Implementation

Introduction

On this page, you will find the proposed implementation of our project XPCures. We defined the complete drug development process (Fig.1). After the iGEM competition concludes and optimization is completed, XPCures will go through IP protection and pre-clinical trials, then it will face two options: to conduct clinical trials followed by a market entry application, or to apply for Investigator-Initiated Trials (IIT) to provide treatment to patients on a non-profit basis. Here, we provide a detailed explanation of how to implement each step of the process in China, along with the necessary requirements that must be fulfilled.

Fig.1 Proposed implementation
Intellectual property

During our meeting with Dr. Na Li from Ethics Committee of West China Hospital, Sichuan University, she strongly recommended us to apply for a patent first. A patent grants our exclusive rights to our invention, meaning others cannot commercially produce, use, sell, or distribute this gene therapy without our permission. This protects our intellectual property and innovation for a specified period (usually 20 years). Besides, patents are often seen as assets that enhance the value of our technology. Investors, pharmaceutical companies, or collaborators may be more willing to support and fund our research and development if the technology is patent-protected. In China, projects that meet the following criteria are eligible to apply for an invention patent:

In China, it usually takes 2-3 years to obtain an invention patent, and the intellectual property protection lasts for 20 years.The simplified timeline of a Chinese patent application is shown in Fig.2. The necessary steps to take are shown below:

  1. Pre-filing Preparation:
    • Conduct a Patent Search: Before filing, it's recommended to conduct a search to ensure your invention is novel and not already patented. This can be done via the China National Intellectual Property Administration (CNIPA) website or other patent databases.
    • Prepare Application Materials: This includes drafting the patent specification, claims, abstract, and any necessary drawings. It's important to clearly describe the invention, its technical problem, and solution.
      • The patent specification should include technical field, Background Art, Summary of the Invention, Brief Description of the Drawings, Detailed Description.
      • The claims should specify the technical features of the invention and define the scope of protection sought clearly and concisely.
      • The abstract should state the name of the invention and the technical field to which it belongs. It should clearly reflect the technical problem to be solved, the key points of the technical solution to address that problem, and the main application of the invention.
  2. Filing the Patent Application:
    • Choose the Type of Patent: an invention patent (for technical solutions).
    • Submit the Application to CNIPA: We need to file the patent application with the CNIPA (China National Intellectual Property Administration). The application must include the patent specification, claims, abstract, and any necessary drawings.
    • Electronic or Paper Filing: Applications can be submitted electronically through CNIPA’s system or in hard copy.
  3. Formal Examination:
    • After submission, CNIPA will conduct a formal examination to ensure the application meets the required formalities.
  4. Publication of the Application:
    • For invention patents, the application is published after 18 months from the filing date or priority date. This allows the public to see the details of the invention but does not grant rights yet.
  5. Substantive Examination:
    • Request for Substantive Examination: After publication, the applicant must request substantive examination within three years from the filing date. CNIPA will then assess whether the invention meets the criteria for novelty, inventiveness, and practical applicability.
    • Examination Process: CNIPA patent examiners will review the application in detail and may issue office actions if additional information or modifications are needed. The applicant has the opportunity to respond and make amendments.
  6. Patent Grant:
    • If the substantive examination is passed (for invention patents) or if formal examination is completed (for utility model or design patents), CNIPA will issue a Notice of Grant.
    • The applicant must then pay the grant fee and the first-year annual fee within the prescribed time to receive the patent certificate.
Fig.2 Patent application timeline. Simplified timeline of the Chinese patent application of XPCures for the first patent. The figure is adjusted from https://cponline.cnipa.gov.cn/
Pre-clinical trials

while obtaining an invention patent, XPCures should move to pre-clinical phase. There are multiple trials need to be done to demonstrate that XPCures is safe and efficient.

Overview of Pre-clinical trials

  1. Vitro studies: Assess the drug's safety and efficacy through in vitro (lab) studies.
  2. Animal trials: Assess the drug's safety and efficacy through in vivo (animal) experiments.
    • Safety Validation Experiments:
      • Acute Toxicity Experiment: Assess immediate toxic reactions after a single administration of the dual AAV system carrying the gene therapy. Determine the maximum tolerated dose (MTD) of the vector system.
      • Subchronic and Chronic Toxicity Experiments: Assess the long-term toxicity of repeated administration of the system.
      • Immunogenicity Experiment: Assess whether the system induces an immune response in the animal.
      • Assessing whether UV light triggers tumor formation prior to inducing XPC expression.
    • Efficiency Validation Experiments:
      • Gene Expression and Function Validation: Validate that the delivery system successfully delivers and expresses the therapeutic genes in epidermal stem cells.
      • UV Protection Efficacy: Test the effectiveness of the UVR8 system in protecting cells from UV damage by triggering XPC expression to repair DNA.
      • Determining the safe and effective UV exposure intensity range.

Required permission

  1. Animal trials:
    • The experiment must be reviewed and approved by the Animal Ethics Committee (AEC). This committee ensures that the proposed experiment complies with ethical standards and safeguards animal welfare. The approval process involves submitting detailed documentation, including the experimental protocol, animal welfare measures, and justification for the use of animals in the research.
    • The institution conducting the animal experiment must hold a valid Animal Use License issued by the local or national Science and Technology Department.
Clinical trials

Once the preclinical trials are completed as required, we need to decide which direction to pursue next. If our goal is to generate profit through XPCures, then our next step is to apply for conducting clinical trials.

Overview of clinical trials

Clinical trials are designed to assess the safety, efficacy, and quality of new drugs or treatments before they can be approved for public use.

Required permission

  1. Clinical trials
    • IND Approval from the NMPA: We must submit an Investigational New Drug (IND) application to the National Medical Products Administration (NMPA). The IND application includes preclinical study data, manufacturing details, and the proposed clinical trial plan. The NMPA will review the application to ensure the drug’s safety and readiness for clinical trials. China has implemented several special policies to encourage the development of orphan drugs, which are used to treat rare diseases. The review and approval time for clinical trials of these drugs and treatments has been shortened to 30 working days. Hopefully, XPCures will be one of them in the near future. Besides, considering that XP is a rare disease, there may not be enough subjects to support the completion of Phase III clinical trials. Therefore, we may need to apply for an international multicenter clinical trial. The simplified timeline of a Chinese IND application is shown in Fig.3.
    • Ethics Committee Approval: The clinical trial protocol must be reviewed and approved by an Ethics Committee (EC). This committee ensures that the study complies with ethical standards, protects the rights and welfare of participants, and follows international guidelines like the Declaration of Helsinki. The approval involves submitting detailed documents, including the clinical trial protocol, informed consent forms, and participant recruitment procedures.
    • Clinical Trial Registration: Once the trial is approved, it must be registered with the Chinese Clinical Trial Registry (ChiCTR) or another recognized international registry. This ensures transparency and allows public and regulatory access to the clinical trial information.
Fig.3 The timeline of a Chinese IND application
Investigator-Initiated Trial

After completing the pre-clinical trials, another choice is to apply for an investigator-initiated clinical trials (IIT) to provide treatment to patients on a non-profit basis. The experimental process of IIT is similar to that of pharmaceutical company-initiated trials, but the aim is to advance clinical research or explore new treatment options rather than directly bringing the drug to market.

In China, there is no need to submit the IIT directly to the National Medical Products Administration (NMPA) for approval, as IITs are considered non-commercial trials. The researcher initiates the trial with the hospital or institution where the trial will be conducted, it will be reviewed by the clinical research center and approved by the ethics committee before conducting. The simplified timeline of a Chinese IIT application is shown in Figure 4.

In China, applying for IIT generally requires meeting the following conditions:

Fig.4 The timeline of a Chinese IIT application
Market authorization

After accomplishing Phase III Clinical Trial, we can Submit a New Drug Application(NDA) to the National Medical Products Administration (NMPA). The timeline of market authorization in China is shown in Figure 5.

The New Drug Application (NDA) process in China involves several key steps:

Fig.5 The timeline of Market Authorization in China