Supporting Entrepreneurship

Overview

Here we describe our effort to build a business case and create a sustainable company from our iGEM project.
This project aims to help patients discover their allergies as early as possible. We would therefore create a company, the “DAISY Laboratory”, specializing in the detection of Immunoglobulins E, responsible for allergies. To create a company, we needed to first identify the needs and customers (see Implementation). We then focused on the strengths and weaknesses of both our team and the project. The next effort was about the scalability and dimensioning of the laboratory destined to run the DAISY method. We then engaged in a business plan and finally, we examined the long-term impacts of the project.



Thanks to the help of Le Catalyseur, a start-up pre-incubator, but also of the iGEM Thessaloniki team, we proceeded to the evaluation of our team’s entrepreneurial skills, as well as the Strengths, Weaknesses, Opportunities, and Threats analysis of our project.


Skills report

Before building a business, it is first necessary to know our resources, strengths and opportunities and to perform a fine analysis of our weaknesses and threats. The goal is to build a strong bedrock to grow our company and to decide about the actions to prevent risks. For this purpose, we have analyzed our potential to know our main needs about the future of our innovative company.

The first tool we used is an evaluation sheet completed by the whole team to point out our expertise in each domain specific to business management. This evaluation allows us to identify the skills of the team. Each point was evaluated with a scale of criticality to know which task would be delegated or not. The evaluation concerns 6 domains of entrepreneurial skills:

  • Selling: to promote our allergic tests and derivative products to health professionals, especially allergists.

  • Marketing: to valorize our product to make it well-known and stand out from the competition.

  • Financial management: to master financial resources to ensure a healthy economic growth of the company.

  • Management: to organize and manage the team in an efficient way.

  • Soft skills: to sum up our abilities to work and tointeract with other people.

  • Human resources: to manage the diversity of professional profiles and ensure that the needed skills are present in the company.

The results of our self-assessment questionnaire can be found on Table 1. You can click on the picture to extend it.

Table 1. Team evaluation of entrepreneurial skills Analysis of our skills in the 6 domains of entrepreneurship Table 1

A remarkable information to be pointed out after this evaluation is that the Financial management, the Human management and the Marketing are well mastered by respectively our Financial leader Thomas, our Organization leader Laure and our Communication leader Charline. These tasks do not need to be delegated. Furthermore, the majority of our team are confident in their ability to work on an entrepreneurial challenge. Our team performs well in mastering soft skills and creativity allowing us to make a good starting alchemy to grow our company.

The results show weaknesses in the Selling competence. Since it constitutes a major and critical weakness, we will delegate these skills. The second critical weakness is Human resources management but it will not be delegated in the short run, because we consider that we need a close team to work efficiently. A Human resources department will need to be created only according to the growth of the company. Moreover, a start-up is the place to learn a lot of things in a short time, so competence investigation is a good point to permit each of us to progress. This self-assessment questionnaire should be updated every year as a way to track our progress.



SWOT analysis

Next, we performed a SWOT analysis (Figure 1) to evaluate the relevance and feasibility of our start-up project which will offer a new detection method of allergies. This helped us to have a clear vision of internal or external factors allowing the success of our business. This work has been done with the help of Le Catalyseur and also of our partners iGEM Thessaloniki.

Figure 1. SWOT analysis Analysis of our strengths, weaknesses, opportunities and threats

We have internal strengths and weaknesses:

Our innovative technology of high throughput allergy detection (see Design part) can bring a response to the increasing number of allergic people. We can also consider the perspective of offering a therapeutic strategy using desensitization medicine by administration of allergens produced by our strains, as well as using the versatility of our method in other developments. Therefore, like each creation process in the medical sector, this needs a lot of development time, effort and investments. For that, being part of the iGEM competition and being supported by French institutional laboratories such as TWB, TBI and CBI is a great opportunity to have visibility to find financial support for the development process (see Supporting Entrepreneurship).

Our idea has to be patented when aggregation will be proved, to protect our idea and then to grow peacefully. The second difficulty that we can meet is the creation of a company, which requires a lot more competence than testing our idea on our school’s lab with the existent support around it. This is a stop and go step, so before creating a company everything has to be prepared, to give us competences, and find new people able to build a lot of things with us for our adventure.

We also need to overcome barriers such as to be better than the current allergic tests and break cliches about GMOs (while our products develop in the respect of laws about GMOs in France and Europe). Finally we can consider diversifying our therapeutic solution to other pathologies requiring antibodies detection.



The laboratory organization

Because we want to take further the DAISY project, we have to think about its scale-up. Even if the central activity of the DAISY company is to detect IgE in the patient’s blood at an industrial scale, the company needs several departments to be thriving. Indeed, the industry cannot be efficient without a performant logistic team to provide the blood sample and the whole company cannot have any activity at all without experts in marketing to bring clients. We, therefore, imagine how our future firm would be organized to be productive and sustainable.

Research & Development

The R&D center is the cradle of the firm’s innovations. It will be the first team to be created in 2023. In fact, as an iGEM team, we already created the R&D center. At first, it will be an undivided team and then, as the company grows, different departments will emerge to focus on the different axes of innovations like desensitization, detection, or antibody production. In 2032, we expect to have our own laboratory with a screening platform, a FACS, and a culture platform. We will therefore need research and technical engineers, technicians, searchers, and PhDs to constitute this efficient team able to discover the next DAISY innovative products and services. Our R&D center will need to be aware of every scientific progress in the allergies field and keep tight connections with other laboratories.

Blood analysis

This department is the basis of our firm and will be created in 2029. It will analyze the blood sample sent by medical laboratories on the prescription of the allergist and produce the results to send back to the allergist. The main analysis activity will be to test the affinity of the patient’s IgE for every allergen by a large screening. Microdroplets are perfectly adapted to this kind of screening and will be the main expertise of this department. It will therefore be composed of technicians and engineers trained to run, maintain, and analyze the results of a microfluidic platform. This department will preferentially interact with the logistic center which will provide the blood sample and receive the analysis results.

Logistic

The logistic department is crucial for the company as it will manage the supplies of all the other departments. That includes the blood samples for the analysis department and all the necessary materials that use the DAISY method, such as culture media, buffers, and plastics. It will also provide the R&D department with the material it needs and manage the delivery of blood analysis results. Two logisticians and one production manager will assure these logistics. This team will be tightly connected to every department of the firm. They will also be in charge of contact with external medical laboratories sending samples and with the allergists receiving the test results. This department will be created in 2032.

Medicine production

The medicine production department represents the major perspective of the DAISY project. As our company aims to help people with allergies to have a better life, it is essential to provide them with efficient and custom-made medicine to desensitize them to allergens. Medicine production is highly controlled and requires specific infrastructures so it will not be the first active department of our company. Still, we will start some research on this subject in 2029.

Marketing and communication

Business goes hand in hand with sales and so, with marketing and communication. This is why we expect to create the marketing department as soon as 2029. This department aims to create a custom base and communication on our new method of IgE detection. As DAISY will implant a breakthrough method in the market of allergy diagnosis, experts in communication are essential to explain to our potential customers all the advantages we have to offer. The marketers will have to be well connected to the R&D department, the blood analysis, and medicine production departments to be aware of what the company offers.

Health and legal

The competitiveness of a company is closely linked to its ability to stand out from competitors. As we are designing an innovative method to detect IgE, it is important for us to keep the exclusivity on it so we keep our added value on the market. Since the microfluidic technology that we are using is patented, we will need to discuss with the owners of the patent and its use with a commercial goal. Furthermore, we use a synthetic protein to aggregate our bacteria in the presence of IgE: a DARPin. This protein is protected by a patent so we need to be careful not to transgress the associated laws. Last but not least, exposing all of our designs and results on this wiki means that all these contents are open and cannot be protected. Fortunately (or not), our first attempts to obtain aggregation have failed, meaning that new improvements are necessary, and these could be protected. Our health and legal department will be really useful to advise the company on their doings and created in 2026. It will be composed of a specialist in intellectual property and a lawyer.

Human resources

We plan to expand quite rapidly over the next decade. This will require hiring a lot of people to help us in the ambitious project that is DAISY. Some Human Resources managers will be in charge of selecting the best profile to hire new collaborators from 2029. This department will make links between the inside and outside of the company to spot the missing skills in our teams that could be brought by hiring.



Dimensioning

To implement our firm into the real world and picture ourselves in the future, we decided to imagine 3D plans of our future laboratory. This exercise was the occasion to become aware of what is required in a firm and particularly in a Research&Development department. We thought of every department needed for the development of a company and organized them in the space.
Therefore we present in the following section what the DAISY laboratory would like in 2042 (Figure 2).

Figure 2 Figure 2: Global 2D view of the DAISY laboratory in 2042.

The DAISY laboratory will be composed by of 3 buildings welcoming every department precedently described:

  • • Building 1: the Blood analysis department and the Logistics department.
  • • Building 2: the front desk, the departments of Marketing, Communication, Human Resources, and Health and Legal.
  • • Building 3: the Research&Development department and the Medicine department.
  • • In the center, we want to integrate a green space to keep a healthy work environment for our employees.

We will detail the R&D department through 3D plans since it is the first department that we plan to create. We deeply thank Mathias Enjalbert who was able to make our own 2D draft plans into realistic 3D plans!

You can find below a visit of our future DAISY laboratory in 3D (Video 1):

Video 1: Visit of our future DAISY Laboratory in 3D


You can click on the following pictures to extend it.



Thanks to this work, we have a clear vision of our goals for our future DAISY company.




The DAISY timeline

To reach the presented business model and operating model, we established the DAISY timeline (Figure 11) that you can read below. We took inspiration from the ANSM (National Agency of Medicines and drugs Safety in France) rules and the timeline of Aimmune Therapeutics, a Nestlé Health and Science company working on allergies desensitization (History | Aimmune, 2022). As we want to explore various perspectives of our project, we also imagined the journey of the firm to commercialize desensitization medicines in 20 years, and the topics of our R&D department. Because we want to help as many people as possible, we planned to expand the DAISY team.

Figure 11 Figure 11: The DAISY timeline and the growth of the DAISY team


The business model

The business model canvas is a very useful tool that provides a global view of a company's value proposition, its relationship with its customers and the expenses and revenues generated by its activities. In our business model canvas built with the help of Le Catalyseur and iGEM Thessaloniki, our value proposition is mainly based on allergen-specific IgE screening. Our startup will also offer recombinant protein production services based on its expertise, and allergy statistics that will be useful to health monitoring organizations and the allergy industry. In the longer term, it will also offer desensitization tools.

Figure 12 Figure 12: The DAISY business model canva

This value proposition is made possible by our Human Resources, who have unparalleled expertise in IgE detection. Some of our employees are also dedicated to research and development, in order to develop ever more sensitive, specific and comprehensive tests. Prospecting laboratories and hospitals is also an important activity that allows us to get known by the medical profession. Finally, our startup will be able to play an advisory role for manufacturers thanks to the know-how and statistical data provided by its employees, in order to improve the quality of treatments offered to patients.

These diversified activities require partners in the medical profession such as allergists, who will be the middlemen between our startup and the allergic patients. The production of recombinant proteins may also be carried out by subcontractors when we have well-defined protocols and specifications. At the same time, we will make our equipment and expertise available to allergy research laboratories in order to develop fruitful collaborations in the search for new allergens. Finally, it is important to obtain the support and approval of key opinion leaders in the allergy field, in order to establish our reputation in the market and to offer relevant services. Scientific societies will also be invited to take part in the startup's scientific advisory board, bringing their experience and advanced understanding of current issues in the diagnosis and treatment of allergies.

Our services must also be known to the general public through our website and our presence on social networks. Likewise, participation in medical congresses is a way to make ourselves known to health professionals. They are the link with our target clientele, especially hospitals and medical laboratories. Finally, research laboratories are part of our clientele by buying allergens and recombinant antibodies, either by direct sale or via local distributors.

Thus, our revenues are generated by our diagnostic tests, the production of recombinant proteins and patients' desensitization. However, there is a cost to maintain these activities, including expensive equipment for blood sample analysis and outsourcing the diagnostic test manufacturing. The most expensive area is Human Resources, to pay for competent and experienced technical or researchers, commercial, legal and administrative staff. Finally, our laboratory will also generate expenses related to its energy consumption and to the exploitation of other patents (such as the use of DARPins for example).

The goal of a business is to be profitable, so revenues must exceed costs to generate profit. The profits generated by the startup will also be an indicator for future investors that our project is viable and worth investing in.



Intellectual Property

Intellectual property is an important area for protecting a startup from competition. It is a real part of the company's resources and takes the form of copyrights, trademarks and patents. The patent confers a monopoly on what it covers and allows the commercialization of an invention. A license can be granted to other companies to exploit all or part of the patent in a defined field. Thus, intellectual property has both legal and economic value.

To fill a patent, the inventor(s) must fill a patent pending to both disclose and protect an invention. An invention is a technical solution to a technical problem.
It can be a process, a product, a composition of matter or an improvement of an older invention. In our case, we want to solve the problem of allergy diagnosis through a system of allergen-specific IgE detection using bacterial strains. A patent also includes "claims" that define the subject matter of the invention, its technical characteristics and the legal limits of what will be protected. These claims may vary depending on the legislation of the country in which the patent is filed.

Our case with the DAISY company

Our patent can be filed with the Institut National de la Propriété Industrielle (INPI) in France, where the patent will be national. This is the equivalent of the United States Patent and Trademark Office (USPTO) in the USA. We can also file it at the European Patent Office (EPO) in Europe if we want to cover the European territory (in 38 countries), or internationally (in 148 countries) through the World Intellectual Property Organization (WIPO). All these offices have a website where the patents filed can be consulted.

Searching for competing patents ensures that we are not marketing a process or product that is already covered by another patent. Our search revealed one patent in particular, entitled "Methods for allergy diagnosis," which uses DARPin E2_79 to detect allergen-specific IgE. The inventor of this patent is Thomas P. Cirrito, and the owner is Immunovent, LLC, based in New York, NY (US). This patent has been filed in several countries and therefore has several publication numbers:

  • - US 20180011108 (A1) in the United States;
  • - WO2016118713 (A1) internationally.

This led us to wonder if our technical solution fell under this patent. We therefore contacted an intellectual property firm. Marianne Lefèvre, from ADAMANTE, provided us with valuable help in our competitive watch. She helped us to use the espacenet.com website to search for existing patents. We had access to the history of the Immunovent LLC's application for a European patent. This allowed us to see how much the claims of a patent can change depending on the country's regulations, since the number of claims has been considerably reduced compared to the US patent, and has still not been published. Among the "claims" that have been withdrawn in the European version of the patent is the taking of biological samples from the human body. In France, living matter is not patentable. The inventor's patent can only cover the work done in the laboratory, without patenting the method of obtaining the biological sample.

Thus, we have seen that the European application was subject to several revisions because of claims that were not compatible with local regulations. Moreover, the international version of the patent (WO) presents claims that do not completely cover our technical solution. In fact, the patent mentions that the method consists in determining “local presence and levels of specific allergy markers, i.e., IgE with specificity to a known allergen, at the site of allergic symptoms and inflammation (e.g., in the mouth, nose, sinus, esophagus) from a mucosal brush biopsy cell sample”. This sampling method differs from the blood sampling we perform to capture allergen-specific IgE. In addition, the results analysis of their method mentions an analysis by "fluorescence-based assay (e.g., ELISA) or by microarray". This also differs from our method, which uses microscopy or Fluorescence Activated Cell Sorting (FACS), among others.

Finally, the DARPin E2_79 sequence mentioned in the patent is used in soluble form, as is or with an N-terminal His-tag. This sequence differs from our protein sequence, which consists of an Lpp-OmpA-E2_79-His-tag fusion expressed on the bacterial surface. The His-tag is therefore C-terminal in our construct, and DARPin is fused to a membrane protein.
This analysis of this competing patent allowed us to rule out the possibility of having to pay a license fee to Immunovent.

However, not every invention can be patented, and must meet certain criteria. For example, the invention must be new, inventive and useful. Our bibliographic research revealed that no method for detecting allergen-specific IgE has been performed using surface display as we have done, to our knowledge. It will also be useful to society, so the criterion of usefulness will normally be fulfilled. The inventiveness criterion remains: the invention must not be obvious to a skilled person of the art. We believe that this criterion can also be met, because of the thinking behind the design of our bacterial strains and the analysis of the results, which differs greatly from the classical methods of analysis by ELISA or microarray.

Once our proof of concept is validated, it will be possible to apply for a patent at the INPI. Indeed, we will first file the patent at the national level in France, then at the European level and finally worldwide. Our interview with the intellectual property firm ADAMANTE and our research on the INPI website led us to a budget of about 8,000 € to file our patent and pay the administrative fees until its publication. This patent will be exploitable for 20 years, and will be considered as an immaterial asset of our startup.

In the iGEM competition, applying for a patent for the method we describe in the wiki is no longer possible due to the disclosure of the project details. However, it is possible to patent an improvement of an invention, and we have thought of many possible improvements that leave us the possibility to protect and commercialize our method. On the other hand, publishing the results of our project can also be a way to protect ourselves from our competitors. Indeed, everything that is in the public domain is no longer patentable, so our technique cannot be patented by other people or companies. This gives us time to develop a solid proof of concept and interesting improvements thanks to our expertise in the field of IgE antibody detection.

Regulation of diagnostic tools and drug treatments

We cannot discuss intellectual property without mentioning the regulation of diagnostic tools and drug treatments. Indeed, several regulatory bodies are responsible for evaluating the safety and efficacy of drugs and diagnostic products. In France, this is primarily the National Agency for the Safety of Medicines and Health Products (ANSM). In the United States, it is the Food and Drug Administration (FDA).
The FDA provides a precise definition of in vitro diagnostic products. “In vitro diagnostic products are those reagents, instruments, and systems intended for use in diagnosis of disease or other conditions, including a determination of the state of health, in order to cure, mitigate, treat, or prevent disease or its sequelae. Such products are intended for use in the collection, preparation, and examination of specimens taken from the human body.” They are subject to pre-market and post-market controls, and are classified according to the individual and collective risk incurred by the use of these products. As the steps involved in bringing diagnostic products to market vary by country and are often complex, we will briefly summarize the results of our research (Figure 13).

Figure 12 Figure 13: Overview of the process of in vitro diagnostic (IVD) test development for clinical use (Taryma-Leśniak et al., 2020)

Regulations affect the development of diagnostic products, but also laboratory practices and the equipment used. In the United States, for example, the performance of diagnostic tests in the laboratory must follow the Clinical Laboratory Improvement Amendments of 1988 (CLIA '88). In Europe, the devices used for performing diagnostic tests must comply with Regulation (EU) 2017/746 (IVDR). Indeed, we cannot use the same devices for diagnosing patients and conducting research; there are many criteria for inter-test reliability and preservation of patient medical data to consider.

Manufacture

From the point of view of the manufacturing of the bacterial strains for our diagnostic method, the production line must be perfectly monitored and controlled, especially because we plan to subcontract them when the DAISY test will be performed on a large scale. Indeed, the DAISY project will focus more on the research and development aspect as well as on the use of the finished diagnostic product on blood samples. Quality management systems (QMS) and very precise documentation are in place to meet ISO standards for the production of biological materials (ISO 13485: 2003 in Europe or CFR21 part 820 in the US).

Regarding our bacterial strains, we know that not all strains can be used in diagnosis. In our proof of concept, we used an E. coli BL21(DE3) strain. Recent advances in synthetic biology have made it possible to develop bacterial strains that can be used in diagnosis and therapy. For example, Daeffler et al. used a commensal strain of E. coli Nissle 1917 to detect thiosulfate and tetrathionate in intestinal inflammation in mice. This strain is also used in several clinical trials, including for the treatment of allergies such as rhinoconjunctivitis (NCT01013259). Many other bacterial strains are also being studied for diagnostic and therapeutic purposes, including cancer.

We plan to use non-pathogenic or even probiotic strains in order to reduce their immunogenicity, which can affect the results of our diagnostic tests, but also to have a better control of biological risks. To meet these regulatory requirements, synthetic auxotrophy systems and sequencing of our bacterial strains already constitute a barrier to accidental contamination of the environment with genetically modified strains. Sequencing allows us to ensure that the selection pressure applied to our strains does not lead them to lose their IgE antibody detection function or their auxotrophy.

After studying the opportunities and challenges to the commercialization of our diagnostic method, we also looked at the regulations regarding the commercialization of desensitization products.

Desensitization products commercialization

In our project, we envisioned oral desensitization to deliver allergens to the gut and stimulate the production of tolerogenic signals. These desensitization products are considered as drugs and are subject to very strict regulations regarding their safety and efficacy. The ANSM in France and the FDA in the US define a precise process for drug development, from fundamental research to clinical trials.

In France, desensitization products must be prescribed by a physician. We distinguish two categories of drugs for desensitization (allergen immunotherapy). First, medications containing allergen extracts sold in pharmacies are subject to a marketing authorization in France, or to FDA approval in the US. There are also Allergens Specially Prepared for Individuals (APSI), which are formulations prepared specifically for a patient and do not require marketing authorization. Stallergenes and ALK are two dominant companies in the ASPI market. Their products are often used as case studies on the effectiveness of ASPIs.

ASPIs are prescribed by physicians and prepared from products already authorized by the ANSM. This is why they are not subject to a marketing authorization. The authorization is issued for a renewable period of five years.
Thus, if we were to propose desensitization treatments for patients using ASPI, we would be able to formulate our own allergen preparations from the list authorized by the regulatory bodies. This knowledge of the regulations is very important for our startup's business model as it allows us to desensitize patients without waiting for a marketing authorization, which can take 10 to 15 years and a significant capital investment. However, ASPIs are mainly used for the treatment of allergic rhinitis and asthma, and not for high-risk allergies for the patient.

It is also important to know that the production of allergenic extracts is highly standardized and that we must respect these production rules when developing new treatments. Indeed, our research and development division may develop new allergenic polypeptides that have not yet been authorized by the ANSM, and knowledge of the law in this respect will enable us to market new proprietary molecules.

Desensitization products marketed without being adapted to each individual must be submitted for marketing authorization. This authorization is issued following the results of phase III clinical trials on these products. This drug development process is much longer but allows for larger-scale production of the same product without having to customize it for each patient. Like ASPIs, these drugs can be covered by health insurance if it covers expenses related to allergy treatment. This is a decisive argument since it considerably reduces the price paid by patients, and has consequences on the business plan of our startup. Indeed, we do not know at the moment if our diagnostic tests will be covered by social security in France or abroad. It is therefore important to be able to offer solutions that are accessible to all populations, regardless of their standard of living.

In conclusion, all of our research and discussions with intellectual property experts have enabled us to better understand the complex regulations governing patents and the development of diagnostic tools and drugs.



Sustainability of our infrastructure

Figure 14 Figure 14: Sustainable Development Goal n°9. Industry, innovation and infrastructure

We want our company to grow as described previously in our prospective timeline (Figure 11). However, we believe this growth can only be achieved in a sustainable way, pursuing the Goal 9 of the Sustainable Development Goals of the United Nations (Figure 14). We want our infrastructure to be resilient. The building should correspond to the criteria of sustainable construction, i.e. respecting the ecology at each stage of the construction and of the use.
The building could be autonomous in energy by using solar panels on the roof of the building. The solar panels will be installed by a local company and the overproduced electricity can be sold, which is an income for the company. For example, according to a company from Occitanie district, 200 m² of solar panels can bring up to 5.000 € a year (Solaire Occitanie, 2022).
The isolation of the building will also be a main concern, as a proper isolation can reduce the energy consumption up to 27% (Gourin, 2021).

We also should think of the discharge of the waste. We will try to limit the production of waste as much as possible. In the lab, the plastic consumption will be limited as much as possible and the use of glass materials will be preferred whenever possible. The sorting of waste will be strictly applied according to the national standards and local instructions in force.
As our company will generate microbiological waste, it is also important to take care of these wastes properly. In France, biological risk is mainly governed by the French Labour Code, and in particular by Decree No. 94-352 of May 4, 1994, the amended Order of July 18, 1994 establishing the list of pathogenic agents, and the Order of August 13, 1996 establishing the technical preventive measures, and in particular the containment measures, to be implemented in the context of this risk.
Every employee will receive proper training regarding these issues. Indeed, we want our company mindset to be as eco-friendly as possible, to always try to take decisions in line with environmental issues, not only for our infrastructure as described, but also in everyday life. We want to limit the use of single-use plastic in every way possible, and in particular by promoting the use of reusable glassware in experiments. Limiting our carbon emissions will also be one of our priorities: by not offering plastic cups at coffee machines, by promoting clean travel to work, by limiting our trips abroad that require air travel, by limiting our energy consumption for heating and air conditioning ... We will make sure that we always question ourselves in order to research and train ourselves on the most ecological ways of functioning as a company. See more in our Sustainability section.


References

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