First generic drug development strategy in the United States

Compared with ordinary generic drugs, the development time of the first generic drug in the United States is relatively long, and the investment cost is relatively high. However, considering the huge return of the 180 day market monopoly period, many enterprises are still willing to join the fierce competition for the first generic drug.

Pre-project investigation

To develop a first generic drug in the United States, we must first make full preparations for information research, and then discuss whether to carry out project research in the light of the company's own conditions. The pre-project research involves drug laws and regulations information, drug registration information, clinical information, market analysis, patent evaluation and experimental technology considerations. Patent evaluation is one of the most important links. Take the original research drug Fingolimod hydrochloride (Fingolimod Hydrochloric, trade name Gilenya) capsule listed by Novartis (Novartis) in September 2010 as an example. In 2011, there was only one patent related to Gilenya in the orange peel book, that is, the US5604229 that expired on February 18, 2019. In addition, the orange peel book also records the NCE market exclusive period of the drug, with the expiration date of September 21, 2015. After calculation, if the first generic drug is declared, the expiration date of the 30-month containment period of the lawsuit is March 21, 2018, which is earlier than the expiration date of the '229 patent, so PIV declaration can be considered for the patent at that time. Since the '229 patent is a compound patent, it cannot be circumvented and can only choose Strategy 1. After that, professional lawyers in the United States will analyze the validity of the patent and whether there are controversial issues in order to strive for the possibility of the first generic drug.

In addition, in the evaluation, in addition to the orange book patent, developers also need to consider and analyze other patents that are not authorized in advance. Still taking Fingolimod as an example, in 2011, the crystal patents and preparation patents related to Fingolimod hydrochloride were in the examination stage, while the treatment method patents, although authorized, have not yet been included in the orange peel book, and these patents will become obstacles to the future product launch. After discussion, the technicians believe that there is a certain possibility to develop new crystal forms and new preparations of fingolimod hydrochloride, and circumvention strategies can be considered to deal with patents that have not yet been included in the orange peel book.

(2) Strategy adjustment and technical improvement

As the patent review process progresses, generic drug companies can often make strategic changes that are beneficial to them. For example, fingolimod hydrochloride, whose hydrochloride crystal form was not finally authorized by the U.S. Patent Office, considering the development cost, generic drug companies can completely abandon the development of new crystal forms and directly follow the crystal form of the original drug company to reduce the risk of "bioequivalence test" in the later stage. However, the preparation patent US8324283 Novartis by the original drug research enterprise was finally authorized and included in the orange peel book. The expiration date of the patent in the United States is March 29, 2026, which is far later than the expiration date of 30 months. As the strategy of avoiding patents has been considered in the early stage, as long as a new prescription can be successfully developed, PIV declaration can be made when ANDA declares, and because it is the argument of non-infringement, there will be a greater advantage in patent litigation.

(3) Determination of patent declaration

After all the research and development work is completed, the patent strategy is basically formed. Generally, two time points will be considered, one is the date of submission of the first generic drug, and the other is the expiration date of patent containment. The patent before the ANDA filing date directly refers to the PII statement. For patents between the filing date and the expiration date of the containment period, the PIII declaration may be considered. For those patents that expire later than the containment period, for crystal forms and preparation patents, if they have been successfully circumvented, a PIV non-infringement declaration can be submitted according to the independently developed crystal forms or prescriptions, and if they have not been successfully circumvented, but there is a possibility of invalidity, a PIV invalidity declaration can be made. For treatment method patents, in addition to the aforementioned methods, you can also submit a "Litter viii Statement", commonly known as the small eight statements, that is, the declared drug will not be used for the treatment of the indications contained in the patent, which can also effectively circumvent the original drug research enterprise's patent. However, if there are only eight small statements in the patent statement submitted with ANDA, the 180-day exclusive period cannot be awarded, and the PIV statement must also be included. In addition, it should be noted that when the small eight statements are made, the relevant information corresponding to the indications in the drug instructions should be deleted together.

To sum up, for the first generic drug in the United States, the patent strategy runs through the project, and must be closely combined with the U.S. patent link system and the project development process to continuously adjust, in order to submit the most perfect patent statement when submitting ANDA materials to FDA, and create the largest winning space for later patent litigation.

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