Eric Langer

Today, most biotherapeutics are manufactured using E. coli, Chinese hamster ovary (CHO), or yeast-based expression systems, and these work-horse systems do the job. However, even these older systems have newer, add-on improvements that may require licenses for commercial applications (including basic commercial research). For example, some E. coli strains and CHO cells are generally used with licensed technologies that improve performance, such as newer vectors, promoters, and selection and amplification systems. So, even though the older technologies may be soon coming off patent, meaning they can be used without licenses or paying any fees, many users are willing to pay royalties or license fees to access improved performance.

AVOIDING PITFALLS

Most companies expecting to manufacture a recombinant protein or antibody get legal advice on how to license technologies. Licensing involves a series of generally predictable tasks, however, starting with an evaluation of the options.

One must decide whether to use one of the old, predominant host systems (e.g., E. coli, CHO, yeast), or seek out a newer system likely offering advantages such as increased yields, cost savings, and adaptability to the use of disposables. A large number of technologies are available for commercial-scale recombinant protein expression. The book, Biopharmaceutical Expression Systems and Genetic Engineering Technologies Directory, is one source of information on licensable expression system technologies. There is also considerable scientific literature related to expression systems. Whether one sticks with an older technology or goes with a newer one, you still may need one or more licenses to get what you really need.

Despite biopharmaceuticals being one of the most complex commercial products, many companies remain short-sighted and either do not explore their options or settle on using the same technologies they've been using. Old technologies can be good enough, particularly if long-term costs of manufacturing are not a major concern. However, by using old technologies you might lose out on efficiency (e.g., higher yield, increased speed), adaptability, and cost-effectiveness in the long term. For example, yields over 30 g/L are now being reported in perfusion culture with the PER.C6 human host cell system from Percivia (Crucell/DSM), compared with the single g/L range in older technologies. Often, older systems involve the use of large fixed stainless steel vessels, whereas newer technologies are more adaptable to modern bioreactors, often including single-use systems. Systems like DowPharma's Pfénex expression technology, a Pseudomonas fluorescens-based platform, is flexible and can be used to produce therapeutics at very high titers. Selexis (Geneva), developed a technology to improve yield of production cell lines in mammalian cells in suspension and in serum-free media more than 20 fold. There are over 300 other technologies awaiting evaluation.¹ So, a first step is simply to be aware of what is available.

Selecting the Right Type of License

Some licensors create complex rules in an effort to get their technologies widely distributed while still ensuring that commercial organizations pay for access. RTC (Tucson, AZ), for example, licenses its Pichia platform to more than 120 companies. A license is required for even research-only use of this technology. Companies can get short-term use of a Pichia kit for evaluation. A commercial license for R&D, however, costs more than $50,000. Moreover, if you commercialize a product, fees can be $75,000 plus 3–5% of revenues. Also, if you buy a kit from a third party, you might end up blocking the rest of your organization from testing the technology until you pay the licensing fee. Similarly, Jena Bioscience GmbH (Jena, Germany) provides its Leishmania expression system without a license to any academic or public institution but charges a license for commercial purposes.