Product Profile: Indoxacarb

Editor’s note: Throughout 2011, Nigel Uttley will examine barriers to entry and market opportunities for key active substances with upcoming patent expirations. Learn how research companies marketed their discoveries and where new business can be found.

Our previous product profile, azoxystrobin, demonstrated how a variety of strategies will help defend the market from off-patent competition once the active substance (AS) patent expires. In particular to azoxystrobin, mixture patents not only segment the market but also create a strong secondary patent portfolio making market entry difficult for the off-patent manufacturer.

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Although the opportunities for mixture products for insecticides are not as great, DuPont‘s process and formulation technology for its indoxacarb products could protect some markets from competition when indoxacarb’s patent expires this year.

Four defense strategies allow inventor companies to protect a molecule after a patent expires:
• Market segmentation
• Synthesis/technology/manufacturing know-how
• Registrations — data protection
• Intellectual Property Rights (IPR)

First reported in 1996, indoxacarb was the result of research by DuPont in the US into the oxadiazine class of chemicals during the late 1980s. It was developed by DuPont as an insecticide for the control of lepidopteran pests, initially on cotton and certain fruits and vegetables. But use rapidly expanded to cover a wide variety of crops, including pome fruit, grapes, top fruit, brassicas, tomatoes, cucurbits, leafy vegetables, corn, soybeans, peanuts, alfalfa, sorghum and turf. It was also developed for non-agricultural usage against cockroaches and ants.

Indoxacarb is especially active in the adult and larval stages of many insect pests, including cabbage armyworms, beet armyworms, bollworms, budworms, cabbage loopers, common cutworms, corn earworms and hairy caterpillars. It is ingested into the stomach, is metabolized and blocks the sodium channels in the insect’s nervous system. The US EPA designated it to be a “reduced risk” pesticide and considered it an organophosphate replacement due to its low acute and chronic toxicity and safer handling. Indoxacarb also has gained favour in the market as it has a complementary profile to other insecticides and has no adverse impact on beneficial insects, so it can be used in integrated pest management programs.

Indoxacarb was first commercialized in 2000 by DuPont under the trade names Avaunt and Steward. These products contained indoxacarb technical, which was a 3:1 mixture of 2 optical isomers: the S-form (this is actually indoxacarb, also known as DPX-KN128) which has the insecticidal activity, and the R-form (DPX-KN127). In 2006, DuPont started to manufacture the optically pure S-form and introduced this in its marketed products.

In 2000 and 2001, DuPont launched indoxacarb in several countries, including the US, Brazil, India, Pakistan, South Africa, Mali, Australia, Austria, Germany, Benin, Burkina Faso, Togo and Japan, where it was licensed to Kumiai and launched as Tornado.

The indoxacarb market expanded in 2004 with the launch of the fire ant bait, Advion, in 2007 with the launch of Provaunt for turf and ornamentals and in 2009 with its approval in the EU as a biocide.

By 2011, indoxacarb had become a commercially successful insecticide marketed in more than 50 countries worldwide with sales of $100 million to $150 million globally, depending on pest outbreaks in any given year.

Additional Patent Protections

Clearly, indoxacarb will be a target AS for off-patent companies, but how easy will it be for these companies to gain market share? To answer this we determine where the major barriers to 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.

Countries offering Supplementary Protection Certificates to DuPont
Country Date of SPC Expiry
France  Jan. 26, 2015 
UK  Jan. 26, 2015  
Germany  Jan. 27, 2015  
Greece  Jan. 27, 2015  
Italy  Jan. 27, 2015  
Spain  Dec. 21, 2015 

In the EU, indoxacarb is protected by EP0565574 (and some national patents) which expires on Dec. 17. However, some EU countries have been granted SPCs that will expire in 2015 (see Table).

The EU dossier for indoxacarb was declared complete in 1998, and the first approval in Switzerland was granted in 2000. But it wasn’t until 2006 that indoxacarb gained Annex I inclusion. Thus the ten years of data protection started in 2006 and will only expire in 2016. Subsequently, extended patent rights and data protection have provided an impressive 52 months of market exclusivity over and above the expiry of EP0565574.

The timeline diagram shows the market exclusivity period in the EU for products based on single AS indoxacarb. Major EU markets will not be open to generic competition for a number of years. However, generic competition is expected soon in other countries.

In the US, indoxacarb is protected by US5462938 which is due to expire on Oct. 30, 2012. The initial registration of indoxacarb in the US was Oct. 30, 2000 and certain studies were granted a ten year exclusive use period. Subsequently, DuPont was granted an additional three years of data protection for 25 minor-use crops. Expiry of patent protection in many other countries is expected at the end of 2011.

Unlike azoxystrobin, indoxacarb is not currently mixed with other actives and thus segmentation of the market and added IPR protection of mixtures. However, the generic sector will have to consider other secondary patents, such as:
• Crystalline form
• Formulations
• Processes
• Intermediates
• Chiral resolution

Chiral resolution may hold the key to DuPont’s ability to protect market share. The structure shown is the S-form.

Originally, registered products were a 75:25 mixture of optical isomers DPX-KN128 (the S-form) and DPX-KN127, but only DPX-KN128 has insecticidal activity. The common name, indoxacarb, refers to the active isomer, DPX-KN128. In 2006, DuPont announced that a new chiral version of indoxacarb was to be introduced, with 25 percent lower manufacturing costs and DuPont is now moving registrations to the S-form only. Off-patent companies will not only have to produce indoxacarb cost effectively but will also have to consider any secondary process patents that may be in force.

In the last two to three years, many patents to mixtures of indoxacarb with other insecticides have been filed, particularly by Chinese research institutes, in addition to patents filed by Shanghai DuPont Agriculture covering:
• Agricultural composition containing indoxacarb and abamectin and application thereof.
• Agricultural composition containing indoxacarb and imidacloprid and application thereof.

A further post-patent defense strategy has seen DuPont sign commercial agreements with companies, for example in 2004, DuPont and Rallis entered a co-marketing deal in India whereby both companies would market indoxacarb supplied by DuPont as Daksh.

Several companies in India and China claim to manufacture indoxacarb, and it will be interesting to see what percentage of the market they can gain in the next 10 years.