meaning of the term, and should, therefore, be detached from the notion of patent thickets. This definition is misleading, and because of the incorrect qualification of this practice by the Commission and the academic community, it has not received adequate analysis under competition law. Therefore, the aim of this paper is to identify what patent thickets are and to dissociate strategic accumulation of patents in the pharmaceutical industry from the concept of patent thickets. It is hoped that the conclusions made in this paper will help to attract attention of the competition authorities to the problem of strategic accumulation of patents for the benefit of the consumer welfare.
It is often suggested that the rate of innovation in a country is essentially dependent on the availability of intellectual property protection. However, the economic literature, particularly on the role of patents, generally dismisses a direct and automatic relationship between such protection and innovation. Patents may not encourage innovations when some contextual factors are not present, while other mechanisms may be more effective. Patents, in addition, are not a good indicator of innovation. Moreover, the proliferation of patents, including in the area of technologies relevant to address climate change, may block innovation and create barriers to the transfer of technology to developing countries. This article argues that a serious discussion on the role of intellectual property, so far eluded by developed countries, should be undertaken in the context of climate change negotiations.
Global Issues in Pharmaceutical Marketing presents a balanced, research-based perspective combined with a practical outlook on the current issues faced by the ethical, biotech, and generic segments of the pharmaceutical industry. It integrates an analytical approach with a global view to examine such issues as market access, digital marketing, emerging markets, branding, and more. The book covers not only the North American and Western European markets, but on non-Western markets, such as Latin America and Asia. Each chapter is written as an individual essay about a given issue, and where relevant, original cases are provided to illustrate how these issues are currently managed by the global industry.
This book offers a thoughtful and thorough description of the industry’s current situation and integrates the latest scholarly and industry research from different disciplines for convenient researcher reference.
Amidst the controversy about promoting innovation through patents while maintaining access to medicines, India's 2005 Patents (Amendment) Act on patent layering offers a novel attempt at entering a middle path. Genuine advance is to be filtered from “evergreening” by requiring new forms of known substances to display enhanced therapeutic efficacy in order to be patentable. For this purpose, substance derivatives are presumed to be the same as the original known substance. While this heightened patentability standard for incremental innovation has been widely discussed from economic, political and legal standpoints, it has not yet been fully considered on natural scientific grounds. In this article, the Sec. 3(d) criteria “enhanced therapeutic efficacy” and the negative presumption on substance derivatives will be explored on the scientific basis of drug development in order to assess the regime's efficiency. This analysis reveals that “therapeutic” and “efficacy” are not entirely suitable as patentability criteria, while the presumption may entail undesired effects. Section 3(d) as it stands offers a novel approach to limiting evergreening and endorsing some incremental innovation, but much can be gained from a closer congruence between natural and legal scientific terminology in the pharmaceutical patenting context. A few interpretive adaptations are proposed to further fine-tune it to this end. © 2015, Max Planck Institute for Innovation and Competition, Munich.
Despite regulatory restrictions, off-label marketing of pharmaceutical products has been common in the US. However, the scope of off-label marketing remains poorly characterized. We developed a typology for the strategies and practices that constitute off-label marketing.
We obtained unsealed whistleblower complaints against pharmaceutical companies filed in US federal fraud cases that contained allegations of off-label marketing (January 1996-October 2010) and conducted structured reviews of them. We coded and analyzed the strategic goals of each off-label marketing scheme and the practices used to achieve those goals, as reported by the whistleblowers. We identified 41 complaints arising from 18 unique cases for our analytic sample (leading to US$7.9 billion in recoveries). The off-label marketing schemes described in the complaints had three non-mutually exclusive goals: expansions to unapproved diseases (35/41, 85%), unapproved disease subtypes (22/41, 54%), and unapproved drug doses (14/41, 34%). Manufacturers were alleged to have pursued these goals using four non-mutually exclusive types of marketing practices: prescriber-related (41/41, 100%), business-related (37/41, 90%), payer-related (23/41, 56%), and consumer-related (18/41, 44%). Prescriber-related practices, the centerpiece of company strategies, included self-serving presentations of the literature (31/41, 76%), free samples (8/41, 20%), direct financial incentives to physicians (35/41, 85%), and teaching (22/41, 54%) and research activities (8/41, 20%).
Off-label marketing practices appear to extend to many areas of the health care system. Unfortunately, the most common alleged off-label marketing practices also appear to be the most difficult to control through external regulatory approaches.
To stem the rising costs of medications provided to patients enrolled in Medicaid, states have implemented varying policies about generic substitution. These policies differ in the extent to which pharmacists or patients can influence which medications they choose. Using national Medicaid data, we evaluated the relationship between different generic substitution policies and the use of generic simvastatin, a cholesterol-lowering drug, after the patent for the brand-name equivalent, Zocor, expired. States that implemented policies requiring patients' consent prior to generic substitution experienced rates of substitution that were 25 percent lower than those of states that did not require patient consent. By eliminating patient consent requirements, state Medicaid programs could expect to save more than $100 million in coverage for three top-selling medications that are nearing patent expiration. Although these consent requirements are probably intended to increase patient autonomy, policy makers should consider the sizable opportunity costs.
Two recent decisions of the Federal Court of Australia have provided interesting insights into the ongoing struggle between originator drug manufacturers and the public interest in Australia. In Apotex Pty Ltd (formerly GenRx Pty Ltd) v Les Laboratoires Servier (No 2) [2008] FCA 607 the court held that an advertising campaign by an originator pharmaceutical company, which sought to persuade doctors to issue prescriptions prohibiting substitution of "a-flagged" generics, constituted misleading and deceptive conduct under s 52 of the Trade Practices Act 1974 (Cth). The decision of the court in Alphapharm Pty Ltd v H Lundbeck A/S (2008) 76 IPR 618; [2008] FCA 559 limits the ability of the manufacturer of a drug based on a purified racemate enantiomer to claim a later registration date on the Australian Register of Therapeutic Goods and subsequently obtain an extension of its intellectual monopoly privileges as well as an exclusivity period for the data it had submitted to safety regulators. Importantly, this case is one of the first to consider recent allegedly pro- and anti-"evergreening" changes to the Therapeutic Goods Act 1989 (Cth) and Patents Act 1990 (Cth) as impacted by the intellectual property chapter (Ch 17) of the Australia-United States Free Trade Agreement.
Rising costs of medications and inequities in access have sparked calls for drug policy reform in the United States and Canada. Control of drug expenditures by prescription cost-sharing for elderly persons and poor persons is a contentious issue because little is known about the health impact in these subgroups.
To determine (1) the impact of introducing prescription drug cost-sharing on use of essential and less essential drugs among elderly persons and welfare recipients and (2) rates of emergency department (ED) visits and serious adverse events associated with reductions in drug use before and after policy implementation.
Interrupted time-series analysis of data from 32 months before and 17 months after introduction of a prescription coinsurance and deductible cost-sharing policy in Quebec in 1996. Separate 10-month prepolicy control and postpolicy cohort studies were conducted to estimate the impact of the drug reform on adverse events.
A random sample of 93 950 elderly persons and 55 333 adult welfare medication recipients.
Mean daily number of essential and less essential drugs used per month, ED visits, and serious adverse events (hospitalization, nursing home admission, and mortality) before and after policy introduction.
After cost-sharing was introduced, use of essential drugs decreased by 9.12% (95% confidence interval [CI], 8.7%-9.6%) in elderly persons and by 14.42% (95% CI, 13.3%-15.6%) in welfare recipients; use of less essential drugs decreased by 15.14% (95% CI, 14.4%-15.9%) and 22.39% (95% CI, 20.9%-23.9%), respectively. The rate (per 10 000 person-months) of serious adverse events associated with reductions in use of essential drugs increased from 5.8 in the prepolicy control cohort to 12.6 in the postpolicy cohort in elderly persons (a net increase of 6.8 [95% CI, 5.6-8.0]) and from 14.7 to 27.6 in welfare recipients (a net increase of 12.9 [95% CI, 10.2-15.5]). Emergency department visit rates related to reductions in the use of essential drugs also increased by 14.2 (95% CI, 8.5-19.9) per 10 000 person-months in elderly persons (prepolicy control cohort, 32.9; postpolicy cohort, 47.1) and by 54.2 (95% CI, 33.5-74.8) among welfare recipients (prepolicy control cohort, 69.6; postpolicy cohort, 123.8). These increases were primarily due to an increase in the proportion of recipients who reduced their use of essential drugs. Reductions in the use of less essential drugs were not associated with an increase in risk of adverse events or ED visits.
In our study, increased cost-sharing for prescription drugs in elderly persons and welfare recipients was followed by reductions in use of essential drugs and a higher rate of serious adverse events and ED visits associated with these reductions.
While neoclassical economic theory suggests that arbitrage will undermine global differential pricing of pharmaceuticals, the empirical results are more complex. Pharmaceutical regulation, IP laws, global trade agreements, and company policies support differential pricing despite the pressure of arbitrage. For essential access programs in particular, the theoretical threat of pharmaceutical arbitrage is shown to be rarely observed empirically. Counterfeiting is demonstrated to be the more serious threat. These conclusions call for changes in the U.S. PEPFAR program for AIDS and in the implementation of the WTO TRIPS Agreement. A more fundamental question, however, is whether pharmaceutical differential pricing is appropriate for consumer welfare. The usual defense of the practice within the OECD is grounded in the need for innovation incentives. This Article proposes and applies the heuristic of globally optimal appropriation (including patent rents). The heuristic alters some of the received wisdom on pharmaceutical pricing, suggesting that nonrival access to prescription drugs can be provided to low and middle income populations for all global diseases without harming innovation. By contrast, arbitrage between high income countries, such as the importation of Canadian drugs into the U.S. over the Internet, is shown to be consistent with optimal innovation incentives.
A large proportion of Americans are enrolled in 3-tier pharmacy benefit plans. We studied whether patients enrolled in such plans who receive generic or preferred brand-name agents when initiating chronic therapy were more adherent to treatment than those who received nonpreferred brand-name medications.
We analyzed pharmacy claims filled between October 1, 2001, and October 1, 2003, from a large health plan for 6 classes of chronic medications: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, calcium channel blockers, oral contraceptives, orally inhaled corticosteroids, angiotensin receptor blockers, and angiotensin-converting enzyme inhibitors. We measured adherence as the proportion of days covered (PDC) in each drug class during the first year of therapy. We evaluated how the formulary status of the initial prescription (generic, preferred, or nonpreferred) influenced PDC and adequate adherence, defined as PDC greater than 80%, over the subsequent year.
A total of 7532 new prescriptions were filled in 1 of the classes evaluated: 1747 (23.2%) for nonpreferred medications, 4376 (58.1%) for preferred drugs, and 1409 (18.7%) for generic drugs. After controlling for patient sociodemographic characteristics and drug class, PDC was 12.6% greater for patients initiated on generic medications vs nonpreferred medications (58.8% vs 52.2%; P<.001). The PDC was 8.8% greater for patients initiated on preferred vs nonpreferred medications (56.8% vs 52.2%; P<.001). Patients initiated on generic and preferred medications had 62% and 30% greater odds, respectively, of achieving adequate adherence compared with those who received nonpreferred medications.
In 3-tier pharmacy benefit plans, prescribing generic or preferred medications within a therapeutic class is associated with improvements in adherence to therapy.
Prescription drugs are instrumental to managing and preventing chronic disease. Recent changes in US prescription drug cost sharing could affect access to them.
To synthesize published evidence on the associations among cost-sharing features of prescription drug benefits and use of prescription drugs, use of nonpharmaceutical services, and health outcomes.
We searched PubMed for studies published in English between 1985 and 2006.
Among 923 articles found in the search, we identified 132 articles examining the associations between prescription drug plan cost-containment measures, including co-payments, tiering, or coinsurance (n = 65), pharmacy benefit caps or monthly prescription limits (n = 11), formulary restrictions (n = 41), and reference pricing (n = 16), and salient outcomes, including pharmacy utilization and spending, medical care utilization and spending, and health outcomes.
Increased cost sharing is associated with lower rates of drug treatment, worse adherence among existing users, and more frequent discontinuation of therapy. For each 10% increase in cost sharing, prescription drug spending decreases by 2% to 6%, depending on class of drug and condition of the patient. The reduction in use associated with a benefit cap, which limits either the coverage amount or the number of covered prescriptions, is consistent with other cost-sharing features. For some chronic conditions, higher cost sharing is associated with increased use of medical services, at least for patients with congestive heart failure, lipid disorders, diabetes, and schizophrenia. While low-income groups may be more sensitive to increased cost sharing, there is little evidence to support this contention.
Pharmacy benefit design represents an important public health tool for improving patient treatment and adherence. While increased cost sharing is highly correlated with reductions in pharmacy use, the long-term consequences of benefit changes on health are still uncertain.
A number of fundamental principles (and misconceptions) of patent law and of the system for granting and enforcing patents lie at the heart of the so-called 'evergreening' debate on patent protection for pharmaceutical products. The purpose of this paper is to consider 'evergreening' from a legal perspective and to evaluate the extent to which the patent system operates to safeguard against the claimed abuses. In the authors' view the allegation that pharmaceutical companies have been able to delay substantially the entry of generic competition by 'evergreening' many of their patents simply does not reflect the reality and mischaracterises how the patent system operates in the context of technological innovation. A patent over an improvement does not restrict a generic company from launching a competitor of the originator product and, in the UK at least, the procedure and attitude of the court is conducive to the speedy and cost-effective challenge of 'weak' patents.
A number of fundamental principles (and misconceptions) of patent law and of the system for granting and enforcing patents lie at the heart of the so-called 'evergreening' debate on patent protection for pharmaceutical products. The purpose of this paper is to consider 'evergreening' from a legal perspective and to evaluate the extent to which the patent system operates to safeguard against the claimed abuses. In the authors' view the allegation that pharmaceutical companies have been able to delay substantially the entry of generic competition by 'evergreening' many of their patents simply does not reflect the reality and mischaracterises how the patent system operates in the context of technological innovation. A patent over an improvement does not restrict a generic company from launching a competitor of the originator product and, in the UK at least, the procedure and attitude of the court is conducive to the speedy and cost-effective challenge of 'weak' patents.
Although the use of qualitative methods has increased greatly in popularity, many still question the defensibility of the qualitative orientation. It is argued here that questions concerning the credibility and status of qualitative inquiry are related to the privatization of qualitative analysis. The particular area of qualitative analysis I focus on is the process of category development. It is my argument that qualitative researchers must make all aspects of their analysis open to public inspection. In order to achieve this objective, I propose a two-dimensional model designed to facilitate the documentation of procedures used to generate categories. The domain representing the first dimension specifies the various components or actions associated with the development of categories. The second domain addresses the temporal aspects of category development. The intersection of these two analytical domains forms a two-dimensional table that may be used to document the nature of the analytical actions employed in a given study. An empirical example is presented with the intention of illustrating the utility of the approach. The implications of this approach, and some possible criticisms, are considered.
"Patent evergreening" is a potentially perjorative term that generally refers to the strategy of obtaining multiple patents that cover different aspects of the same product, typically by obtaining patents on improved versions of existing products. Although the patent system allows improvement patents to be obtained in any industry, evergreening is said to be most common in the pharmaceutical industry. Some observers believe that the availability of so-called continuation applications at the U.S. Patent and Trademark Office (USPTO) may promote evergreening practices. USPTO regulations that would have restricted the availability of continuation applications have been struck down by the courts on the grounds that the regulations exceeded the agency's statutory authority to promulgate. Others believe that the Hatch-Waxman Act, specialized legislation that governs the resolution of patent disputes between brand-name and generic drug companies, may also encourage evergreening in the pharmaceutical industry. However, 2003 amendments to the Hatch-Waxman Act may have mitigated some of these concerns. Critics of evergreening assert that the ability to obtain multiple patents on a product, over a period of many years, effectively extends the term of exclusivity that the patent holder obtains. They further assert that this practice is abusive, impedes the introduction of generic medications, and has a negative effect upon public health in the United States. Other observers believe that the term "evergreening" is itself inappropriate. In their view, sound intellectual property policy allows innovators to obtain patents on improvement inventions. Most technological advance occurs incrementally, they observe, and many improvement patents cover advances that are of considerable practical significance to patients and other consumers. In addition, patents on improvements may not impede the ability of competitors to market products that were covered by expired patents on original technologies. Finally, the developer of the "original" product is not always the same entity as the developer of "improvement" technologies. The ability of any innovator to obtain a patent upon an improvement invention is said to promote competition. Should Congress conclude that the current situation is satisfactory, then no action need be taken. If Congress wishes to intervene, however, a number of options present themselves. Congress may wish to consider the regulation of continuation applications or the introduction of statutory provisions that more directly address the perceived problem of evergreening. In addition, more generalized reform of the patent system may address concerns over evergreening. Current bills before the 111th Congress would potentially introduce a broad range of reforms in an effort to improve the patent system, and would perhaps respond to criticisms of evergreening practices.
Background:
The apparent decrease in the rate of approval of new molecular entities has provoked extensive discussion and fears that the productivity of biopharmaceutical research and development has severely declined in recent years.
Objective:
To investigate the extent to which traditional measures of innovative output neglect important innovations that occur after a drug receives initial market approval.
Methods and results:
Data on drug utilisation by diagnosis for the period 1999-2004 were combined with data on the approval histories of three important classes of drugs: ACE inhibitors, histamine H(2)-antagonists/proton-pump inhibitors, and selective serotonin/norepinephrine reuptake inhibitors. Counts of new drug approvals by the FDA were classified as new indications, new dosages, new combinations, new formulations, and labeling for expanded populations. Large numbers of such "supplemental" approvals were obtained. The share of drug utilisation in indications other than that specified in the initially approved labeling was computed, and found to be very substantial in two out of the three drug classes considered.
Conclusions:
Significant incremental innovation to existing pharmaceutical products has been occurring in the form of supplementary approvals for new dosages, formulations, and indications. These innovations account for a substantial share of drug utilisation and associated economic and medical benefits. Productivity trends for research and development based on counts of new molecular entities alone have therefore overlooked an important source of innovation in biopharmaceuticals.
Observers worry that generic patent challenges are on the rise and reduce the effective market life of drugs. A related concern is that challenges disproportionately target high-sales drugs, reducing market life for these "blockbusters." To study these questions, we examine new data on generic entry over the past decade. We show that challenges are more common for higher sales drugs. We also demonstrate a slight increase in challenges over this period, and a sharper increase for early challenges. Despite this, effective market life is stable across drug sales categories, and has hardly changed over the decade. To better understand these results, we examine which patents are challenged on each drug, and show that lower quality and later expiring patents disproportionately draw challenges. Overall, this evidence suggests that challenges serve to maintain, not reduce, the historical baseline of effective market life, thereby limiting the effectiveness of "evergreening" by branded firms.
Manufacturers of brand-name drugs and manufacturers of generic drugs are traditionally fierce competitors, making it noteworthy that both have lobbied for the legality of a controversial practice: "pay for delay" settlements to resolve drug-patent lawsuits.(1) Before most generic drugs can be marketed, the generic manufacturer must initiate a legal proceeding against the brand-name manufacturer that seeks to invalidate patents protecting the product or prove that the generic version does not infringe those patents. However, in the past several years, settlements that leave the patents intact and the generic version off the market have become increasingly common. When these settlements involve . . .
Enantiomer patents (ENPTs), constituents of chiral switches, claim single enantiomers of chiral drugs previously claimed as racemates. In this article, the strategy of ENPTs and recent court decisions and trends in case law worldwide are highlighted. ENPTs are challenged frequently (e.g. anticipation, obviousness, double patenting and insufficient disclosure), even though the novelty of enantiomers is not destroyed by the description of racemates. For establishing inventiveness (nonobviousness), the description in ENPTs should include superior pharmacological and/or pharmaceutical properties of enantiomer vis-á-vis racemate, above the expected 2:1 ratio. ENPTs were 'obvious-to-try' (unless taught away) since the mid-1980s. General concern about evergreening by ENPTs is not justified. ENPTs should be evaluated on a case-by-case basis. ENPT litigations are especially susceptible to settlements.
Many developing countries have enacted intellectual property laws allowing patents on pharmaceutical products. These countries now must figure out how to provide legitimate protection of innovative discoveries while avoiding drug patents that do not conform to their laws. Using case-study examples, including the antiretroviral tenofovir disoproxil fumarate (TDF, or Viread), we demonstrate the importance of having outside experts participate in the review of drug patents. Vibrant patent review systems require sharing information among developing countries and active consultation with local public health authorities.
Cost-containment policies frequently focus on reducing drug expenditures, although prescription drug costs are a relatively small proportion of total health care expenditures. Data show that very few drug cost-containment policies can selectively reduce unneeded care while maintaining essential care. In the early 1980s, the New Hampshire Medicaid program introduced a drug-payment limit (a "cap") that set the number of reimbursable medications a patient could receive per month at 3. Analyses reviewed in this article indicate that New Hampshire's drug cap, while in effect, reduced the use of prescription drugs among the elderly and the mentally ill but increased hospital and nursing home admissions, partial hospitalizations, distribution of psychoactive medications by community mental health centers, and use of emergency mental health services. Vulnerable populations are most likely to experience adverse effects from hastily-applied drug cost-containment policies, and resulting compensatory measures may create more expenses than the policy removes.
Medical process patents, which protect intellectual property in medical and surgical procedures, threaten to complicate medical practice, increase health care costs, and restrict access to therapeutic and diagnostic modalities. Few countries allow such patents, but they have been granted in the U.S. in increasing numbers. Proponents of medical process patents note their value in encouraging medical innovation, while the American Medical Association and others object that conditioning access to advancements in care modalities on payment of a licensing fee conflicts with physicians' professional ethical obligations. A case recently heard by the Supreme Court, Laboratory Corporation of America (LabCorp) v. Metabolite, illustrates the legal and policy challenges raised by the expansion of proprietary rights over everyday medical practices such as making a diagnosis or treating a patient in a particular way. The LabCorp case centered on an effort to patent the "process" of reading an assay for homocysteine levels and inferring, based on the test result, that a patient had a vitamin deficiency. The Supreme Court's decision in the case leaves unresolved important questions about the scope of patentability of medical processes and the effects that patent law will have on the science and practice of medicine. In this article, we review the law of medical process patents and the policy issues that counsel against expansion of intellectual property rights in this area. Please contact the authors for an electronic reprint.
Rising prescription drug costs present a critical policy issue for Medicaid. Generic substitution can reduce costs, but the effects are undercut by extensions of intellectual property (IP) protection, elevated generic prices, and low substitution rates. Using Medicaid prescription data for amoxicillin/clavulanate, metformin, and omeprazole, we calculated the savings that could have been realized if generic drugs had been available and fully substituted at their lowest cost when IP protection first expired (an average delay of twenty-six months). The delay in availability, elevated prices, and slow uptake of generic alternatives for these three drugs alone cost Medicaid 1.5 billion dollars in 2000-2004.
Lopinavir, an HIV protease inhibitor, is coformulated with ritonavir to enhance the bioavailability and pharmacokinetics of lopinavir. The original solid oral formulation of lopinavir/ritonavir, a soft-gelatin capsule (SGC), requires refrigerated storage, is taken as 6 capsules daily at the recommended adult dose, and is administered with food to maximize the bioavailability of lopinavir. Melt extrusion technology was used to produce a tablet formulation reducing the number of dosage units administered per day and simplifying storage requirements. Three studies assessed the bioavailability of tablet doses of lopinavir/ritonavir at 800/200 mg or 400/100 mg under different meal conditions compared with equal doses of the SGC after a moderate-fat meal. The tablet was bioequivalent to the SGC after a moderate-fat meal with respect to lopinavir and ritonavir areas under the concentration-time curve. Compared with the SGC formulation, the tablet formulation resulted in more consistent lopinavir and ritonavir exposures within and across studies and across meal conditions. The diminished food effect and decreased variability of the tablet are likely to result in more consistent lopinavir and ritonavir exposures, minimizing the likelihood of extreme high or low values compared with the SGC.
The patent system plays an important role in stimulating the economy and advancing the quality of life in the United States. It serves as an incentive for innovation by giving inventors an exclusive right to their inventions for a limited period of time. It also increases and hastens the publication of useful knowledge by requiring inventors to disclose their invention to the public. Patents are particularly important in the pharmaceutical and biotechnology industries because they provide a mechanism by which the extremely high product development costs may be recouped. The United States Patent and Trademark Office acts as a gatekeeper in the patent system to prevent patents that do not meet the legal requirements from being thrust on the public. The legal requirements for obtaining a patent are discussed, particularly as they relate to pharmaceutical and biotechnological inventions. The process of examining an application for a patent is briefly described, along with some of the burdens faced by examiners when deciding the patentability of therapy-related inventions.
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