Patented technologies for schistosomiasis control and prevention filed by Chinese applicants | Infectious Diseases of Poverty


Analysis of patents in three phases in schistosomiasis control

The patented technologies related to schistosomiasis control and prevention have gone through three stages. These phases corresponded with three phases in schistosomiasis control in China: the first stage (transmission control strategy through snail control, from the mid-1950s to the early 1980s), the second stage (morbidity control based on chemotherapy, from the mid-1980s to 2003), and the third stage (integrated control strategy with an emphasis on infection source control, 2004 onwards) [6, 28], with the implementation of patents for interventions on infection source control, transmission control or transmission interruption, and protection of susceptible population [29]. Only two patents were applied in the first stage in China, which is the same as other outputs, such as articles. There were application patents with 77 pieces during the second stage, 30 (39.0%) related to snail control, and 13 (16.9%) related to chemotherapy. It was expected to summarise the previous stage’s technologies, and thus there were significant patents that referred to snail control, the primary strategy in the first stage. During the third stage, the majority of patents (163) accompanied strategy under trial, which may become valid patents. All 184 valid patent applications were made after 2004. A total of 128 invention patents indicate more creativity with longer protective time than utility models. The number of patents has gradually increased. Through continuous research and development (R&D) and technological innovation, significant preliminary research results referring to genes, proteins, especially recombinant proteins, nucleotides, and pathways, with part of the primary research mentioned applied to multiple studies. Meanwhile, some devices used for experiments have become patents to promote basic research. The number of articles of schistosomiasis control strategy increased after 2004, with the same tendency for patents [30].

With the increasing number of imported schistosomiasis cases [31,32,33,34,35,36,37], there is currently a patented technology for producing a filter membrane for filtering S. haematobium eggs, and nine patents related to S. manosni and S. haematobium are under trial.

The technical field distribution from the analysis of IPC can also provide specific corroborative evidence to patent technologies. A study [24] found global patents for Schistosoma between 1985 and 2014. A similar application was also observed. The IPC classification of patents mainly concentrated around A61P33/12 (schistosomicides) and A61K39/00 (medicinal preparations containing antigens or antibodies). Patents on Schistosoma in China focused on A61P33, C12N15, and A61K31 after six years, of which A61P33/12 is the most common one. The technology subdomains are also pharmaceuticals and biotechnology.

It is necessary to carry out the patent layout for numerous invalid patented technologies for schistosomiasis control and prevention, especially the patent for which rights have been terminated without paying the annual fee (n = 214), with a high proportion of improper maintenance for a low commercial value [24]. We can explore technical points, actively pay attention to R&D trends, and seek technologies such as PCR and LAMP, etc., valuable detection and diagnosis technology points are patented.

Patents for infection source control

There are 13 patents for detecting S. japonicum infection, including pathogenic diagnosis, serological diagnosis, and molecular diagnosis. Only one valid patent referred to the traditional pathogenic method (faecal examination: detecting schistosome eggs in faeces of infected source), the Kato-Katz technique as the ‘golden method’ to judge whether Schistosoma is infected or not. However, the pathogen-detecting method is effort-intensive, mainly it requires faecal sample collection, a long diagnosis cycle, and low sensitivity (especially in areas where the overall endemicity has become low), the high false-negative rate of approximately 5.56–89.47% [38,39,40].

There are five kit patents related to serological diagnosis, and many more patents in basic research targeted this kind of diagnosis. Serological diagnosis using four methods, that is, indirect haemagglutination assay (IHA), ELISA, dye dipstick immunoassay (DDIA), dot immunogold filtration assay (DIGFA), have simple operation and high sensitivity, and have the advantages of increased compliance with the people in epidemic areas; however, they cannot distinguish current infections from past ones. Such tests proved unsatisfactory specificity and were not suitable for early diagnosis [41, 42]. Currently, there are eight test kits approved by the National Medical Products Administration, that is, DDIA (n = 1), IHA (n = 3), ELISA (n = 2), and IHA (n = 2).

Eight kit patents referred to molecular diagnostic techniques, such as LAMP, RAP, PCR, etc., which have proven significant because of their speed, high specificity, and sensitivity. However, there is no molecular detection kit approved by the National Medical Products Administration, as they are relatively expensive, require a controlled environment, and are likely to cause false positives because of contamination. Inventions described in most of these types of patents are still used for humans and one for livestock. However, domestic animals are also the primary source of infection, and relevant testing products are urgently needed.

Generally, the diagnostic options and related products are still few, especially kits for detecting schistosomiasis. A more efficient, convenient, and rapid kit is urgently required to facilitate a more sensitive and rapid diagnosis of schistosomiasis.

The intervention approaches also included chemotherapy for humans and livestock. The large-scale deployment of praziquantel to control schistosomiasis in China significantly reduced morbidity due to S. japonicum [43, 44]. To date, there are only four valid patents regarding praziquantel formulations and compounds. Three patents related to artemisinin and its derivatives (artemether and artesunate) could have anti-schistosomal properties [45]. Many patents about new chemotherapy are mainly associated with in vitro trials and effective herbal extracts for anti-schistosomsis; however, the National Medical Products Administration has approved praziquantel among 19 products as the only therapeutic drug. Giving a green passageway to speed up approval of the adaptation of older drugs artesunate and artemisinin for anti-schistosomiasis will aid in controlling schistosomiasis.

It is challenging to control livestock, an infectious source that plays a crucial role in schistosomiasis transmission, as a primary reservoir host [41]. Patented technologies for oral drug delivery devices for cattle and sheep have emerged. After control and prevention measures, infectivity in cattle has been basically controlled, but sheep have gradually shown increasing infectivity and have become the primary infection source. One reason is that sheep dung, which is scattered everywhere and is not easy to collect. The use of a patented sheep dung collection device has been promoted, and other patented technologies such as equipment for the harmless treatment of faeces, washroom pan, etc., have been used for faeces management. Finally, faecal matter with infected eggs is being prevented from contaminating water sources to cut off the transmission.

Patents for transmission control or transmission interruption

O. hupensis, the only intermediate host of S. japonicum, is not easy to control. The snail habitats in endemic regions are enormous, with approximately 3.6 billion m2 [9, 46, 47], a large majority located in the lake regions. With the restoration and protection of the ecological environment, many factors, such as temperature, rainfall, vegetation, and soil moisture, have also increased snail spreading. Thus, mass snail elimination campaigns have been developed for schistosomiasis control [41]. There are many patented technologies for snail management, and it is essential to apply scientific and technological strategies, such as a drainage system, and armamentarium for O. hupensis, and molluscicides to control snails. Patented snail control technologies that have low toxicity and are environmentally friendly [48], and effective snail surveys also have market application prospects.

One of the other primary strategies for snail control is chemotherapy. Niclosamide, the only approved molluscicide, is the most widely used in China [49], and has six patents, including patents for powder formulations, suspension concentrate formulations, and spreading oil formulations. Several new chemical compounds have been developed for snail control. Metaldehyde has excellent molluscicidal effects against O. hupensis and has low toxicity [44]. Calcium cyanamide (CaCN2) is not only a molluscicide but also can be used to kill S. japonicum eggs. It also acts as a nitrogen fertiliser and is both economical and environment-friendly. At present, further investigation is required for broader applications in the field. Several molluscicides and schistosomicides from herb extracts have been developed for patenting, which could potentially be safer. The government has been recommended to increase investment and provide supportive policy innovation services to promote effective herbal extracts.

Patents for susceptible population protection

The development of the patented schistosomiasis vaccine is an adjuvant measure of strategic significance; it protects the susceptible population and helps in the integrated control of schistosomiasis. WHO Special Programme for Research and Training in Tropical Diseases (TDR) has placed the development of schistosomiasis vaccines at the forefront of research on the control and prevention of schistosomiasis. Currently, the schistosomiasis vaccine is mainly used in animals. More clinical trials for determining safety and efficacy in humans are required [50, 51].

Limitations

This study has several limitations. First, patent retrieval is a complicated process, and it is challenging to identify targeted patents in online Chinese patent databases completely. Second, patent databases have drawbacks in terms of data collection. As databases have different retrieval standards, although the exact keywords were used, the results have significant differences. It is likely that this introduced some personal bias, as the system cannot automatically and accurately filter data.



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