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Licensing of the HIV-1 protease gene by the NIH Office of Technology Transfer (OTT) provides an example of the effective use of the principles of the NIH Research Tools Policy, which was designed to provide broad access to important biomedical technologies. The OTT licensing experience is presented in detail as it was applied to research reagents, diagnostics and drug development to thus enhance the overall development process for a wide variety of medical products.
The development of HIV-1 protease inhibitors has not only revolutionized HIV therapy but also has provided a successful model for how institutional technology transfer policies for easy & rapid dissemination of research tools with a minimum of administrative impediments can effectively help enhance the timely overall development process for an entire new class of drugs. Since drug discovery efforts conducted at either industrial or academic facilities require rapid access to state-of-the-art research tools, rapidly evolving fields such as HIV drug discovery are such that unreasonable restrictions or delays in providing access to needed research tools can have an adverse effect on the development of new products and treatment of patients. However in the case of HIV-1 protease, the NIH Office of Technology Transfer (OTT) was able to effectively use policies exemplified in the NIH Research Tools Policy to provide broad, non-exclusive access to an important HIV-1 protease patent (Oroszlan, et al.) that is useful both in clinical diagnostics (genotyping) and in therapeutic development (drug targeting & reagent use). Rapid access for these uses helped ensure the development and dissemination of a number of important new medical products from several companies as well as ensuring access to the research community.
A number of strategies have been devised in an attempt to change HIV-1 infection from a fatal disease to a manageable and treatable one. Initial efforts focused on inhibiting the viral reverse transcriptase with nucleoside analogs and resulted in drugs such as Videx® (ddl), Hivid® (ddC), and AZT (azido-T). These compounds act as competitive substrate inhibitors and cause chain termination of the replicating viral DNA strands as they are incorporated into newly synthesized DNA. Many of these compounds were readily available because they had been synthesized for their potential use in cancer therapy and basic biomedical research.
The next HIV treatment strategy was to inhibit HIV-1 protease. The enzyme is required to cleave the viral polyprotein into its mature component proteins, so inhibition of the protease prevents viral assembly. Starting in the late 1980s, the HIV-1 protease gene was identified, by Stephen Oroszlan and colleagues at the NIH,1 and its amino acid sequence deduced from its DNA sequence. At the same time, its three-dimensional protein structure was determined via X-ray crystallography to map the enzyme's active site. With the three-dimensional structure of HIV-1 protease known (For example, see Figure 1) it became possible to use this knowledge to design novel HIV-1 therapeutics based upon inhibiting the enzymatic activity of the protease itself.
Hoffman LaRoche was the first to market with an HIV-1 protease inhibitor under the trade name Invirase®. Subsequent inhibitors were developed and marketed by other pharmaceutical companies as detailed in Table 1.
HIV-1 protease inhibitors are able to dramatically reduce viral load, sometimes to undetectable levels, and are well tolerated because of their specificity. The availability of a number of different HIV-1 protease inhibitors is important because the viral protease develops resistance to an inhibitor over time. It is therefore important to have a new inhibitor available when treatment with the previous one begins to fail. The inhibitors can also be combined with reverse transcriptase inhibitors or another class of HIV-1 drug to delay the development of resistance.
The development of significant resistance to HIV-1 protease inhibitors coincides with a rise in viral load, as detected by PCR testing. However, the FDA as a condition of drug approval and in order to properly manage a protease inhibitor treatment regimen requires more sensitive and specific tests.
Those specific tests sequence the protease gene in HIV-1 virions from patient samples to determine which nucleotide sites may be changing under pressure from the protease inhibitor treatment. Usually, the reverse transcriptase (RT) is also sequenced at the same time to detect any resistance to RT inhibitors. The sensitivity of these tests goes down to about 600 virus copies per milliliter of blood. About 40 mutation sites have been associated with resistance to one or more of the HIV-1 protease inhibitors. Available HIV-1 protease genotyping kits and reference lab tests are listed in Tables 2 and and33.
Once a protease genotype is obtained, a physician can determine which remaining inhibitors will still be effective against the patient's virus (salvage therapy). Besides helping to keep the patient's viral load low, genotype monitoring also helps to prevent resistant viral strains from being spread to uninfected or treatment-naïve individuals. It is important to note that the genotype obtained in each patient is an average over the most prevalent viral strains in a patient sample. There can be dozens to hundreds of different HIV-1 strains in the same patient, each with a different genotype. Strains present at less than about 20% of the total will not contribute to the test genotype.
A discovery such as the one made by Oroszlan's laboratory can present an interesting challenge for a research organization when it comes to distribution for research and commercialization. On one hand, it can be quick and expedient to grant a single exclusive license for all fields of use; on the other hand it is important (especially for publicly-funded research) to have the technology made available to as many possible users for as many possible applications. For the licensing efforts on behalf of an invention such as HIV-1 protease, the NIH Research Tools Policy proved to be a very beneficial model in terms of showing an effective policy to maximize the use of the invention by a variety and quantity of commercial organizations and researchers while still providing a way for the patent holder to reach its institutional goals both in terms of facilitating additional research, medical product development and also financial returns. The major elements of the key patent behind the technology are shown in Table 4.
In terms of the NIH Research Tools Policy itself, this policy3 was adopted in 1999 by the NIH for application to all NIH funding recipients, including the NIH intramural research program. This NIH policy consists of two parts, the Principles and the Guidelines. There are four basic principles (Table 5) that need to be adhered to in furthering the research enterprise: ensure academic freedom and publication; promote commercialization consistent with the Bayh-Dole Act; minimize administrative impediments to support research; and ensure dissemination of NIH-funded tools. As a complement to this, the Guidelines provide specific information, strategies, and model language for recipient institutions to use in obtaining and disseminating biomedical resources.
In its licensing practices for its own internally-generated tools, the NIH has been able, through OTT to show the practical utility of its Research Tools Policy in successfully achieving the balance of promoting competition and commercial development without unduly encumbering future research and discovery by distributing tools for research use or commercial sale. Indeed, many of the Guidelines themselves evolved from policies and practices originally developed and tested through the NIH intramural research and technology transfer programs.4 For the HIV-1 protease technology, applications of the NIH Research Tools Policy of Principle Two (commercialization) and Principle Four (distribution) were the most critical.
For transfer use and commercialization of the HIV-1 protease technology, it was essential that NIH maximize utilization by the research community (both academic and industry) but concurrently also provide for timely transfers to industry for commercialization. Generally the transfers to industry would be achieved via licensing but it was critical to avoid unnecessarily restrictive licensing practices. These were all necessary in order to be able to maximize benefits of the tool for use by the public, especially given the ongoing need for new products in the HIV-1 area. For distribution of the technology, NIH's goals were to simplify licensing to industry for internal research use as well as to focus on non-exclusive commercial licensing (where possible) in appropriate fields of use. Because of the ongoing need for NIH to continue its research in this area as well as to have others (both in academic and corporate settings) do so as well, the NIH would retain rights to use the technology and continue distribution of it to others in the future.
At the time the licensing of this technology started, there were three different types of commercial applications of the technology that fell under the DNA sequence claims of the HIV-1 protease patent. These three types of commercial applications were: Research Reagent Sales; Diagnostics; and Drug Development—with each distinct by type of product as well as by the characteristics of the licensee.
Research reagent sales include licensees that would be producing recombinant protease for sale to laboratories as a research reagent. This type of licensee is often small, and carries an extremely large number of different products, nearly all of which are low-volume sellers. However, having them as licensees is very valuable to the research community as a whole because they are a quick and efficient source of products to be used in new studies. Through its experience, the NIH has found that non-exclusive licensing works best here since there are typically low levels of investment and risk involved to bring such products to the market. Typically, companies do not require exclusive rights to enter this commercial market.
Diagnostics includes licensees that were either reference labs or kit manufacturers that offer HIV-1 protease genotyping tests as a diagnostic service or test kit. This type of licensee is typically larger and can provide the HIV-1 protease testing either as a service at a reference laboratory location or as diagnostic kit that is sold to a wide variety of clinical settings. The level of investment here is higher, especially for licensees looking to manufacture kits, as these would typically be subject to FDA or similar national regulatory approval. The NIH experience has been that reference laboratory service testing can be licensed on a nonexclusive basis but that FDA-regulated products may require an additional incentive of exclusive licensing in order for a company to bring a product to market if the market appears to be only modest in size.
Here the primary licensees would be undertaking HIV-1 protease inhibitor development and Phase IV testing of patients receiving these protease inhibitor drugs. Licensees would be large pharmaceutical companies (or biotech companies and their large pharmaceutical company partners) that had or were looking to develop and market HIV-1 protease inhibitor drugs. Here the HIV-1 protease invention is used in internal (and often very distinct) R&D at each commercial organization. It is the NIH experience that these types of commercial uses can be licensed on a non-exclusive basis.5
In the first and second cases, OTT felt that earned royalties on sales were appropriate for the technology, as they would be on any product or service sold by a licensee that directly used claims of the patented technology. In the third case, OTT felt that earned royalties on sales were not appropriate for the technology as a licensee would not be selling the technology but only using it in drug discovery or evaluation. In this instance the technology was licensed to pharmaceutical or biotech companies as a research tool under internal use license agreements without “reach through” to sales of products based upon discoveries or other research done in their labs based on the technology. The NIH Research Tools Policy discourages reach-through royalties as they can tend to place a high cumulative royalty burden on a final product even when there is little or no direct connection with it. This can be a disincentive to use the tool or even likely a cause of delayed product development through the need to avoid the use of the tool entirely in research by product developers.
The licensing strategy for this technology was to develop non-exclusive license agreements for each of the three product areas. Non-exclusive licensing was selected because of the need to provide broad access to the technology to the various companies developing products in their individual market segments (research reagents, diagnostic and therapeutic development) without inhibiting or delaying development of products and research. Additionally, exclusive licensing approaches were not needed, even with diagnostic products, due to the number of competitive firms developing or looking to develop products in the various product areas. This is largely reflective of the accepted and maturing market for HIV testing in general, of which HIV-1 protease-based testing has become an important part in patient care. In general the licensing strategy that was followed for HIV-1 protease is also illustrative of the basic concepts that were later described in the Best Practices for the Licensing of Genomic Inventions which were published by the NIH in 2005.6
The results to date of the NIH licensing program for HIV-1 protease in terms of number and types of licensees as well as the typical financial terms that were reached for these license agreements are shown in Tables 6–8 and a summary of overall results is shown in Table 9.7 While financial terms in license agreements can be influenced by a variety of factors individual to the technology and/or its marketplace, it is clear from the results summary that non-exclusive strategies can produce dramatic product results, especially in the reagent and drug discovery fields. While not all research discoveries coming from early stage research programs can obtain the results shown here for the HIV-1 protease technology, it is important to have frameworks such as the NIH Research Tools Policy and the Best Practices for Licensing Genomic Inventions in place to help guide research organizations to made effective choices for distribution, use and commercialization of their technologies.
By utilizing a licensing strategy based upon the principles outlined in the NIH Research Tools Policy, it was possible to achieve both drug development internal research uses and commercialization of an important discovery in HIV research. Ensuring broad access to tools for drug discovery and other basic research applications while preserving opportunities for product development requires thoughtful, strategic implementation of the Bayh Dole Act (or similar statues governing federally-owned inventions such as the Federal Technology Transfer Act), but is indeed possible as shown by this case study.
Research organizations in government, academia and the private sector all need to develop creative approaches for achieving both commercialization and dissemination of important new tools. As the example of HIV-1 protease shows, it is possible to concurrently achieve these multiple outcomes by focusing on non-exclusive field-of-use licensing for research reagent sales and internal commercial use applications and also still encourage future research. In this instance it was possible for NIH to use non-exclusive licensing in the diagnostic fields due to the number of providers, the lower costs and risks involved in bringing these diagnostics to the market and the growth of the overall diagnostic marketplace as companion products to help physicians make proper treatment choices for their patients based upon the substantially increasing number of therapeutic choices.8 However, the option remained open at the time of initial licensing of the technology to grant exclusive licenses, if such were needed, to provide additional incentive for development of diagnostic products should the investment risk or regulatory obligations be too substantial for companies to develop them on a non-exclusive basis while yet offering internal research use licenses on a nonexclusive basis.
Additionally, this example confirms when novel discoveries such as HIV-1 protease are made that these NIH policies provide for a way for the discovery to be fully shared and brought into developmental pipelines for as many types of products as may be commercially feasible. The success that has been achieved for HIV-1 protease also shows the value of technology commercialization approaches that include strategies outlined in the Best Practices for the Licensing of Genomics Inventions. It remains a goal for the scientific community, both corporate and non-profit, to work together to achieve this outcome for research discoveries in order to most effectively and most efficiently further basic research studies, enhance discovery, support a robust research enterprise, and thus ultimately improve public health.
By broadly licensing the HIV-1 protease gene technology in a variety of fields of use and by not reaching through to therapeutic sales, the NIH has made the technology fully available for all commercially feasible products and services. This example shows that the principles of the 1999 NIH Research Tools Policy and the subsequent 2005 NIH Best Practices for Licensing of Genomic Inventions do in fact work well in real-world situations relating to R&D and commercialization and so remain an effective model for institutional technology transfer programs.
The authors also wish to acknowledge the helpful suggestions and comments of Ann Hammersla, Director for the Division of Policy for the NIH Office of Technology Transfer.
George H. Keller specializes in technology license monitoring and enforcement at the NIH Office of Technology Transfer. He has negotiated numerous license agreements and assured compliance of NIH licenses during his fourteen years at OTT. Prior to OTT, he provided consulting services to companies developing diagnostic tests for infectious diseases and molecular biology research reagents. Dr. Keller provided advice and management for grant proposals, patent applications, technology licensing, technical due diligence, research, product development groups and business development. A graduate of the University of Maryland with a B.S. Degree in chemistry, he also earned a Ph.D. Degree in Biochemistry from Penn State. He has authored more than twenty scientific publications and co-authored two books on DNA Probe Technology.
Steven M. Ferguson currently serves as the Deputy Director, Licensing and Entrepreneurship for the NIH Office of Technology Transfer. Prior to re-joining NIH in 1990, Ferguson served in marketing and management positions in biomedical firms subsequent to being a scientist at the National Cancer Institute. He has been an economic reviewer for Maryland Industrial Partnerships (MIPS) as well as the Advanced Technology Program (ATP) grant programs and is an instructor for both the USDA Graduate School and the NIH FAES Graduate School where he is also the department chair for the Certificate in Technology Transfer Program. Registered to practice before the USPTO and a Certified Licensing Professional (CLP), Mr. Ferguson also holds Master's Degrees in Business Administration (George Washington University) and Chemistry (University of Cincinnati) as well as a Bachelor's Degree in Chemistry (Case Western Reserve University). He has published extensively on licensing and technology transfer issues.