Grass Pollen Allergens
Allergic rhinitis is a common disorder worldwide, with a significant impact on the quality of life. It may also increase the risk of comorbidities such as asthma1Radulovic et al., Systematic reviews of sublingual immunotherapy (SLIT), Allergy, 2011, Vol 66: pp740–52. For patients with severe allergies, who may not respond well to usual therapeutic approaches such as intranasal corticosteroid sprays and oral or topical antihistamines, immunotherapy is a viable option.
Immunotherapy for allergic rhinitis involves repeated administration of high doses of allergen, such as grass pollen, with the aim of inducing clinical and immunological tolerance in the recipient. Immunotherapy formulations contain an extract of one or more species of grass pollen and are administered either as a course of subcutaneous injections or as daily sublingual drops or dissolving tablets. Regulatory standards require that immunotherapeutics be standardised for allergenic potency using techniques such as enzyme-linked immunoassay (ELISA), which requires antibodies specific for the relevant allergen. Such antibodies can also be used to measure environmental levels of allergens.2Benitez et al., Determination of allergenic load and pollen count of Cupressus arizonica pollen by flow cytometry using Cup a1 polyclonal antibody, Cytometry B Clin Cytom., 2013, Vol. 86: pp63–9
This report provides an overview of technology relating to pollen allergens in general, with a particular focus on immunoassays and diagnostics, through the lens of intellectual property (IP). It uses the scale and intensity of patent activity to provide an overview of innovation in the area.
Scale of Patent Activity
We identified 274 unique INPADOC patent families relating to pollen allergens, using a combination of classification marks and keywords in PATSTAT. The timeframe for the analysis in this report is applications with a priority date after 1 January 1995 until 31 of December 2014. This is in order to concentrate on contemporary technology and also to reflect the fact that the majority of patents will expire 21 years from their earliest priority date. Figure 1 shows these patent families by priority year.
Although we did not identify a large number of patent families, the number of families has generally been steady since the late 1990s. A high percentage of families have at least one in-force patent (91 per cent, data not shown) which suggests each family has value to the applicant. The drop in patent families in 2013 and 2014 is due to publication lag of applications.
Figure 1: Patent families by priority year
Figure 2 shows the top applicants in pollen allergens based on number of patent families. Three of the top four applicants, ALK Abello, Biomay and Stallergenes, are companies that specialise in the development of allergy immunotherapy products. ALK Abello is a Danish company that launched the world’s first sublingual tablet-based vaccine, GRAZAX®, in Europe in 2006. GRAZAX® (known as GRASTEK is the United States and Canada) is indicated for treatment of grass pollen-induced rhinitis, specifically Timothy grass pollen allergy. Biomay’s product portfolio includes recombinant grass pollen antigen vaccines comprised of wild-type allergens, peptide-carrier fusion proteins or hypoallergenic vaccines, as well as RNA vaccines for allergy prophylaxis. Stallergenes, recently merged with Greer laboratories to create Stallergenes Greer, is headquartered in London (UK). In 2014 they gained FDA approval for ORALAIR®, a sublingual allergy immunotherapy tablet containing extracts from five grass types— Sweet Vernal, Orchard, Perennial Rye, Timothy and Kentucky Blue grass.
Figure 2: Top Applicants
Figure 3 shows the number of patent families originating from each country worldwide, based on applicant address. The most families have been filed by US entities, although US entities do not feature in any of the top individual filers. European countries Denmark Austria, Germany, and Spain all feature strongly (represented by ALK Abello, Biomay AG, Merck Group and Phadia AB). Australia is the equal 12th filer with Belgium and China. Japan rates highly in terms of number of families filed, which is consistent with Japanese tendency to file multiple applications in parallel.
Figure 3: Applicant origin
Figure 4 shows a breakdown of the technology categories. Each patent family was assigned a broad technology category based on classification marks (a detailed schema can be found in Appendix C).
Figure 4: Technology Categories
The major category was Immunoassays, which represent methods of making immunoassays, methods of using immunoassays to detect allergens or to detect antibodies in patients, as well as assaying the efficacy of anti-allergic vaccines or drugs. Medicinal Compounds represent drugs specifically used to treat pollen allergies. Polypeptides covers allergen proteins, as well as antigenic fragments (usually containing the dominant T-cell epitope) and mutated versions. The Vaccine category includes not only differing types of vaccines, but also differing compositions relating to the methods of delivery e.g. subcutaneous vs sublingual. Although broadly relating to therapeutics, Antibodies include patent families specific to the production/standardisation of antibodies. The final category, Nucleic Acids, includes patents to nucleic acids encoding allergens and those with immunomodulatory properties. Whilst the top individual category was Immunoassays, patents relating to therapeutic approaches (Medicinal Compounds, Polypeptides and Nucleic Acids - in purple in Figure 4) made up the majority of the technologies (61 per cent).
Sub-classification of Immunoassays and Antibodies technologies
Figure 5 shows a breakdown of patents relating to Immunoassays and Antibodies (in blue in Figure 4), which are the two categories directly related to diagnostic and measurement technologies in the field. This breakdown includes 105 patent families, and each patent family within Immunoassays and Antibodies was manually assigned to one of the following subcategories based on the title and abstract of a representative patent application from the family:
Figure 5: Technological subcategories within the immunoassay and antibody fields
Description of sub-categories
- Allergen - new pollen allergens that include immunoassays relating to development of antibodies or immunoassays to said allergens
- Modified Allergen - inventions for modifying pollen allergens to make them more suitable for vaccination
- Diagnostic - biomarkers or assays for prognosis/monitoring of allergies
- Measurement - analysis of pollen/allergens
- Antibody - production/standardisation of antibodies
- Preparation - preparation of pollen allergens/vaccines
In order to look at target markets of the technologies directed to pollen allergies, we can look at the countries where applicants elected to enter national phase. As shown in Figure 6, the highest number of filings are in the US and Japan. Australia is third, with similar numbers of applications to Canada and China. This shows relative strength of the Australian market in this field. The results in individual European countries represent member state patents which are generated when a European application is granted.
Figure 6: Worldwide patent application coverage
Figure 7 shows the major applicants with in-force applications (pending and granted) in Australia. Merck, ALK Abello, and Biomay and Circassia make up the largest rights holders. This indicates that these major players believe Australia to be an important market. Of the other major applicants, Selecta Biosciences features prominently. They have a platform technology using nanoparticles to co-present antigens and immunotherapeutic molecules to specific immune cells. Allergy is an area that is being targeted. Dynavax has both agonists and inhibitors of Toll-like receptors (TLRs) to modulating immune responses. TLRs are an important class of receptors that cells use to recognise foreign bodies including pollen allergens.
Figure 7: Applicants with Australian applications in force
This patent analytics study set out to encompass not only pollen allergen vaccines, but also immunoassay technologies (according to the IPC marks usually associated with antibodies and immunoassays) that were related to pollen allergens. However, only a small number of the applications returned by the search related to immunoassay technology.
Despite a low number of patent families located overall, the majority of the families still had at least one in-force member (Figure 1) indicating the commercial relevance of the work that is undertaken in the field.
Even within those technologies with the relevant IPC mark for immunoassays or antibodies, the majority of the patent families were directed to either wild type or modified allergens. The presence of an immunoassay or antibody classification in those cases was presumably a secondary indexing. This is perhaps not surprising given the ubiquity of antibody-based techniques in molecular biology.
The fact that only seven patent families could be identified pertaining directly to antibodies, and 17 pertaining to immunoassay-mediated measurement, suggests that there has not been a significant amount of research relating to pollen immunoassay techniques in general over the past 20 years. This may be due to the fact that standard techniques for generation of antibodies are well established. Furthermore, in the patenting area, it is generally considered that the disclosure of a new antigen makes it obvious to generate antibodies3Trilateral Project 24.1 Comparative Study on Biotechnology Patent Practices (USPTO, EPO, JPO) see top of p23 (and therefore makes them generally unpatentable in their own right).
Analysis of patent family data on different pollen species gives an indication on which species are considered the most commercially relevant, including Birch, Poaceae, Ryegrass, Timothy grass and Japanese cedar. Monash University has a patent family relating to Bermuda grass antigens. The low numbers of forward citations on pollen antigens indicates that once an allergen has been cloned, this does not generate a significant amount of follow-on patenting activity for that allergen.
Although the US has the greatest share of parent families, the most significant applicants are European. Merck, Alk Abello and Biomay appear consistently as the top applicants across each of the technology classification, and also appear among the holders of the largest patent families. This is consistent with the fact that these companies have active product portfolios in the field of pollen allergen immunotherapy.
In summary, the patent landscape of pollen allergens is concentrated around pollen vaccines in commercial development.
Glossary of Terms
The Patent Cooperation Treaty (PCT) is a mechanism that allows a single patent application to be used as a basis for filing later applications around the world. Each PCT application receives an international (WO) publication and a preliminary examination report. The PCT entered into force in 1978 and WO publications have been issued since 1980.
PCT applications are a useful metric for inventive activity because in general there will be one PCT application for one invention, regardless of how many later applications may be filed around the world to cover that invention.
PCT applications are also considered to represent valuable inventions in the sense that their applicants intend to obtain patent protection overseas.
To assist patent searching and examination, patents are classified into technical categories. This study uses the International Patent Classification (IPC) and the Cooperative Patent Classification (CPC). The CPC has been developed jointly by the US and European patent offices and combines both offices’ systems into a single classification. Each published patent application is assigned one or more CPC marks representing which technical fields to which it relates.
Methods and databases
The data set for analysis was obtained by searching the EPO PATSTAT database (Spring 2015 edition) for all PCT applications that contained the IPC or CPC mark A61K39/36, which encompasses medicinal preparations (i.e. vaccines) relating to pollen allergens, C07K 16/-, a mark for immunoglobulins in general, and G01N 33/53 (and sub-marks), with the keyword pollen in the title or abstract. We identified 274 PCT applications. 44 patent families were removed as they did not contain inventions related to pollen allergens based on their titles and abstracts. CPC marks (alphanumeric codes) were replaced with descriptive text in all figures.
The technology breakdown was as follows: