A U.S. patent broadly covering ex vivo gene therapy has been granted to the National Institutes of Health (NIH; Bethesda, MD) which has already granted an exclusive worldwide license to Genetic Therapy, Inc. (GTI; Gaithersburg, MD). The official abstract and exemplary claim for this patent are in the "U.S. Patents" section below. The first claim of the patent covers, "A process for providing a human with a therapeutic protein comprising: introducing human cells into a human, said human cells having been treated in vitro to insert therein a DNA segment encoding a therapeutic protein, said human cells expressing in vivo in said human a therapeutically effective amount of said therapeutic protein." While the patent appears to broadly cover all ex vivo gene therapy, many companies and research organizations involved in gene therapy will likely be carefully reviewing the scope of this patent. Although the patent covers ex vivo gene therapy using any method for cell transformation, most development, examples and clinical testing have involved the use of retroviral vectors jointly developed by NIH and GTI. If the patent is interpreted as broadly covering all ex vivo gene therapy, challenges can be expected.

The impact of this patent on other companies is not yet known. Dr. M.J. Barrett, Chairman/CEO, GTI, remarked that his company plans "to undertake a strategy that could involve partnerships or in a few cases sub-licenses and cross-licenses. We hope to use it as a platform for the company to develop some serious corporate relationships...We don't think it would be consistent with our duties to give everybody licenses." GTI appears to be more interested in strategic linkages and collaborations with other companies, rather than following a strategy of granting nonexclusive (sub)licenses to all interested parties. The terms of GTI's license from NIH do not require it to sublicense or grant licenses to all interested parties. It is too early to determine the extent to which GTI's strategy may force some companies currently developing gene therapies to abandon their efforts. Besides this patent, GTI has exclusively licensed at least eight other patent properties from NIH, many developed jointly with NIH, and has nonexclusively licensed several other NIH gene therapy technologies. Many of these licensed technologies involve retroviral or other gene therapy vectors and specific therapeutic vector constructs for treatment of particular diseases, rather than claiming broad enabling technologies such as the recently issued patent.

The recent patent includes the use of retroviral vectors for ex vivo transformation of blood or other cells, so that transformed cells express therapeutic and/or marker proteins, and return of these cells to the patient. Of the approximate 100 gene therapy clinical trials conducted in the U.S. to date, about two-thirds or more involve this technology which might be termed first generation gene therapy technology. This technology was developed through formal Collaborative Research and Development Agreements (CRADAs) between NIH and GTI that began in 1988, with the first U.S. patent application filed in June 1989. CRADAs offer the collaborator the option to exclusively license inventions jointly developed with federal laboratories. Until recently (as discussed in the story above), exclusive licenses from NIH, including those resulting from CRADAs, included a clause requiring the licensee to assure "reasonable pricing" of resulting products. With the abandonment of this policy, GTI will have essentially no restrictions or oversight of the pricing of its gene therapies. In general, most commercial development of gene therapies is progressing beyond this first generation ex vivo therapy towards direct in vivo gene therapy, such as Viagene's direct injection retroviral and non-viral vectors (described in a story above).

Challenges to this patent may be expected. The first reaction of many companies and researchers involved in gene therapy was that the patent appeared to be too broad and that similar ex vivo gene therapy patents have issued with earlier priority dates. For example, the Whitehead Inst. (Cambridge, MA) has received two U.S. patents with earlier priority dates covering ex vivo epithelial cell gene therapy and three European patents covering transformation of epithelial cells, endothelial cells and fibroblasts. These patents have been exclusively licensed to Somatix Therapy Corp. (Alameda, CA) whose CEO remarked, "The mature thing to do is to enter into cross-license agreements and save money on attorneys. It's a huge market and there's no way all the gene therapy companies will get in each other's way. The smart thing is not to get in a big patent battle." However, NIH in collaboration with GTI was clearly the first to demonstrate the clinical efficacy of ex vivo gene therapy. As discussed in the March 31 issue of Science (p. 1899), several other researchers performed ex vivo gene therapy experiments as early as 1980 and others who were part of the NIH team working in this area may seek to have themselves added as inventors. This broad patent will likely be the subject of news stories and controversy for years.

Many patent experts expect the patent to either be subject to an interference proceeding or be challenged years from now when one or more products apparently covered by the patent approach market approval. There appears to be little incentive for companies developing similar gene therapies to initiate a challenge to the patent now. The recent change in U.S. Patent and Trademark Office policy to not strictly require demonstration of clinical utility (discussed in the February Bulletin, p. 45) may affect the validity of the claims of this patent. If previous in vitro work is interpreted as coming under the broad claims of the NIH/GTI patent, the claims could be substantially restricted or the entire NIH/GTI patent could be withdrawn. However, the inclusion of clinical data in the recent patent tends to provide support. Another broad patent in a related area, antisense oligonucleotide gene therapy involving Enzo Biochem Inc. and Calgene, Inc. (discussed in the May 1993 Bulletin, p. 137), that might provide guidance has just come to trial.