Product Profile: Picolinafen

Our previous product profiles, azoxystrobin and indoxacarb, demonstrated that a variety of strategies is required to defend a market from off-patent competition on expiry of the active substance (AS) patent. For azoxystrobin, mixture patents not only segment the market but also create a strong secondary patent portfolio and for indoxacarb, the move to the optically pure (S)- isomer and a novel manufacturing process makes market entry difficult for the off-patent manufacturer.

Here, we feature picolinafen a foliar herbicide for post-emergence use to control annual broadleaf weeds in winter/spring small grain cereals. It was discovered by Shell International Research which was acquired by American Cyanamid Co. and subsequently by BASF AG in 2000.


How will the four key market defense strategies be employed by BASF?

• Market segmentation
• Synthesis/technology/manufacturing know-how
• Registrations/data protection
• Intellectual Property Rights (IPR)

Picolinafen is a selective, post-emergence, aryloxypicolinamide or nicotinanilide herbicide for use on winter cereals, such as wheat, barley, oats, rye and triticale for control of meadow grasses and annual broad-leaved weeds including: poppies, field pansies, cleavers, fumitory, cranesbill, wild radish and hedge mustard.

Picolinafen is absorbed through the leaves and roots and works by inhibiting the activity of phytoene desaturase, an enzyme in the carotenoid biosynthesis pathway in susceptible plant species. This leads to a reduction of carotenoid pigments in the leaf chlorophyll and therefore disruption of photosynthesis. An indication that picolinafen is being effective is that weeds become bleached in appearance.

Picolinafen obtained its first registrations in 2001 in the UK, Germany and Australia. The herbicide was also launched first in 2001 in Australia, as the mixture with MCPA, Paragon, and in the UK as the mixture with pendimethalin, PicoPro (now superseded by Flight and PicoMax brands).

Cyanamid submitted an application in 1999 for picolinofen to the EU review system for New Active Substances and it was included on Annex I from Oct. 1 2002, therefore gaining data protection until Sept. 30, 2012. In November 2010, the EU extended the period of inclusion on Annex I until Dec. 31, 2015. When issuing this extension, it was noted that picolinafen is very toxic to aquatic organisms (algae, fish and aquatic plants) and must, therefore be used with mitigation measures to protect these organisms.

In Europe, picolinafen is currently registered in Belgium, Denmark, Estonia, France, Germany, Ireland, Italy, Latvia, Lithuania, Luxembourg and the UK and registration is in progress for Austria. Picolinafen is marketed in Europe by BASF mostly as a mixture with pendimethalin but is also sold as a single AS product, Pico.

BASF gained conditional approval for picolinafen in Canada in 2002, and in 2006, it was recommended for full approval but it is not yet marketed there.

In Australia, BASF licensed picolinafen to Nufarm in 2004, where it continues to be marketed as Paragon.

How New Market Entrants Can Compete

Clearly, picolinafen is an attractive target AS for off-patent companies, but how easy will it be for these companies to gain significant market share? To answer this we need to assess where the major barriers to market entry exist.

The EU recognized that a significant erosion in effective patent term existed for pharmaceuticals and this resulted in insufficient market exclusivity period to recoup the substantial R&D costs and as a result Supplementary Protection Certificates (SPCs) were introduced in 1992. SPCs give up to 5 years additional patent protection to the normal 20 year term and as a result of extensive lobbying by the agrochemical R&D sector SPCs became law for agrochemicals in 1996.

In the EU, picolinafen is protected by EP0447004 (and some national patents) which expires on March 12, 2011 and in Austria, Denmark, France, Germany and Italy SPCs have been granted which will only expire in 2016. In addition to these countries, picolinafen is registered in Belgium, Estonia, Ireland, Lithuania, Luxembourg, Latvia and United Kingdom but no SPCs have been granted and thus an opportunity to enter these markets after expiry of EP0447004 and National patents exists. This clearly demonstrates how complex the area of IPR surrounding an AS can be and why the generic manufacturer needs to analyze the full spectrum of IPR carefully.

Many patents to mixture products containing picolinafen have been filed but in practice only two mixture products appear to be of commercial interest:

1) European and national patents have been granted to a mixture of picolinafen and pendimethalin and SPCs have been granted in 6 countries extending protection to 2016, and in Germany until 2018.

2) A further mixture patent to picolinafen with flupyrsulfuron-methyl exists and has an associated SPC in the UK which doesn’t expire until 2017.

Picolinafen was included into Annex I on Oct. 1, 2002 and the data protection period expires 10 years after this date.

The timeline diagram shows the market exclusivity period in the EU for products based on single AS picolinafen. From the time-line it can be seen that the major EU markets will not be open to generic competition for a number of years, however, in other EU countries this will not be the case and generic competition is expected once data protection expires in 2012.

The generic sector will also have to consider other secondary patents, such as:
Crystalline form

The chemistry and technology involved in the manufacture of picolinafen is relatively straightforward and should be achievable by a number of generic and contract manufacturers. The availability of key intermediates is an important consideration when assessing how easy it is for generic companies to manufacture an active substance, in the case of picolinafen three intermediates are key to the manufacturing process:-

1 3-hydroxy benzotrifluoride – this is also used in the production of diflufenican which is manufactured by many generic companies

2 4-fluoroaniline – this is also used in the manufacturing of other ASs such as benthiavalicarb, bixafen and quinoxyfen.

3 6-chloro-picolinoyl chloride – this intermediate is not used in the synthesis of other agrochemicals and sourcing it may be a problem, alternatively generic manufacturers will need to manufacturer it in-house from the commercially available 6-hydroxypicolinic acid.

The potential market for picolinafen products has been estimated by EMR to be $70 million per year. Thus, whilst picolinafen has a relatively small market size and application area, opportunities exist for the generic manufacturer which is prepared to assess the IPR implications and establish a market presence in smaller markets in advance of the larger markets opening up.