Twenty years of HFA pMDI patents: facts and perspectives

Authors


Philippe Rogueda, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia. E-mail: philippe.rogueda@monash.edu

Abstract

Objectives  Over the past 20 years, the inhalation drug delivery industry has undergone a quiet revolution after the phasing out of the chlorofluorocarbon propellants used to formulate pressure-metered dose inhalers (pMDIs). This review looks back to the creative landscape of those 20 years through a study of patent application trends. To this end, an analysis of the hydrofluoroalkane pMDIs patent landscape was undertaken.

Methods  A statistical analysis demonstrates that 20 years after the introduction of hydrofluoroalkanes in the inhalation delivery field, the original patent applications are coming to the end of their legal life.

Key findings  Detailed analysis revealed that, from a total of 971 of the patents identified, up to 2.3% will expire within the next 5 years, rising to up to 7.3% in the next 10 years. The UK and USA were the main patent destinations and locations of inventive activity, as measured by patent filing location. Interestingly, the UK was the first destination and location of inventive activity in Europe, largely due to the activity of GlaxoSmithKline, followed by Italy, thanks to the work of Trinity-Chiesi. The analysis also showed that patent assignees are not always major pharmaceutical companies, with suppliers of propellants, as well as companies without major inhalation activity (such as Novadel), making substantial contributions to the landscape.

Conclusions  These developments may have a significant impact on innovation trends and key company activity around novel pMDI formulations, in particular for generics manufacturers.

Abbreviations
BRIC

Brasil, Russia, India, China

CFC

chlorofluorocarbon

DPI

dry powder inhaler

GSK

GlaxoSmithKline

HFA

halofluoroalkane

IP

intellectual property

INPADOC

International Patent Documentation Center

IPAC

International Pharmaceutical Aerosol Consortium for Toxicology Testing

IPC

International Patent Code

pMDI

pressure-metered dose inhaler

PTO

Patent and Trademark Office

R&D

research and development

USPTO

United States Patent and Trademark Office

Introduction

Over the last 20 years inhalation drug delivery has been adjusting to the phasing out of chlorofluorocarbons (CFCs). Following the signing of the Montreal protocol[1] on 16 September 1987 (and its coming into force on 1 January 1989), there has been a rush for pressure-metered dose inhaler (pMDI) re-formulation. This led to the advent of dry powder inhalers (DPIs) and to a buoyant hydrofluoroalkane (HFA) pMDI patent field, rapidly resulting in a crowded patent landscape. The complexity of this landscape has led to myths and confusions about the risks and opportunities in formulating HFA pMDIs. This review aims to improve our understanding of the intellectual property (IP) landscape since understanding the past could help industry participants plan the future of pMDI inhalation delivery.

A recent USA patent from Boehringer Ingelheim prompted the need for this review. This patent,[2] filed on 3 September 2004 and granted on 9 January 2007, contains only one claim:

A pharmaceutical formulation for administration of micronised or powdered drug to the respiratory tract of a warm-blooded animal via inhalation wherein propellant gases are employed, the improvement comprising employing 1,1,1,2,3,3,3-heptafluoropropane as the sole propellant gas.

This patent is related to prior, now abandoned, applications and divisional filings, the earliest dating back to 1 October 1992. In effect, this patent claims the sole use of HFA 227 as a propellant carrier for inhalation delivery. This is somewhat puzzling as by 1992 the use of HFA 227 as a propellant in pMDIs was already well documented by prior art. Furthermore its grant in 2007, or 15 years after first filing, goes some way to highlight the difficulties faced by HFA formulators. It also shows to what extent the field is controlled by early players, leaving little space for newcomers. This, however, is likely to change soon, as discussed in this review.

It is also interesting to note that the main patent owners are sometimes not the companies that one would expect from inherited wisdom. A large market share or strong inhalation product presence is not necessarily synonymous with an extensive patent portfolio. It was therefore seen as opportune to review this field of inhalation delivery to gain a factual understanding of the state of play.

This review is the first of its kind to analyse the extent of IP coverage of the HFA pMDI formulation field, looking at geographical spreads, inventorship, aggregate expiry times and other parameters. It also aimed to track down the original HFA patents filed at the turn of the 1990s, and show how these fostered and/or hampered further invention filings.

In addition, further strategic questions can be answered, such as:

Does the expiry of key patents filed since 1989 mean that the HFA pMDI formulating will become a more open field?

What could be the implications for innovation trends and key players' strategies?

This review will first look at the methods employed to harvest and find the most relevant HFA pMDI patents, with a view to identify IP owners, geographical spread and aggregate theoretical expiry times, and then will review trends in inventive claims in the early patents.

This review is not concerned with other inhalation delivery routes; it focuses solely on the use of HFA as propellant media in pMDIs.

Methodology

The analysis of the patent landscape is based on an extensive search of patent databases. The search followed CambridgeIP's IP Landscape propriatory methodology, which is explained in the following paragraphs. The initial search was carried out on 1 May 2011. A mixture of commercial and publicly available database services were used, which provided coverage of most key countries (for both patent applications and grants): the US Patent and Trademark Office, Japan, the European Patent Office and key European national patent authorities and most large countries covered by the International Patent Documentation Center (INPADOC) database (The INPADOC collection by the European Patent Office provides patent family documents from 71 patent offices worldwide and legal status information from 42 patent offices worldwide, from 1968 to the present. See http://www.epo.orgfor more details on the INPADOC collection). The time span covered ranged from 1968 to the present time. Due to delays in patent application publications it is possible that data for 2011 and part of 2010 will be under-represented in the dataset.

The patent search strategy focused on identifying patents that related to the use of propellants, and in particular propellants to formulate drug molecules for inhalation. At the outset, a technology field matrix was developed, where the types of propellants used in the field and the types of devices they can be expected to be associated with were identified. Discrimination was made between organic propellants (HFA propellants or others) and inorganic propellants.

An iterative patent search methodology was used to minimise false negative exclusions and exclude false positives. The initial search resulted in 7924 patents and patent applications that were broadly related to propellants and propellant use in inhalers. Subsequent quality control steps were undertaken using proprietary database analytics software, and an expert review of selected patents was made to develop two datasets used in the analysis. This led to the formulating of two working datasets:

Focus dataset: A patent dataset of 971 HFA-related patents focused on or related to pMDI applications, used as the primary dataset used for most of the analysis.

Control dataset: A patent dataset of 2010 observations, representing the wider pMDI propellants field, used for control and cross-checking regarding broader trends in the pMDI patent landscape.

Results

Key categories in the patent space

The 971 propellants-related patents and applications in the focus dataset were sub-categorised to distinguish between patents purely focused on a propellant, and propellants-focused patents that also involved some type of formulation. The ‘pure’ HFA patents account for about 48% of the overall space, while 62% of propellants-related patents also cover uses of other propellants. These results are consistent with a view that the majority of innovative activity post 1989 focused on the application of specific propellant types in commercial products, which involve the combination of propellants with different formulation types.

Industry overview: industry segments

The international patent classification (IPC) codes under which patents and applications are filed are a proxy for the use of a technology. IPC codes for the focus dataset are summarised in Table 1. Although the majority of uses of HFAs are in the medical field, and hence are for pMDIs, a number of references covered other uses. IP filing around HFAs uses for inhalation delivery extends beyond medical applications. This reflects the alternative industrial uses of propellants by cross-disciplinary players such as Dupont, 3 M or Solvay (formerly Hoechst). This is an important consideration to bear in mind when carrying out IP analysis, as it testifies to patenting strategies. The most common IPC codes in this study were A61K (preparations for medical, dental or toilet purposes), A61P (therapeutic activity of chemical compounds or medical preparations), C09K (materials for applications not otherwise provided for), C07C (acyclic or cyclic compounds) and A61M (devices for introducing media into or onto the body).

Table 1.  Distribution of IPC codes in the focus dataset (971 HFA patents) related to the use of propellant in pMDI products (60% of patents are filed in the medical field)
IPC codeReferences in focus dataset (%)
A61K60
Preparations for medical, dental or toilet purposes
A61P11
Therapeutic activity of chemical compounds or medical preparations
C09K6.3
Materials for applications not otherwise provided for
A61L1.2
Methods or apparatus for sterilising materials or objects in general; disinfection, sterilisation, or deodorisation of air; chemical aspects of bandages, dressings, absorbent pads, or surgical articles; materials for bandages, dressings, absorbent pads, or surgical articles
Others (F25B etc)21.5

Key players

The top 10 HFA propellant assignees are summarised in Figure 1. Unsurprisingly, GlaxoSmithKline (GSK) holds the highest number of HFA propellant-focused patents and applications. It confirms industry perceptions of its leadership status in the field of HFA pMDI formulation.

Figure 1.

Top 10 pMDI patent publication assignees.

Surprisingly, Chiesi has the second highest number of patents, possibly related to its ethanol-based platform Modulite®, demonstrating the company's dedication to HFA pMDI development. It is also interesting to note that many Chiesi patents are co-owned with Vectura, which highlights the established and well-known collaboration between the two companies.

Dupont has the third highest number of patents. This reflects its activity in propellant manufacturing overall. However, it is more surprising to find Dupont with a strong position in medical pMDI patents, suggesting an inhaler-industry specific strategy.

A surprising discovery in the top 10 was Novadel, a relatively unknown player in the inhalation field. Further research showed that Novadel engages in developing drug delivery solutions based on non-polar solvents to deliver molecules via sprays to the oral mucous membranes. Although their use of HFAs features prominently in their formulations, it is not dedicated to inhalation. Nevertheless, Novadel's patent portfolio is likely to be of interest around many types of molecules that are potentially of use in inhalation delivery.

Analysing the citation frequency distribution of patents can help to identify the patent groups of high influence in a large patent space. In any patent landscape, only a minority of patents attract a high number of citations by other patents. Within the propellants dataset of 391 USA patents, 40 patents had 1 citation, 39 patents had 10 or more citations, and only 3 patents had more than 100 citations. As Table 2 shows, 2 of the top 10 most frequently cited patents are propellant focused, but the most frequently cited patent is fomulation focused.

Table 2.  Top 10 most frequently cited HFA pMDI patents
RankNumber of forward referencesApplication datePublication datePublication numberTitle
  1. Ranking based on forward citations from the focus dataset (971 HFA patents). These patents can be considered as the basis of the HFA technology patenting history.

 11052002-04-032002-10-31CA2441549AAIpratropium formulation for pulmonary inhalation
 2841993-09-292002-07-10EP679088B1Pulmonary delivery of active fragments of parathyroid hormone
 3831992-12-041995-09-27EP616525B1Pharmaceutical aerosol formulation
 4812006-10-202008-11-13US2008279788A1Propellant for dosing aerosols comprising packagings
 5732000-03-102002-11-26NZ514319AProteinic pharmaceutical agent solubilised in aerosol propellant in a pressurised container
 6702000-10-022004-02-10US6689822Azeotrope-like compositions of pentafluoropropane and water
 7642003-04-012005-09-22US2005207984A1Formoterol and ciclesonide aerosol formulations
 8631992-12-041993-06-24CA2125666AAMedicaments
 9611992-12-112001-08-29EP717987B1Suspension aerosol formulations
10591998-08-032000-06-27US6080721Pulmonary delivery of active fragments of parathyroid hormone

Inventor country origins

Data on patent filing locations can be used as a proxy for the location of key markets and key corporate locations (Figure 2). It comes as no surprise that this analysis highlighted the USA as the most important patent filing destination, both as a market and as the location of key research and development centres and manufacturers. European patents account for 21% of the entire patent filing destinations. Perhaps the most atypical patent country filings for the pharmaceutical industry are Canada, with a 14% share of all patent filings, and Mexico, with a 3% share. This latter percentage possibly indicates the importance of an integrated North American market, as well as the location of research and development facilities in Canada. This geographic analysis can be extended further by analysing patent inventor locations. Here a more granular picture is observed. The USA is again a leading destination, but within Europe, the UK and Italy emerge as highly important. While it is no surprise that the USA and the UK are the dominant countries in this field (the UK is the birthplace of pMDI inhalation delivery), the presence of Italy is more interesting, and can be traced to the extraordinary work of Triniti-Chiesi.

Figure 2.

Geographical distribution of patent publications.

Filing timelines

Given the large number of pMDI patents filed since 1987 a drastic reduction in the number of patents in force over the next 5–10 years can be expected. In order to quantify this likely change, patent applications expiry dates were recorded. Note that this analysis is based on official dates, and does not take into account patents and applications that might have lapsed through non-fee paying, or that might have been abandoned or revoked on the back of patent litigation. In addition, complex patenting strategies around product systems can in some cases extend the de facto protection of a specific technology, even if the original patents have expired.

As shown in Figure 3, the number of patent applications increases notably in 1990, with a peak in 2003. In the initial years of 1989 and 1990 HFA 134a propellants were more readily available, and initial uses and product trials led to a higher use of HFA 134a. Since then, the field has seen a rapid growth. By 2008, there were 658 patents using some type of fluorocarbon molecules in the inhalation space. Since 2004, the number of publications has been in decline, demonstrating a rather mature formulation field and a shifting of interest to DPIs and other forms of inhalers. Correspondingly, the number of patents due to expire is now increasing. Currently, only about 8% of the technology space patents and applications have expired.

Figure 3.

Number of HFA pMDI patent publications per year.

Discussion

Birth of an industry: the early HFA patents

A pressing question often asked is: What are the original HFA pMDI patents? One of the key ‘start’ dates is, of course, the signing (1987) and entry into force (1989) of the Montreal protocol. However, patent filing and innovation started before the protocol. HFA propellants, alongside a number of other chemicals, including CFCs, had long been identified as useful for inhalation delivery. The Montreal protocol merely focused the interest of scientists and industry on HFAs as the preferred route. The adoption of HFAs by the industry was facilitated through the work of International Pharmaceutical Aerosol Consortium for Toxicology Testing (IPACT) between 1994 and 1995 on HFA 134a and HFA 227.[2] These were the only substances which met the criteria required at the time for pMDI propellants with regard to non-combustibility, toxicological safety, availability and, above all, technical suitability in terms of physico-chemical characteristics.

The use of HFAs as propellants for inhalation delivery precedes these two events. The earliest patent application mentioning fluorocarbons as suitable propellants for pMDIs was published in 1987.[3] The earliest specific mention of HFA use was filed on 6 December 1988[4] with a direct example using HFA 134a by Ryker laboratories. This invention was subsequently submitted for a European patent application on 27 November 1989.[5] It describes a self-propelling aerosol formulation that may be free from CFCs, comprises a medicament, 1,1,1,2-tetrafluoroethane, a surface-active agent and at least one compound having a higher polarity than 1,1,1,2-tetrafluoroethane. It is now the member of a 47 patents extended family. A measure of this patent's visibility and influence is the frequency with which other industry players have opposed it. Norton Healthcare, Schering, Boehringer Ingelheim, Smithkline Beecham and Fisons, among others, filed opposition to the patent filed in 1995, 1996 and finally obtained in1999.

A frequently cited patent application[6] (with 77 USA forward citations) by Fisons describes the use of HFA 134a. This patent was filed on 30 January 1991 and has become a member of a 25 patents extended family with a priority date of 4 April 1990.[7]

Soon afterwards, Virginia Commonwealth University filed a patent application[8] on the use of HFA134a (14 February 1991). It describes an aerosol formulation for use in metered dose inhalers, which includes 1,1,1,2-tetrafluoroethane alone and in combination with other compounds, as well as various hydrocarbon blends. Eighty-four other later patents cite it.

The patenting of the use of HFA 227 can be traced to two patent applications. The older application was filed by Hoechst[9] on 6 December1990 (now owned by Solvay Fluor). It describes the use of HFA 227 and mixtures for inhalation delivery. Boehringer Ingelheim filed a second important application on 3 February 1990.[10] It describes a novel, advantageous vehicle gas mixture, containing two or more components, at least one of which is a partly fluorinated lower alkane, which may be used in medical preparations.[11] These patent applications constitute traceable prior art for the use of HFA in pMDI formulations, but have now been superseded by further applications and grants by patent family members. While Hoescht's patent is the original HFA227 related patent, the Boehringer Ingelheim patent family has had the biggest impact in the industrial field, as measured by backward citations. As this analysis shows, the question of ‘who was first’ is fairly complex.

Evolution of the industry: focus on 2003

The aggregate numbers over a 20-year period hide many details of the dynamics of the industry. Over such a long period, the key patenting companies as well as the focus of patent filings change. It is interesting to see how the industry focus has evolved from the ‘origins’ to the present. To get a better understanding of industry activity a glance at the patent activity in 2003, a year of particularly high activity, with 105 patent filings, is useful.

The majority of patents (80) in 2003 were focused on fluorocarbon patents, while there were only two patents with inorganic propellants. From the 80 fluorocarbon patents, at least half included HFA 227 and 134a molecules, while 32 of the patents included additives, predominantly surfactants or polymers. The most active companies in that year were Chiesi and GSK (with 21 and 12 patents, respectively). Other important players included a range of individual inventors, such as Harry A Dugger[12] and Thanh Hang Pham,[13] which accounted for 31 patents. The presence of a large number of individual inventors not affiliated to larger institutions is a noteworthy feature of HFA pMDI inventions.

Oppositions and fate of some major patent families

Analysing the citation frequency distribution of patent applications can help to identify the patent groups of high influence in a large patent space. This analysis revealed 39 patents with more than 10 forward citations. These are the bulk of the influential patent space in HFA pMDI formulations.

Numerous HFA patents have been opposed and sometimes revoked in the past 20 years. Long established inhalation companies such as GSK or Boehringer Ingelheim have developed extensive patent families that have evolved and often are referenced as prior art. It is worth looking at these in detail.

GSK was the first big pharmaceutical company of today's market to protect formulations with HFA 134a. It built a small family of 28 members around the patent USA5126123.[14] This enabled GSK to build another family including HFA134a formulations a few years later. Today, this extended family includes 241 members. This high number of members shows the importance of this innovation for GSK. One of the early members[15] was filed on 19 May 1995, and one of its latest members was filed on 9 May 2005.[16] This late filing shows that the family is still active, and that GSK owns strong rights in the pharmaceutical HFA 134a formulation field.

Another main player in the inhaler industry, Boehringer Ingelheim, built its IP protection for inhaler formulations around HFA 227. Boehringer Ingelheim's patent families (medium sized, 49 patents) are a reference in the industry and are often highlight cited, such as in patent application WO09111496A1.[17] The early patents in this family are gradually lapsing, but the family is still active and the latest member[18] was added on 3 September 2004. However, numerous members[19,20] of this family have been revoked following opposition actions from Solvay, SkyePharma, Adir et Compagnie, AstraZeneca, Schering and Les Laboratories Servier.

3M is one of the earliest players in this field and owns several patent families relating to both HFA 134a and HFA 227. One of its earliest HFA patents[21] now forms part of a 47-strong family. Some 3M patent families,[22] built on the concomitant use of both HFA 134a and HFA 227, have faced fierce opposition from Jago Pharma, Norton Healthcare and SkyePharma, leading to the European Patent Office patents of this family being revoked in 1999. However, the family built around US5980867,[23] filed on 6 July 1998, with 20 members, and built around the use of HFA 134aand HFA 227 with Flunisolide, faced opposition from Chiesi, but its rights were subsequently confirmed in Europe.

This short review shows that patent rights in the field of HFA pMDI formulations are highly contested and the landscape keeps changing. Detailed analysis of latest rights is needed to fully understand invention coverage.

Impact on the industry

The statistical analysis of the HFA propellant patents has highlighted that a substantial change in the patent landscape is to be expected in the field of HFA pMDI formulation and new molecules over the next few years. At the aggregate level, the industry will see a decrease in valid patents over the next 10 years. While currently only about 1.6% of the technology space has expired, in the next 5 years this will increase to 2.3%, while in the next 10 years, 7.3% of the original patent applications will expire. Expiration is defined as 20 years after first application. Expiration will differ by jurisdiction and the history of the patent or patent family. Further analysis is required to define the fate of each patent or patent family.

These developments may open up significant opportunities for innovation in the formulation community where the risk of patent infringement may have been an inhibiting factor thus far. It will be of considerable interest to observe whether such opportunities are seized by the generics industry, emerging markets players or incumbents. Even for established industry players, such developments can bring benefits: there may be an opportunity of greater innovation and higher variety of pMDI products, as well as increased variety of sources of HFAs. In combination with increasing purchasing power in key developing economies, the total monetiseable market for pMDIs and HFA formulations may well compensate for the reduced profitability on previously protected product lines.

Conclusions

The theoretical patent expiration timelines highlighted in this review, more than a definite guide to the future, are a measure of the creative activity that has surrounded the field of HFA pMDI formulation in recent years.

This analysis reveals that pMDI research has gone through a peak. It is possible that patenting of HFA pMDI formulations has seen its ‘gold rush’: those who had the foresight to invest in this field are now reaping rewards. The decline of inventiveness in the field is felt in the number of recent pMDI patent filings, and also in the market share of pMDI vs. DPI, and in the number of DPI products being launched. This is particularly marked in the European Union, and increasingly so in the USA.

Based on these statistics, it can be suggested that a number of the patent applications filed over the last 20 years will lead to a number of patent expiries over the next few years. This has one major consequence: HFA formulation routes, hitherto not available generally, will become accessible to many more players, and in particular to the generics industry. However, expiry timelines need to be reviewed for each patent application and patent family. The case of the Boehringer Ingelheim patent mentioned in the introduction is a good example: it was first filed in 1992, but only granted after a number of modifications and withdrawals in 2007, thus bestowing a much longer exclusivity to the invention than could be predicted from theoretical expiry timelines. In 2010 Boehringer Ingelheim covered the registration fees for the next 4 years, suggesting a patent extension of 3 years. The European patent equivalent received much opposition in 2000, 2001, 2002, 2003 and 2007 from Skyepharma, Solvay, Adir, AZ, Achering and Servier. As a result it would appear that it lost exclusivity in Europe except for a few countries such as Greece. The HFA pMDI field is still a well-protected and complex area, with main applications often protected by complex patent thickets, as illustrated by the numerous oppositions filed against this Boehringer Ingelheim patent.

The availability of IP for HFA formulations could lead to a renewed interest in the field of HFA formulations, and more investment in HFA pMDI products. This in turn could spark a new IP rush, as many problems associated with HFA pMDI formulations still remain unsolved: there is still no panacea to remedy the poor soluble properties of HFAs or their low surface tensions, which lead to drug adhesion onto device surfaces. These issues are still present and are mines for inventions; indeed the need to create better HFA pMDI formulations remains. But will this happen?

From a commercial point of view, the future for HFA pMDI products is uncertain. The IP landscape is only one factor. Factors such as market needs, new therapies, the role of Brasil, Russia, India and China, and further environmental regulations will dictate the future of HFA pMDI formulations as much as the IP landscape.

For instance, the HFAs used in the pharmaceutical industry are by-products of those from the automotive and refrigeration industries. When the use of HFAs in these industries is effectively banned, the pharmaceutical industry may face a reduced supply of HFAs and/or an increase in price that may lead to the phasing out entirely of HFA pMDIs because of supply issues.

The use of alternative propellants (CO2) and technologies (soft mist inhalers) could also take over and replace HFA pMDIs. This would not only bypass the need for HFAs, but offer new IP opportunities for all players in the industry, away from HFAs.

Declarations

Conflict of interest

The Author(s) declare(s) that they have no conflicts of interest to disclose.

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