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.
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.