Legal Forum: Patenting Strategies to Delay Biogeneric Competition

Patents protecting the first commercial biological products are now nearing expiration. These patents protect some of the largest selling biologics, such as interferon, human growth hormone, insulin, and Epogen (Procrit). As with small molecule therapeutics, the expiration of the patents creates an opportunity for generic products to enter the market. Thus far, there is no legal framework under which generic biologics, also called biogenerics or follow-on biologics, can be marketed in the US. However, the FDA will inevitably provide a regulatory pathway for the introduction of biogenerics. The regulatory time lag provides an opportunity for the innovator biotechnology companies to consider and implement patent strategies that could delay generic competition even after a regulatory pathway exists. Some of these strategies include patenting preferred formulations, manufacturing methods, protein modifications, and avoidance methods of adverse drug reactions.

Narinder Banait

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.

Another strategy includes obtaining patent protection on adverse drug reactions (ADRs) using pharmacogenomics. ADRs include side effects, allergic reactions, and unusual and unpredictable reactions. The innovator company is required by the FDA to document ADRs for marketed products. Because of this regulatory requirement, the data must be collected, and is available solely to the innovator company. If the innovator company can discover novel drug–drug and drug–food interactions, and negative interactions between drugs and certain phenotypes, genotypes, and pre-existing conditions, then methods of obtaining and using this information to avoid ADRs could be patented.

The challenge of this strategy is to identify genetic differences that influence drug metabolism and response, and to correlate that data with drug efficacy and safety information. The goal is to identify patients who are likely to suffer drug related adverse events and to ensure appropriate dosing by identifying the patient's rate of drug metabolism. Thus, the patents would be to ensure the safer use of the innovator's drug by avoiding these interactions.

The innovator company could patent compositions of isolated therapeutic proteins, and of course the nucleic acid sequences encoding them, that are responsible for these differences, as well as methods for obtaining the pharmacogenomic data and methods for diagnosis and treatment of subjects based on the data. Thus, a generic company could be prevented from using the pharmacogenomic data obtained by the innovator company to recommend appropriate dosing of the biogeneric, thereby delaying the entry of the biogeneric until the pharmacogenomic patent expired.

The major patenting issues for patent protection in pharmacogenomics are utility, enablement, and written description. However, because of ADR data for the particular biologic drug, these issues should be minimal, and the innovator company should be able to obtain patent protection fairly readily.

A patent strategy that considers the particular details of the marketed therapeutic protein, the methods of manufacturing the protein, patent term extensions, and ADRs could increase the market exclusivity of a biologic. After the initial patent applications are filed and the product has been further developed, the patent strategy of the companies should include filing applications on the approved product itself, and claim the product characteristics required for FDA approval, the final manufacturing process, ADRs, as well as patent-term extensions.

Narinder Banait is an attorney at Fenwick & West LLP, 801 California Ave., Mountain View, CA 94041, 650.335.7818, fax 650.938.5200, nbanait@fenwick.com