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GenericsWeb Industry Newsletter May 05
Welcome to the May edition of the GenericsWeb newsletter. This month's drug in focus is Lamotrigine, also Annette Cunningham - European Director of Intellectual Property at Ivax Pharmaceuticals UK - has contributed an excellent summary of Bolar provision history and future directions in Europe, and Peter Wittner provides an analysis of the North-South divide that exists in the European generics industry.
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DRUG IN FOCUS: LAMOTRIGINE |
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The end of May 2005 will see the expiry of patents covering the antiepileptic active ingredient Lamotrigine (Lamictal) in some major markets, which will likely result in a flurry of generic activity. Based on information contained in the GenericsWeb Pipeline Selector report for Lamotrigine, this month’s Drug In Focus analyses the patent landscape surrounding this product with a view to launching generic equivalents.
The Lamotrigine General Information (Table 1) indicates that, in general, two different formulations are currently marketed for administration of Lamotrigine via the oral route, a conventional tablet and an orodispersible (chewable) tablet. 2mg and 5mg strengths are registered for the chewable tablet, whereas the lowest strength in the conventional tablet form is 25mg.
Table 1: Lamotrigine General Information
The Key Patent Indicator (Table 2) for Lamotrigine confirms that the extensions on the Lamotrigine active ingredient patent expire in Australia, Germany and the UK toward the end of May 2005, whereas the US equivalent 4,602,017 does not expire until July 2008. This disparity is due to the differing terms of both the original patent and the extension in the USA.
In addition to the molecule patent family, one other constraining patent family has been identified by the Key Patent Indicator, relating to tablet formulations containing a swellable clay, which forms a dispersion in a defined manner. This formulation clearly protects the orodispersible tablet, which contains magnesium aluminium silicate. Although IMS data indicates that this formulation represented approximately 5% of Lamictal sales in the US in 2004, Teva challenged the US equivalent patents resulting in the grant of an exclusive licence to Teva to sell their own generic orodispersible tablets prior to expiry of these patents in 2012 . Two British patents from this family were revoked in 1997 and 2001, however an equivalent European patent is in force in the UK with an estimated expiry date of 2011.
Although these formulation patents may represent a barrier to launch of generic orodispersible Lamotrigine products in major markets, it is not likely that they will prevent generic competition completely. The relative sales of this particular dosage form compared to the standard tablet formulation may cause some generic companies to focus solely on the latter, more simplistic route into the market for this active ingredient.
Table 2: Lamotrigine Key Patent Indicator
Study of the Patent Risk Analysis section, based on comprehensive patent data (details of which are accessible in the corresponding Pipeline Developer subscription) indicates that patenting activity relating to this drug is fairly evenly distributed across process, formulation and use patents (Figure 1). This indicates that caution is necessary with regard to manufacturing, formulating and labelling of generic products to ensure that all relevant patents have been considered.
Figure 1: Patent Category Distribution
The Top Patent Applicants analysis (Figure 2) reveals that Ranbaxy is also very interested in launching a generic version of this active and protecting its investment in doing so, applying for 4% of the identified patents. Noteworthy is that 47% of the patent applications are made by companies other than GlaxoSmithkline, Ranbaxy & Teva, demonstrating a significant interest by generic competitors.
Figure 2: Top Patent Applicants
In summary, the market for Lamotrigine has not been well protected by the innovators beyond the life of the active ingredient patents, however full consideration of the numerous molecule, process, formulation and use patents is essential prior to launch. Later development of the orodispersible formulation will provide only limited protection as generic companies are likely to circumvent the formulation patents or concentrate on competing for the much more significant conventional tablet formulation.
Comprehensive data for patent families relating to Lamotrigine, based on professional patent searching, may be accessed by subscribing to GenericsWeb Pipeline Developer reports which include twelve monthly updates to keep you abreast of recently published patents and applications. During the month of May, GenericsWeb are pleased to offer a 20% discount on the standard price of a Pipeline Developer subscription to Lamotrigine. GenericsWeb Pipeline Selector reports are available for any active ingredient upon request.
Click here for more info on GenericsWeb's Pipeline Selector and Pipeline Developer patent intelligence.
Leighton Howard
May 2005
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DEVELOPMENTS AT GENERICSWEB |
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Data Inclusion Policy
For an explanation of what data is included in our PipelineTM patent intelligence, please read our newly rewritten 'scope and limitations' page. This page is extremely useful to help you clarify what information goes into our Pipeline Developer and Selector reports and why we deem this information to be relevant to the development of generics.
Calculating Expiry Dates
For a handy reference on how to calculate expiry dates in major territories around the world, download our latest help sheet by clicking here.
New Drug Reports
This month our patent department added Pipeline Developer reports for Simvastatin and Quinapril. The comprehensive patent analysis contained in our Pipeline Developer reports for these and many more drugs can be provided within one business day. Click here for more info on GenericsWeb's Pipeline Selector and Pipeline Developer patent intelligence.
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If you are new to GenericsWeb you may not know that there is daily generics news archived at our site:
Click here for this month's major generics news headlines
This month's guest contributor is Annette Cunningham, European Director of Intellectual Property at Ivax Pharmaceuticals UK. If you would like to contact Annette click here.
Bolar Provision: A Global History and The Future For Europe
The availability of pre-patent expiry provisions for working patents for the purposes of obtaining regulatory approval or other commercial purpose, generally in regard to pharmaceutical products, (sometimes referred to as Bolar provisions), varies throughout the world.
The situation was initially unclear in the USA, and the subject of litigation in the Roche-Bolar case decided in 1984 (Roche Products Inc v. Bolar Pharmaceutical Co. Inc. 221 USPQ 937 (Fed. Cir. 1984)). The Court held that exception for experimental use must be construed narrowly, and that experimentation for pure speculative research was not infringement, but that as soon as the experiments were directed to a clear commercial goal, then infringement occurred.
An ensuing compromise between R&D based and generic companies culminated in the Drug Price Competition and Patent Term Restoration Act of 1984 (known more familiarly as the Hatch/Waxman Act) in which Congress overruled the decision in Roche-Bolar, specifying that it was not an infringement to make, use, or sell a patented invention “solely for purposes reasonably related to the development and submission of information under a Federal law which regulated the manufacture, use, or sale of drugs.” Clearly pharmaceutical research is included in this definition. However it does not extend, for example, to agrochemical products.
However, for Europe the situation, until the emergence last year of Directive 2004/27/EC was less clear cut. The present position is that an experimental use provision does exist in most national laws, but the nature of what is experimental is left to the discretion of individual EU member states. Case law at present disallows the provision of samples in the UK and Netherlands during the patent period. Germany allows the working of patented products only if it is part of a general research investigation. In the UK and Germany, in litigation between Monsanto and Stauffer in 1985, Stauffer made extensive trials of a herbicide very similar to Monsanto’s patented Roundup. Although not literally falling within Monsanto’s claims the product was arguably close enough to be an infringement if sold commercially. The courts held consistently that the field trials were as much an infringement as commercial sales would have been.
“…trials carried out in order to demonstrate to a third party that a product works or, in order to amass information to satisfy a third party, whether a customer or a [regulatory body] that a product works as its maker claims are not, in my judgement, to be regarded as acts done ‘for experimental purposes’.”
Subsequent litigation introduced doubt into this narrow interpretation, especially as the judgement did not address the situation where experiments or trials may have a dual purpose, that of true experimentation and also that of submission to the authorities. A decision of the German Federal Supreme Court in Clinical Trials I, in 1995, resulted in the summary which essentially provided that a collateral non-experimental purpose does not prevent true experimentation from being non-infringing experimentation. However, this case did arise under special circumstances.
A subsequent decision, in 1997, in the German Federal Supreme Court concerned the protein erythropoietin in Clinical Trials II [1998]RPC 423. The court held,
“the intention that is associated with an activity begun and carried out for research purposes cannot render such an activity infringing merely because the results of the research will not solely serve research purposes but above all will serve commercial purposes as well.”
While the situation is not entirely clear it does appear that submitting the results of trials to the regulatory authorities does not render those trials unable to be the subject of the experimental use defence, provided that those trials really are experimental.
Italy allows testing during extended patent term (SPC). In Portugal the Ministry of Industry has indicated developmental work may be possible. Hungary has a Bolar provision in its patent law, and Poland and Slovenia have provisions in their draft laws.
Outside Europe the position is clearer. Canada, Japan, Israel, Australia and New Zealand all have some provision for pre-patent expiry activity. In Japan the Tokyo District Court, in Otsuka/Procaterol Hydrochloride 7430/1966 refused to consider testing as infringement, based on public policy considerations. In Australia the patent law was amended in 1998 to allow extension of term of pharmaceutical patents, but it was also enacted that not only in the extended period, but also in the main term of the patent from the day that the application for extension is granted, testing for commercial purposes will not be considered as infringement. In New Zealand, in December 2002, the Patents Act was amended by the insertion of new Section 68B, stating;
“It is not an infringement of a patent for a person to make, use, exercise, or vend the invention concerned solely for uses reasonably related to the development and submission of information required under New Zealand law or the law of any other country that regulates the manufacture, construction, use or sale of any product”.
Interestingly, this provision is not limited to pharmaceutical products. The existing law in Canada extends the provision to allow manufacture and stockpiling of a patented product prior to patent expiry.
The position in Europe has clarified considerably with the EU Directive 2004/27/EC which must be implemented in all member states by 30 October 2005. Article 10(6) of the Directive states,
“Conducting the necessary studies and trials with a view to applications of paragraphs 1, 2, 3 and 4 and the consequential practical requirements shall not be regarded as contrary to patent rights or to supplementary protection certificates for those medicinal products.”
Paragraphs 1, 2, 3 and 4 define the regulatory requirements for obtaining regulatory approval for medicinal products.
What is not yet clear is what text will be used in each of the member states in implementing the Directive, how and when each member state will implement it, and how it will be interpreted. For example, there is some concern in the generic industry that the proposed implementation text in Germany omits the exemption for “consequential practical requirements”. In addition, while the type of studies and trials which would not be contrary to patent rights have been discussed, no list has been agreed at an EU level. What is certain is that the precise scope of Bolar in Europe will be a matter for some debate and no doubt litigation in the future.
Annette Cunningham
European Director - Intellectual Property
IVAX Pharmaceuticals UK
| Contributor Peter Wittner has been in the pharmaceutical industry for 30 years. He has worked for the former Evans Medical and then Norton Pharmaceuticals (now part of IVAX) where he was responsible for European Sales & Marketing. After leaving Norton Peter set up his own consultancy in 1993 and operated independently until 1996 when he joined the Indian company Ranbaxy to set up the infrastructure of their new st1:country-region w:st="on">UK subsidiary. For the last 7 years he has been a consultant in the field of generics. |
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If you would like to contact Peter to give feedback or enquire about Interpharm Consultancy, please email him at peter@wittner.freeserve.co.uk
Europe – The North-South Divide
In my first article for this newsletter, I included the following paragraph:
“The other reason for the particularly strong UK-India ties on product development was the fact that most other European countries, with the exceptions of Germany and the Netherlands, had no generic industry of any size. The reasons for this will form the subject of another article in a future edition.”
Well, this is the article that was promised for a later edition.
This divide does still exist, but market changes over the first few years of the new decade have eroded it considerably. There are therefore two issues to explore:
1. Why did the divide exist at all?
2. Why is it now beginning to disappear?
For many years the countries of northern Europe exercised a fairly free-market approach to pharmaceuticals and pharmaceutical pricing. The result was that countries like Germany and the UK had high-priced products and a reasonably productive pharmaceutical R&D arm. The Netherlands and Denmark were also fairly liberal in their approach to pricing, but the size of their populations limited their ability to support any intensive R&D activity.
This was important from the generic perspective as these high priced products gave the generic companies attractive targets to aim at after patent expiry. This issue of patent expiry is another of the factors that made the northern countries so attractive for generics. Product patents and their rigorous enforcement gave the owners of the brands time to build themselves a strong business with the brands, thereby offering generic copies a good sized market to attack when the time came.
Another important criterion was the freedom given to the pharmacist in those countries to negotiate the price with the generic supplier so that he could increase his own profit margins by buying cheaper. This led to vigorous competition between the suppliers to grab the pharmacist’s attention and obtain his business.
Contrast this with the situation in the southern countries. Admittedly, “southern” is a loose term in that it includes France, but since France also stretches to the Mediterranean, the word is accurate enough.
In these countries such as Belgium, France, Greece, Italy, Portugal and Spain, repeated state intervention in the pricing and reimbursement process resulted in countries that generally occupied the lower section of any international price comparisons for pharmaceuticals. In several of them, copy products were only allowed a price at least 10% or sometimes 20% below the original, which was itself relatively low-priced.
As a result, there was little incentive for companies to rush to introduce an unbranded generic after patent expiry. In addition, these patents did not even exist in certain of the countries that were late in introducing product patents so that what were effectively branded generic copies flooded the markets in places such as Italy and Spain. These devalued the original brand, further reducing its attractiveness as a target for generic copies.
Add to these factors a situation where prices were low and fixed so that there was no opportunity for the pharmacist to improve his margins and the result is an environment that is as unattractive as it possibly can be for a generic industry to develop.
It was this combination of circumstances that led to strong generic markets in Denmark, Germany, the Netherlands and the UK, and weak or non-existent markets in Belgium, France, Greece, Italy, Portugal and Spain.
The second question asked why this divide has started to disappear. Towards the end of the 1990’s everything started to change as the more socialist, southern states concluded that they had to do something to reduce their enormous healthcare costs and realised that perhaps generics were the answer.
However, two barriers existed at the professional level that could block governmental attempts to promote generics. Firstly, doctors had no incentive to prescribe generically and secondly, pharmacists had no incentive to dispense generically.
The methods used to resolve this at the physician level included reaching agreements to pay doctors a supplement per patient in return for writing more generic prescriptions and close monitoring of prescribing costs with threats to penalise those doctors whose costs rose above a national or regional average.
For pharmacists one particularly important measure was to change the method of reimbursement to ensure that pharmacists did not lose out by dispensing generics. In countries where the margin was a fixed percentage, the pharmacist inevitably has more interest in receiving x% of a high price than x% of a low price.
In addition, the right of substitution has become widespread in these countries so that even when a doctor does prescribe a brand, the pharmacist can chose to dispense a cheaper generic unless the doctor prohibits it on the prescription.
Although none of these countries yet has a generic market to rival those of the more mature generic countries, the measures have had some positive effect and markets are growing. In 2004 the market share of generics by units was 4.4% in Italy, 5.4% in France and 7.1% in Spain.
Clearly all of the developing generic markets are set for high growth rates as they try to catch up to the market penetration rates that already exist in the mature generic markets. There is still a long way to go – according to the UK’s Department of Health Statistical Bulletin for 2003, the level of generic prescribing there had reached the staggering level of 78%!
Peter Wittner
April 2005
www.interpharm-consultancy.co.uk
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EVENT WATCH APRIL - MAY 2005 |
Interphex Japan 2005
18-20 May, Tokyo: International pharmaceutical, costmetic and detergent R&D and manufacturing technology expo/conference. Asia's largest pharmaceutical event.
FCE Pharma 2005
17-19 May, Sao Paulo: Latin America's largest trade show for technology for the pharmaceutical industry. In 2004 more than 300 suppliers of raw material, packaging, equipment, machinery and services displayed their products.
EGA Symposium on Biogenerics
26-27 May, London: Topic - moving forward with biosimilar products in Europe.
Cosmo Amman
4-6 June, Amman: Middle East trade fair for cosmetics and pharmaceuticals; technology transfer, agents, distributors and raw materials.
CPhI China
14-16 June, Shanghai: Business meeting place for the leading Chinese and international pharmaceutical ingredient manufacturers and traders. Expecting 11,000+ attendees.
IGPA Conference
20-22 June, Malta: Market status: industry and regional perspectives, keys for competing successfully in Generics. Pre-conference seminars on the 19th.
EuroPLX 24
29-30 June, Amsterdam: Global bio/pharma industry partnering event. Proposed orientation of EuroPLX 24 is towards collaborative agreements in clinical and approved, patented drugs.
If there is a generics-relevant event of significance that we have missed, please email us and we will consider its inclusion in the next newsletter.
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Generic Company reports from Espicom Business Intelligence:
Provide an insight into each Generic company, reviewing its current business structure and activities.Recent quarterly and annual financial results for each company are illustrated with comparative figures, charts and a detailed review of the data allowing you to track the company's progress. Information is provided on the company's active product lines and ANDA approvals, along with a review of major developments, such as M&A activity, strategic alliances, and litigation. Companies covered include: Able Laboratories, Andrx, Dr Reddys, Ranbaxy, Sandoz, Stada Arzneimittel. For a full list of all Espicom’s Generic Company Reports, including a full list of the companies covered and up-to-date prices of each report, click HERE.
Biogenerics: An Emerging Global Market?
A strategic report from Espicom Business Intelligence published August 2004. There are big rewards for those companies who can overcome the regulatory, legal and technical obstacles related to biogenerics. That is why this critical new report is essential reading for everyone involved or interested in the sector.
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The GenericsWeb Patent Intelligence Newsletter is available in both HTML-format (text & images) and text-format. If you have any problems with the format, please let us know by emailing: info@genericsweb.com . If this information is not relevant or of interest, please accept our apologies.
Disclaimer: Please note that all information provided in this newsletter is considered accurate at the time of writing but is not guaranteed and may change over time. Opinions expressed in this newsletter are those of the authors and are not intended to represent legal or investment advice. Information should be verified for accuracy and advice should be sought from a suitable professional before acting upon any information contained herein. |
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