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© 2000 Nature America Inc. • http://structbio.nature.com perspectives Patent protection for protein structures and databases Thomas C. Meyers, Thomas A. Turano, Duncan A. Greenhalgh and Patrick R.H. Waller © 2000 Nature America Inc. • http://structbio.nature.com Patent protection is available for certain inventions in the field of structural genomics. A review of the patent application procedure is provided, and patentable aspects of protein structural information under US law are discussed. Strategic and international factors to consider when seeking patent protection for an invention also are presented. In the United States, patent protection is now available for many types of inventions that may not have been protectable 10 years ago. A developing body of case law now supports the patentability of inventions, such as three-dimensional atomic structures, structural databases, and their uses, which may result from research in the structural genomics field1–3. describe an invention which could be described by a combination of prior art references or events. The claims of a patent determine who the inventors are. Inventorship is not synonymous with authorship. In order to be an inventor, a person must contribute to the conception of at least one of the patent claims10. Performing laboratory work under the direction of another or writing a technical explanation of the invention does not necessarily qualify one as an inventor. In the US, each inventor is a joint owner of a patent and may exploit the patent without accounting to the other owners11. Thus, before initiating a joint research program, parties should reach an agreement defining their rights to any intellectual property resulting from the joint research. After a patent application is filed, the claims and disclosure are evaluated by a patent examiner in light of the statutory requirements. The examiner considers the clarity, breadth and scope of the claims in view of the patent disclosure, and assesses whether the claimed invention is novel and non-obvious in view of prior public information and disclosures. Typically, the examiner initially rejects patent claims in a written office action. An inventor can respond in writing to issues raised by an examiner. The response generally amends the claims and explains why the scope of the claims is supported by the teachings of the application, and why the claimed invention is novel and non-obvious over art applied by the examiner. The application is allowed when the examiner is satisfied that the application and claims comply with the statutory requirements. The exchange between the examiner and the inventor may be repeated several times before an application ultimately is allowed. The Patent Office issues an allowed patent after an issue fee is paid. The total time from filing an application to issuance usually averages between 1.5 to 4 years. In general, an issued patent can be enforced against third parties to prevent the unauthorized practice of the patented subject matter for a period of 20 years measured from the date of filing. However, in some cases it is possible to obtain extensions to the patent term if there are procedural delays at the Patent Office or if the product covered by the patent is delayed from being sold due to regulatory requirements such as FDA approval. Obtaining patent protection In the US, inventors may be granted exclusive rights to their inventions in exchange for full disclosure of their inventions to the public. A patent provides the right to exclude unauthorized third parties from making, using, offering to sell, selling, or importing an invention claimed in a valid issued patent4. Patents may permit the development of market exclusivity, for example, by providing strategic barriers to entry by competitors and time for the patent holder to develop technical and commercial expertise. Patents also provide licensing opportunities. Thus, patents create and enhance the commercial value of technology simply by making the patent holder the exclusive agent for the technology. Patent protection may be particularly important in fields such as structural genomics, where a large investment of time, money, and effort may be required to develop a commercial product. In the US, patent rights are obtained via an administrative procedure that involves submitting a patent application to the US Patent and Trademark Office. The patent application, before a patent is issued, must satisfy specific statutory requirements. The patent application must fully disclose the invention and include at least one claim to the invention5. The patent application must provide a written description of the invention in sufficient detail to enable a practitioner in the art to make and use the invention without undue experimentation, and must also describe the best mode (that is, the best way) for practicing the invention5. A patent claim is a single sentence6 that defines the invention in the form of a new and useful process, machine, manufacture, or composition of matter, or a new and useful improvement in any one of the above7. In addition, a claim must meet the statutory requirements of novelty8 and unobviousness9. In general, novelty requires that a claim not describe an inven- Protein structures tion which has been described completely by a single prior art Under appropriate circumstances, it should be possible to obtain reference or event, and unobviousness requires that a claim not commercially significant patent protection for certain aspects of Testa, Hurwitz & Thibeault, LLP, 125 High Street, Boston, Massachusetts, 02110 USA. Correspondence should be addressed to P.R.H.W. email: [email protected] 950 nature structural biology • structural genomics supplement • november 2000 © 2000 Nature America Inc. • http://structbio.nature.com © 2000 Nature America Inc. • http://structbio.nature.com perspectives a protein structure. Although case law has held that data sets per se are not patentable, they may be protected indirectly by associating the data set with a particular physical structure or use. For example, it may be possible to protect the three-dimensional structure of a protein or a portion of that protein when the requisite data set is included in a computer-readable memory. In theory, a new protein structure may still be patentable even if the structures of homologous proteins, such as naturally occurring isoforms or species or allelic variants, are known. However, the scope of any available patent protection may be very narrow, because the new protein structure must meet all the statutory requirements discussed above, including novelty and non-obviousness. In practice, significant protection will most likely be available only if the new protein structure has sufficient features to render it novel and non-obvious in view of the known structures. It is important to understand that patent protection may also be available for a new protein structure even if another patent has already issued with claims to the general features of the new protein structure (for example the general structural features of a protein family). Again, the new protein structure must have novel and non-obvious structural features in order to obtain patent protection in view of the issued patent. Remember that a patent does not give the patent holder the right to practice the claimed invention, it only gives the patent holder the right to exclude others from practicing the claimed invention. Under this scenario, the previously issued patent is referred to as a dominant patent. This means that even if patent protection is obtained for the new protein structure, use of that protein structure may infringe the claims of the previously issued patent. However, the owner of the previously issued patent would not be entitled to infringe the claims of the patent on the new protein structure. The impact of gene patents on the field of structural genomics is difficult to predict. It is not likely that many claims covering protein structures will be allowed by the US Patent Office based solely on amino acid sequence information deduced from a new gene sequence. However, claims to an isolated protein based on the gene sequence may issue, provided that the patent application contains sufficient information to show that the protein is useful and to enable claims to the isolated protein. Such patent claims, based primarily on gene sequence information, may dominate some of the claims in subsequent protein structure patents. As discussed above, this would not prevent the inventor of a protein structure from patenting the invention. However, it could mean that the inventor would infringe some of the gene patent claims when using the new protein structure information It may be possible to protect certain uses of the three-dimensional structure. Exemplary uses may include using the threedimensional structure to identify structural analogs that can then be tested for agonist or antagonist activity, or to identify amino acid residues that may be modified by site-directed mutagenesis. Examples of patentable uses are (i) to enhance bioactivity by modifying amino acid residues in a protein’s active site (ii) to modify stability by introducing or removing intramolecular bonds that do not affect the functionality of a protein (iii) to reduce immunogenicity by modifying surface accessible residues of a protein, or (iv) to alter solubility by modifying solvent accessible portions of a protein. However, the type of available patent protection will vary on a case-by-case basis. Several recently issued patents illustrate forms of protection available in the US for three-dimensional structures or their use12–16. One of these patents, U.S. Patent No. 5,835,382 to Wilson et al. entitled “Small Molecule Mimetics of Erythropoietin,” claims a computer-assisted method for identifying erythropoietin mimetics. nature structural biology • structural genomics supplement • november 2000 The steps include, among others, entering three-dimensional coordinates of a subset of atoms of a specified peptide when the peptide is cocrystalized with a portion of the erythropoietin receptor, and selecting chemical structures similar to the three-dimensional structure of the subset of atoms of the specified peptide. In view of this issued claim, anyone who uses the coordinates to identify structures similar to the specified peptide may be an infringer, and consequently may be liable for damages and/or enjoined (that is, prohibited) from using this method to find erythropoietin mimetics. From a theoretical standpoint, it may be most desirable to obtain ‘reach-through’ patent claims to cover therapeutic compounds such as agonists or antagonists developed using the threedimensional protein structure information17. Reach-through claims based solely on a method for identifying a compound are often difficult to obtain due to the lack of specific information concerning the compound’s expected structure, especially if the identification method requires screening large numbers of candidate compounds. However, the use of structural genomic approaches for identifying therapeutic compounds may provide a patent applicant with sufficient information on the structural features of candidate compounds to obtain some form of protection before the compounds are synthesized and tested. Informatics and business methods The advent of structural genomics raises new avenues for commercial exploitation of protein structure databases. Several aspects of these databases may be patentable. In the US, a software or business method invention is patentable, provided that the invention meets the same statutory standards required of all patentable inventions3. Databases, defined as simply collections or arrangements of data, are generally not patentable subject matter2. If the database includes protein sequence and structure information, the data is patentable only to the extent that the information making up the data is itself patentable. However, although databases are not patentable per se, patent protection is available for database-related inventions. First, special structural features of the database in conjunction with physical memory, such as organizational features that make access to the data in the database easier or faster in random access memory, may be patentable18. Second, uses to which the databases are applied may be patentable. Third, algorithms that extract or mine data from databases may be patentable19. Systems that include a database may be patentable20. Finally, a business method for using the database may be patentable3. For example, there are potentially six areas of patent protection available for a database containing protein sequences and structures for individuals who exhibit certain genetic diseases and for which a severity index has been determined correlating the severity of the disease with the protein information: (i) the amino acid sequences and structures of the protein; (ii) a computer system including the database and an interface that accesses the database; (iii) the general architecture of the database (the links, pointers, and so forth.); (iv) a program to access the protein information and generate a severity index correlating the protein sequences and structures to the severity of a disease; (v) the severity index and its method of calculation; and (vi) a method of doing business that includes the steps of obtaining protein sequence information from a patient, querying the database for the patient’s sequence variations and related structural information, calculating a number of severity indices, and counseling the patient. The validity of structural genomics patents has not yet been tested in the courts. However, when litigated, the validity of each patent claim will be tested under the statutory requirements dis951 © 2000 Nature America Inc. • http://structbio.nature.com perspectives © 2000 Nature America Inc. • http://structbio.nature.com cussed above. The outcome of any patent litigation is very factdependant, and it is difficult to make generalizations concerning the validity of any one type of claim. However, the scope and validity of reach-through claims to compounds based on structural information of target proteins is likely to be very contentious. Strategic planning Since an invention may be protected with numerous types of claims, it is often important to obtain the strongest protection for the lowest cost. This requires strategic planning which is determined in part by the business objectives of the patent holder. Strategic planning is of particular importance to a company, because competitive pressures may require that specific products and markets be protected. Academic institutions, on the other hand, typically obtain patents as part of a licensing program and focus their patent strategy on the interests of potential licensees. Strategic planning often involves identifying key areas that represent technology bottlenecks. Once identified, the patentability of such a bottleneck is evaluated. Assuming patentability, each bottleneck should be protected by a cluster of patents, with at least one patent providing broad generic protection for the cluster. Additional patents should protect specific attributes of the bottleneck that represent potential entry points for competitors. Multiple patents create a more formidable barrier than a single patent. A potential infringer would be more reluctant to ignore five or six relevant patents than just one. The odds favor the patent holder in this situation, because it is very difficult and expensive to prove lack of infringement or invalidity of numerous relevant patents. It is important to understand that patent protection does not entitle a patent holder to freely exploit a patented invention. The practical use of a patented invention may infringe the claims of another patent. For example, a first party patent may cover methods for designing candidate compounds based on protein structural information. However, screening the candidates to identify pharmaceutically effective compounds may require using a gene expression assay that is covered by a second party patent. This type of situation may arise when different parties pursue the structural and genetic aspects of a disease. However, patents may be useful as both defensive and offensive assets. For example, when different parties own patents relating to a similar business activity the parties may be more likely to obviate or settle a potential dispute by cross-licensing their respective patent rights. tions must ultimately be filed within national or regional patent offices in order to secure patent rights, this procedure has the advantages of delaying certain costs, such as translation and filing fees, and permitting an applicant’s own patent attorney to interact with WIPO during this stage of the proceedings. An important aspect of foreign patent rights is the requirement for absolute novelty. Patent protection is not available in most foreign jurisdictions when an inventor has disclosed the invention, for example by printed publication or other public disclosure, such as at a seminar . In contrast, in the US, an inventor can file a patent application up to one year after publicly disclosing the invention. However, if foreign protection is desired, it is important to file the patent application before any public disclosure is made. Another consideration to bear in mind is that not all inventions are equally protectable in all jurisdictions. For example, although patent protection is now available in the US for at least some of the inventions related to structural genomics as described above, similar protection may not be available in other countries. Differences in the availability of patent protection in different countries, therefore, may be one of the many factors to be considered when determining whether, and if so, where, to pursue patent protection. Conclusion In principle, there are multiple ways in which the intellectual fruits of research in the field of structural genomics can be protected. However, patent protection for structural genomics is an evolving and largely untested area of patent law, and, therefore, the scope and strength of available protection remains somewhat uncertain. Nonetheless, it is important to consider intellectual property issues during the early stages of a research project, and to seek advice in order to prevent the inadvertent loss of rights in any of a large number of jurisdictions. Web resources Additional information may be found on the following web sites: US Patent and Trademark Office (www.uspto.gov), European Patent Office (www.european-patent-office.org), and the World Intellectual Property Office (www.wipo.org). Affiliations Thomas C. Meyers and Thomas A. Turano are Partners, Duncan A. Greenhalgh, Ph.D., is an Associate, and Patrick R.H. Waller, Ph.D., is a Technology Specialist, at Testa, Hurwitz & Thibeault, LLP, Boston, Massachusetts, USA. International considerations The previous discussion pertains only to US patents and patent law. However, the availability of patent protection in additional countries may be an important aspect of a business plan. A foreign patent application may claim the benefit of a US filing date if it is filed no later than twelve months after the US filing date. A variety of foreign filing strategies are available and the optimal filing strategy will depend upon the facts and circumstances of a particular case. For example, a patent application may be filed directly in a national patent office. Alternatively, some countries belong to regional patent offices, and a patent issued by one of these regional offices may be enforceable in every country belonging to that regional office. The benefit of a regional filing is that patent examination occurs once and is accepted by all the member countries of the regional office. Furthermore, as an additional option, prior to filing in national or regional patent offices, an applicant may file a patent application with the World Intellectual Property Organization (WIPO) via the Patent Cooperation Treaty. Although applica- 1. In re Alappat, 33 F.3d 1526 (Fed. Cir. 1994). 2. In re Warmerdam, 33 F.3d 1354 (Fed. Cir. 1994). 3. State Street Bank & Trust Co. v. Signature Fin. Group, Inc., 149 F.3d 1368 (Fed. Cir. 1998) cert. denied, 525 U.S. 1093 (1999). 4. Title 35 of the US Code, §271. 5. Title 35 of the US Code, §112. 6. Manual of Patent Examining Procedure, 608.01(m). 7. Title 35 of the US Code, §101. 8. Title 35 of the US Code, §102. 9. Title 35 of the US Code, §103. 10. Title 35 of the US Code, §116. 11. Title 35 of the US Code, §262. 12. Wilson, I.A., Livnah, O., Stura, E.A., Johnson, D.L., & Jolliffe, L.K., Small Molecule Mimetics of Erythropoietin, U.S. Patent No. 5,835,382, issued Nov. 10, 1998. 13. Wilson, K.P., Griffith, J.P., Kim, E.E., & Livingston, D.J., Crystal Structure and Mutants of Interleukin-1 beta Converting Enzyme, U.S. Patent No. 5,856,116, Jan. 5, 1999. 14. Hendry, L. B., Design of Drugs Involving Receptor-Ligand-DNA Interactions, U.S. Patent No. 5,888,738, issued Mar. 30, 1999. 15. Read et al., Modification of Pertussis Toxin, U.S. Patent No. 5,965,385, issued Oct. 12, 1999. 16. Svendsen, A., Bisg.ang.rd-Frantzen, H., & Borchert, T. V. α-amylase mutants, U.S. Patent No. 5,989,169, issued Nov. 23, 1999. 17. Claims 3-6 of U.S. Patent No. 5,835,382. 18. In re Lowry, 32 F.3d 1579 (Fed. Cir. 1994) 19. Stevens, F.J. Myatt, E.A., & Solomon, A. Method for Detecting and Diagnosing Disease Caused by Pathological Protein Aggregation, U.S. Patent No. 6,063,636, issued May 16, 2000. 20. Sabatini, C.E. et al. Database and System for Storing and Displaying Genomic Information, U.S. Patent No. 5,966,712, issued Oct. 12, 1999. 952 nature structural biology • structural genomics supplement • november 2000