Product observation: SDHI fungicide Fluopyram’s compound patent expiring in China

Fluopyram is an SDHI fungicide which is discovered, developed and produced by Bayer. Since its market release in 2012, Bayer has made its effort on the market development, with the participation of several companies including BASF. Within three years of market launch, the product has grown into a fungicidal product variety exceeding sale of US$100 million. In 2023, Fluopyram’s compound patent is expiring in many countries and regions around the world, among which the compound patent protection in China has expired after August 7, 2023. As an excellent fungicide and nematicide, it is a very noteworthy and attractive product.

01
Development and action mode of SDHI Inhibitors

In recent years, SDHI fungicide has become a sparkling and overwhelming product variety, which has gradually risen out of the niche product varieties, reaching the top three among the fungicidal product family. Along with triazole and strobilurins, the three product varieties form a ″three-in-hand″ product portfolio which are the major driver to the boomed development of fungicides.

At present, more than 20 SDHI fungicides have been launched to the global market, at total sales of US$2.3 billion in 2021. Among the sales, there are six products exceeding the sale of US$100 million, namely fluxapyroxad, benzovindiflupyr, boscalid, bixafen, fluopyram and sedaxane. According to IHS Markit forecast, the sales of SDHI fungicides are going to break through US$3 billion in 2025.

Fluopyram, like other SDHI fungicides, is a respiratory inhibitor on pathogenic bacteria. By binding to the respiratory electron transport chain complex II, the succinic acid in the tricarboxylic acid cycle is catalyzed to become a fumaric acid, which inhibits the activity of mitochondrial succinodehydrogenase to obstruct the tricarboxylic acid cycle, causing deficiency of amino acid and sugar, thus obstructing the synthesis of ATP which is the energy source of pathogenic bacteria, thus  interfering with cell division and growth, which lead to the death of bacteria. Although the action mode of Fluopyram is similar to the same kind of fungicides, studies show that there is no cross resistance with boscalid and carboxin in respect of some of the mutant genotypes of pathogenic bacteria like powdery mildew and gray mold in some melon species. This is attributable to the unique flexible activity chain of Fluopyram, which can break through the inherent binding mode with succinodehydrogenase, thus effectively reducing the risk of cross resistance with similar products.

02
Product characteristics and application development

Fluopyram is a broad-spectrum systemic fungicide with protective and curative functions, with a wide range of applications. It can be used for foliar treatment and seed treatment, as well as for soil conditioning. When used as a fungicide, it can effectively control gray mold, powdery mildew, sclerotinia, brown rot and sigatoka across 70-plus crops covering grapes, potatoes, nuts, vegetables and field crops. In addition to control of fungal diseases in crops, Fluopyram has been developed by Bayer into an excellent nematicide, which is applied to economic crops such as tomatoes, cucumbers and bananas for control of root knot nematodes, root rot nematodes and rotting stem nematodes.

Fluopyram, when used alone or in combination with other fungicides, has an excellent efficacy at low doses. With its excellent physicochemical property, various formulations have been developed, such as SC, SE, EC and seed treatment agent. Fluopyram is also used as a resistance management tool, which is a key component of Bayer’s fungicide Luna family, as being mixed and used in Bayer’s Luna series of formulations including prothioconazole (Luna^®Pro), trifloxystrobin (Luna^®Sensation) and tebuconazole (Luna^®Experience). The series of formulations have greatly enhanced Bayer’s fungicide market position and enabled Bayer’s fungicides to become a new top fungicidal brand in the high-end fungicide market. Furthermore, Fluopyram is mixed with imidacloprid as a soil treatment agent, which is an extended application of the distinctive functions of Bayer’s nematicides.

Table 1   Summary of Fluopyram Mixtures

03
Global market development

In 2012, the global sales of Fluopyram hit US$13 million, which thereafter rose quickly up to US$145 million in 2014. In the following years, its growth fluctuated but generally increased. In 2021, its global sales reached US$189 million, arriving at a compound annual growth rate of 35% from 2012 to 2021. Within 10 years of market release, it jumped to become a global leading fungicide in a short period of time. Bayer predicted that the annual peak sale of Fluopyram would reach EUR200 million, which is going to be achieved soon.

Figure 1   2012-2021 Fluopyram Global Sales Growth
     Global sale (US$ million)

Source: IHS Markit

Up to date, Fluopyram has been registered and launched in more than 60 countries and regions worldwide. From a global perspective, France and the United States are important markets of Fluopyram. In 2021, its sales in France and the United States were respectively US$21.53 million and US$19.03 million, accounting for 11.4% and 10.0% of the global sales respectively, followed by Japan at US$13.7 million accounting for 7.3% and Germany at US$12.2 million accounting for 6.5%.

Fluopyram is mainly for application to grapes, grains, potatoes and rapeseed. In 2021, its sales for application to grapes were US$26.14 million accounting for 13.8% of global sales, followed by grains at US$22.71 million accounting for 12.0%, potatoes at US$15.56 million accounting for 8.2% and rapeseed at US$15.53 million accounting for 8.2%.

Fluopyram is a dominant product on the French grape market, ranking the second in the fungicide product variety applied in France, second only to prothioconazole; in the United States, Fluopyram ranks on the top 5 fungicides for application to grapes and potatoes while ranking first for application to cotton; In Japan, Fluopyram ranks second for application to grains, sugar beets and potatoes among the fungicide varieties; in Germany, Fluopyram ranks among the top 3 fungicides, second only to mancozeb and mandipropamid.

04
Registrations in China

The first registration in China was granted on November 5th, 2012: Fluopyram 96% technical and Fluopyram 41.7% formulation, in the trade name of 路富达^®.

Registrations to date are as follows:

Up to date, there have been one Fluopyram technical registration and 10 Fluopyram formulation registrations in China, involving two single agents and five mixtures.

Fluopyram: Both single agents are nematicides of Bayer, being used for control of root knot nematodes in watermelon, cucumber, tomato and banana. Common nematicides include fosthiazate and carbofuran, which are somewhat harmful to crops and the environment, whilst Fluopyram has a high activity against nematodes, being long lasting in soil, safe for humans and the environment.

Fluopyram.copper quinolate: Registered by Qingdao Audis Biotechnology Co., Ltd, with two active ingredients of different action mode. The mixture has an extended spectrum of control, which not only controls various higher fungal diseases, but are also functioning against oomycete and bacterial diseases, such as the cucumber target leaf spot.

Fluopyram.trifloxystrobin: Registered by Bayer, the mixture is of the action mode of both pyridyl ethyl benzamides and strobilurins, being protective and curative to some extent. The mixture can prevent and control various fungal diseases including peach brown rot, tomato gray mold, cowpea anthracnose, potato early blight, strawberry gray mold, lychee anthracnose, grape gray mold, bitter melon powdery mildew, grape white rot, cucumber target leaf spot, watermelon stem blight and tomato leaf mold.

Fluopyram.pyrimethanil: Registered by Bayer, the mixture is of high activity, good systemicity, long-lasting effect, being used for control of various fungal diseases such as cucumber anthracnose, cucumber target leaf spot, tomato leaf mold, banana scab, apple tree alternaria leaf spot, citrus resin, pear tree black spot, tomato early blight, citrus black spot and watermelon stem blight.

Fluopyram.pyraclostrobin: There are three registrations at different content level – the highest content is registered by BrightMart: The Fluopyram 25% + pyraclostrobin 25% SC for control of grape gray mold；the Fluopyram 15% + pyraclostrobin 15% SC registered by Hailir for control of cucmber target leaf spot; the Fluopyram 10% + pyraclostrobin 20% registered by Zhongxun for control of cucumber powdery mildew. This mixture is of dual action mode, which has a broader fungicidal spectrum.

05
Patent authorizations

In 2003, Bayer Crop Science filed for Fluopyram’s compound patent, including PCT patent, European patent, US patent and the Chinese patent.

PCT patent: WO2004016088, filed on August 8, 2003, expiring on August 7, 2023.
European patent: EP1531673, filed on August 8, 2003, expiring on August 7, 2023.
US Patent: US7572818, filed on August 8, 2003, expiring on August 8, 2023.
Chinese patent: CN1319946C (ZL03819471.6), filed on August 8, 2003, expiring on August 7, 2023; The invention name is Novel 2-pyridyl ethyl benzamide derivative.

Although the compound patent expires this month, Fluopyram is still protected by multiple types of patents, covering mixed ingredients which are still valid from 2025 to 2031. The mixes include trifloxystrobin, azoxystrobin, fluoxastrobin and picoxystrobin. In addition, Bayer owns the patent protection for the use of Fluopyram as nematicide, which will not expire until April 11, 2028.

06
Conclusion

Fluopyram is a multi-purpose compound, which can be used as a fungicide, nematicide, seed treatment agent, preservative agent and resistance management tool. Its multiple functions include: 1) Excellent plant compatibility, especially its xylem delivery capability; 2) Unique flexible chain structure which enables stable control and less occurrence of resistance; 3) Good adaptation to formulation which can improve the appearance and nutritional quality of fruits via application of the rich product mixes, while prolonging the shelf life of fruits and vegetables.

Bayer has developed a lot of Fluopyram mixture brands to meet the differentiated demand from different market segments. Judging from the market deployment in recent years, nematode control may be Bayer’s key field of development, for example the Verango Prime^® launched for use in soybean, sugarcane, potato and coffee crops in the Brazilian market, or the recent launch of Baixianwei in the Chinese market for tomato, cucumber, ginger, watermelon and banana crops. The writer holds the view that this will be an important driver to the growth of Fluopyram in its post-patent time.

References:

1.Veloukas T, Karaoglanidis GS. Biological activity of the succinate dehydrogenase inhibitor fluopyram against Botrytis cinerea and fungal baseline sensitivity. Pest Manag Sci. 2012 Jan.

2.Schleker ASS, Rist M, Geibel S. Mode of action of fluopyram in plant-parasitic nematodes. Sci Rep. 2022 July.

3.Mekonnen TF, Panne U, Koch M. New Photodegradation Products of the Fungicide Fluopyram: Structural Elucidation and Mechanism Identification. Molecules. 2018 Nov.