An often overlooked, but readily available strategy is for the innovator company to apply for patent-term extensions for the patents claiming the therapeutic protein. Under the present regime, up to five years of patent-term extensions are available for a patent that claims an FDA approved human drug product. The active component of the new drug must include both small molecule and biologic therapeutics, according to the Food Drug and Cosmetic Act and the Public Health Service Act. This strategy is particularly important for products that are marketed near the end or after the expiration of the patent, but patent-term extensions should be automatically evaluated by the companies for all approved drugs.
Typically, a company files an early patent application shortly after discovering a new therapeutic protein, or a new therapeutic use of a known protein. These early applications mature into patents early in the lifecycle of the commercial product. In the US, the term of the patent is calculated to be 20 years from the date of filing the application. The commercial product, therefore, may lose patent protection just as sales are ramping up. To extend protection of the marketed product, companies should consider filing patent applications for specific details of the biologic itself, or later-developed methods of manufacturing the biologic. These potential patents will be entitled to a longer patent term than the earlier filed applications.A patent application for the biologic itself could be directed to the protein, a composition of proteins, or a formulation. Typically, the biologic that is marketed may have different characteristics than the initially identified protein. For example, the biologic often is not a single molecular entity as is typical for small molecules, but is made up of a group of slight variants of the therapeutic proteins, such as a collection of proteins that have varying lengths or slight differences in amino acid sequences. These small differences result from the cell cultures used to manufacture the protein. An independent patent application claiming the particular slight variants and methods for manufacturing the variants could be filed. Caution has to be exercised since the later filed application will likely be rejected by the US Patent and Trademark Office over the earlier application, or be subject to obviousness-type double patenting rejection. However, the patent attorney could address these issues at the time of filing the application and overcome the rejections. In some cases, only certain cell lines are useful for manufacturing the approved product. Therefore, obtaining claims covering the particular cell lines approved by the FDA for the manufacture of the product would provide the innovator companies the ability to exclude the generic manufacturers from using the cells in producing biogenerics.
The cell cultures used to manufacture the biologic can cause specific modifications to the protein or the peptides. The most common and important type of modification that occurs is the glycosylation of the protein. For example, Epoetin and Herceptin are both glycosylated, although equally important biologics, insulin and somatropin, are not. The pattern of glycosylation is known to contribute to the occurrence of immunological reactions in patients. Thus, in order to avoid immunological reactions and for approval by the FDA, the generic manufacturer will very likely strive to conserve the glycosylation pattern in the biogeneric product. Therefore, innovator companies should consider obtaining claims on the marketed protein where the amount, type, and location of glycosylation or other post-translation modifications are specified. If the regulatory requirement for bioequivalence includes the showing of similar modifications, then biogenerics would infringe on the claims covering these modifications. This could be a powerful barrier to the entry of a biogeneric into the market.