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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]
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© 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-
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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.
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Patent No. 5,888,738, issued Mar. 30, 1999.
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12, 1999.
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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.
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