Some Thoughts On Patents In The Approval Of Generic Drugs

In the establishment of a generic drug project, in addition to the clinical, market, technical and registration strategy evaluation of the generic drug, there is another core template — patent evaluation, which is also a topic of great concern to everyone. For example, which patents are involved in generic drugs, how to ensure that the patent search is complete during the project approval process, and can learn about its patent status in China as soon as possible, and whether it constitutes an infringement of other people’s patents, etc. Today, let’s talk about the issues related to patents involved in the establishment of generic drug projects.

Regarding the patent issues involved in the process of domestic generic drug project approval, we first clarify the following three points, and then sort out the types of patents that may be involved in the project approval one by one. It should be added that the patents mentioned in this article refer to Chinese patents.

1. my country has not yet established a link system for drug patents and drug registration review, but developed countries such as Europe and the United States have established one. Or understand it this way, our country has not yet extended the patent for medicines, and the protection period is 20 years from the date of application.

2. The protection scope of the patent shall be subject to the claims of the authorized patent text, but any application such as “invention patent application shall be deemed withdrawn after publication”, “invention patent application shall be rejected after publication”, “patent right termination” or Patents are all invalid, and these applications or patents will not have a substantial impact on the development of generic drugs.

3. The legal status of patents is a dynamic process, and it is necessary to update the legal status of patents related to generic drugs in China at any time. For example, after a period of time, the legal status of a patent application that is in the “validation of substantive examination” may change to “deemed to be withdrawn after the publication of the invention patent application”, “rejected after the publication of the invention patent application”, or even “Authorization”. In addition, it is also necessary to follow up the situation of PCT patents in China that are subsequently applied by original research companies or generic drug companies.

After clarifying the above three points, we need to clarify what are the patents related to drugs. Generally speaking, the types of patents involved in pharmaceuticals include patents on compounds, preparation processes, preparation compositions, drug combinations (compound preparations), crystal forms, uses, and preparation of intermediates. Drugs are protected from multiple dimensions through the above-mentioned different types of patents. In the process of project approval, it is necessary to focus on sorting out the above different types of patents one by one.

For a drug approved for marketing in the United States, we can first understand the patents that have been included in the Orange Book of the US FDA, and find the corresponding Chinese patent family and their legal status for each patent that has been included in the Orange Book. In this way, we have a preliminary understanding of the patent situation of the generic drug in China. Then, with the help of professional databases such as Scifinder, systematic literature search is carried out, and then the patents related to the generic drug are classified and analyzed one by one according to the patent type.

Part 1 Compound Patent

First, the structural formula of the compound in the specification approved by the US FDA or EMA should be confirmed. To be precise, it is necessary to confirm whether the original product on the market is an anhydrate, a hydrate or a solvate. In the case of hydrates or solvates, the specific conditions of water molecules or solvent molecules should be confirmed.

Usually, the original research company first applies for the patent of the general formula compound, and then applies for the patent of the specific compound. The compound patents we often refer to generally refer to specific compound patents. If both the general formula compound and the specific compound patent are granted, the expiration time of the compound patent shall be calculated based on the specific compound patent. For example, the compound patent (A patent) that the original research company first applied for was authorized, and the monohydrate patent (B patent) that was applied for 2 years later was also authorized. After investigation, it was found that the original product on the market was a monohydrate, and the object of the imitation was also a monohydrate. At this time, the expiration time of the compound patent was calculated as the B patent.

It is worth mentioning that compound patents often disclose the specific synthesis method, formulation composition, and use of the compound (that is, commonly referred to as indications). The information disclosed in compound patents cannot be ignored and is of great significance. Often, compound patents cannot be circumvented.

Part 2 Use Patent

Usually, a drug is used to treat only one disease. However, multidrug use is not uncommon (for example, sildenafil, originally used to treat erectile dysfunction in men, was later developed for pulmonary hypertension). If the generic drug has multiple indications, it is first necessary to clarify which target indication is being developed when establishing a project.

Unless the original research company or other companies develop new uses, in most cases the indications disclosed by the compound patents are often the indications that the original research company first or focused on developing. To determine the expiration date of a use patent, it is first necessary to identify the target indication for development and then confirm whether the indication has been disclosed in the compound patent. If yes, the expiry time of the utility patent shall be calculated according to the compound patent. If not, use patents related to the target indication should be retrieved and used as the date of expiration of the use patents. In general, indication patents cannot be circumvented.

Part 3 Crystal Form Patent

When establishing a project, it is necessary to pay attention to whether there are polymorphs in the generic drug. In addition to original research companies, many generic drug companies will rush to apply for patents if they find that the generic drug has a new crystal form or a new preparation method that already has a crystal form during the research and development process. The more crystal form patents involved in generic drugs, the more we will be disturbed. However, it can be sorted out through the following ideas.

Since we are talking about the approval of generic drugs, we must first confirm whether there are polymorphs in the generic drugs. If it exists, it is first necessary to confirm the crystal form of the original product on the market through various means. After confirming the crystal form of the original product on the market, find a patent that is consistent with the crystal form of the original product on the market, and use this to determine the expiration time of the crystal form patent.

In fact, many times what we are confused about is not when the crystal form patent will expire, but what kind of crystal form the original research product is on the market. During the development of generic drugs, although the crystal form of the generic drug is not clearly required to be exactly the same as that of the original drug, it is necessary to ensure that the generic drug is bioequivalent to the original drug. Under the premise of adhering to this principle, the crystal form patent of the original research company can be effectively avoided.

Part 4 Preparation Process Patent

It is very common that a compound can be obtained by multiple synthetic methods. Therefore, it is reasonable that there are many synthetic process patents related to generic drugs.

When establishing a project, it is necessary to carefully evaluate the synthesis methods reported in patent or non-patent literature, and finally from impurities (generally process impurities, API degradation impurities will not vary significantly due to different synthesis processes), yield, cost, post-treatment, Multiple factors such as the three wastes and the degree of industrialization are considered comprehensively and the relatively dominant synthetic route is determined as the process development route.

Although the compound patent has disclosed one or more preparation methods of the generic drug, in many cases the preparation method disclosed in the patent or literature applied for later may be more dominant, which needs to be carefully evaluated and weighed. After the synthetic route is determined, the expiration time of the synthetic process patent is determined according to the synthetic process patent corresponding to the determined synthetic route.

Of course, if it is found that the published synthetic route is not the best, it is also a good choice to design a route with more advantages. This can not only effectively avoid other people’s patents, but also apply for patents and obtain patent protection. In the industry, such cases are not uncommon nowadays.

Part 5 Preparation Patent

Nowadays, there are quite a lot of formulation patents involved in a product.

First of all, it is necessary to confirm whether the generic drug is a single preparation or a compound preparation, what kind of dosage form (such as tablet, capsule, oral liquid or injection, etc.), whether it is an immediate-release preparation or a controlled-sustained-release preparation, etc. Secondly, focus on information such as the types of excipients used in the instructions approved by FDA or EMA.

Although the compound patent gives a simple formulation formula, it is often found that the types of excipients published in the approved instructions are quite different from the types of excipients announced in the compound patent. Mainly, the final formulation of the original marketed product is determined through continuous screening and optimization, so the search, analysis and evaluation of the formulation patent cannot be ignored just because the formulation formula is given by the compound patent.

Special attention should be paid when searching for the patent applied by the original research company that is closest to the type of excipients published in the manual. This patent is likely to be the core preparation patent of the original research company. In this case, further confirmation can be made in conjunction with the relevant information in the US FDA Orange Book. If the patent has a family of patents in the United States and has been included in the FDA Orange Book, more attention should be paid.

For the patent of the original preparation, patent circumvention can be effectively implemented by reducing/changing the types or proportions of excipients. For the preparation patents of non-original research companies, there is no need to specifically circumvent them, because what we make is generic drugs, and it is enough to ensure that they are consistent with the original research.

Part 6 Patents For Intermediates And Preparation Methods

Patents on intermediates and preparation methods are not uncommon. When searching for numerous patents on intermediates and preparation methods, it is first necessary to confirm which intermediates will be involved in the selected synthetic route. Don’t be disturbed by the patents of intermediates and preparation methods that are not involved in the synthetic routes at all. Patents for preparation methods of intermediates can be effectively circumvented by changing reaction conditions.

Part 7 API Purification Method Patent

In addition, patents related to API purification methods are frequently searched. When encountering this type of patent, you can combine compound patents, synthetic process patents and crystal form patents with careful analysis and judgment, and analyze specific issues in detail. Because the purification method of API generally affects important indicators such as impurities and crystal forms of the product.

After clarifying the above-mentioned different types of patents, we have a relatively clear understanding of the patent situation of generic drugs in China. For patent applications that cannot be fully confirmed (such as the PCT patent that the original research company has just applied for, but has not yet entered China; the legal status is “effective for substantive examination”, etc.), it is still necessary to follow up and upgrade at any time.

In short, patent retrieval, analysis and infringement judgment is a huge systematic project. In order to avoid infringing patents of others when generic drugs are launched in the future, a thorough search, analysis and evaluation of the above-mentioned different types of patents should be carefully carried out. Even if a new patent is retrieved during the research and development process, no judgment or decision can be made arbitrarily, and it is necessary to carefully evaluate whether it will have a substantial impact on the development of the generic drug.