Reflections on Microorganism Patents
May 1, 2003
HARAKENZO WORLD PATENT & TRADEMARK Intellectual Property Law Firm
I. Deposit of Microorganisms
In order to obtain a patent for, among biotechnology-related inventions, an invention on a microorganism, the applicant is required, if persons with ordinary skill in the art cannot easily obtain the microorganism, to deposit the microorganism to an international depositary authority under the Budapest Treaty prior to the filing of the patent application, and to attach to the application a document proving the deposit (Implementing Regulations to Patent Law, Rule 27(2)). In Japan, the International Patent Organism Depositary at the National Institute of Advanced Industrial Science and Technology is the sole local depositary for patent purposes, and is designated as an international depositary authority under the Budapest Treaty.
Therefore, in making a patent application for a novel microorganism screened by an inventor from the natural environment, it is necessary to deposit the microorganism to the International Patent Organism Depositary so as to obtain a deposit number prior to the filing of the patent application.
The deposit of microorganism to the International Patent Organism Depositary is made by submitting a deposit application and other documents. In the format of deposit application, there is a section titled "scientific description and/ or proposed taxonomic designation," which is to be filled on a voluntary basis. For the purpose of efficient technical deposit service, however, the International Patent Organism Depositary recommends that this section be filled as long as possible (Reference 1, p. 7).
The scientific description includes the shape of the organism, physiological and biochemical characteristics of the organism, and the like. The proposed taxonomic designation is, for example, the kind of the deposited organism and the genus and kind of the deposited organism. Therefore, it is highly desirable that the deposited organism be classified to the extent that the genus and species of the organism is made clear.
The basic classification unit in biology is species. The main ranks that constitute the hierarchy of classification are, beginning at the most subordinate one, species, genus, family, order, class, and phylum ("division" in botany). Among these ranks, species and genus are found in nomenclatures of organisms (Reference 2).
Each organism has a nomenclature consisting of a generic name and a species name. For example, the nomenclature of E. coli bacteria is Escherichia coli , meaning the coli species of Escherichia genus. The nomenclatures of bacteria are regulated by the International Code of Nomenclature of Bacteria. In principle, nomenclatures are written in italics. In the case where italics are not available (when handwritten, for example), the nomenclatures should be underlined.
It is highly desirable that the deposited organism be classified to the extent that the genus and species of the organism is made clear. This is not only for the purpose of efficient technical deposit service as described above, but also for the purpose of emphasizing the patentability of the invention on the microorganism. In an invention on a microorganism, the scientific characteristics of the microorganism may be clear for the most part, because the microorganism is an important feature of the invention. However, for the purpose of claiming that the organism is novel, it is highly desirable that the genus and species of the organism be made clear.
For example, the characteristics of microorganisms vary from individual to individual (that is, from strain to strain), even if the microorganisms fall under the same genus and species, taxonomically. Therefore, there is a need for depositing microorganisms even if they are taxonomically well-known (Reference 3, p. 27). To put it the other way around, even if the genus and species of microorganisms are well-known, there is a reasonable likelihood that the novelty of the strain is admitted, if the strain has a novel scientific characteristic that is useful to solve the problem to be solved by the invention.
As described above, in making a patent application for an invention on a microorganism, it is critically important to classify the microorganism and to identify the scientific characteristics of the microorganism.
II. Classification of Microorganisms: Classical Method
Initially, organisms were classified by similarity in appearances. Microorganisms were no exception. For example, attempts were made to classify bacteria by appearances (shapes), such as a spherical shape, bacilliform shape (rod shape or cylindrical shape), spiral shape, and the existence of flagellum. However, it is difficult to classify microorganisms by their appearances, because most microorganisms are single-cell organisms having little difference in appearances. In classifying microorganisms, therefore, physiological and biochemical characteristics are more important than appearances.
In classifying microorganisms, Gram staining is very important, in addition to the physiological characteristics. Gram staining was invented in 1884 by Christian Gram (1853-1938), a Danish bacteriologist. In Gram staining, bacteria are stained with gentian violet or crystal violet, decolorized by treatment with alcohol, and stained again with fuchsine, safranine, or the like. The bacteria that are left stained violet without being decolorized by the treatment with alcohol are gram-positive bacteria. The bacteria that are stained red by the second straining are gram-negative bacteria. The positive/negative judgment by Gram staining is a significant ground in classifying bacteria.
Whether or not Gram staining can be employed depends on the structure of the cell membrane of the bacteria. However, the specific mechanism of this phenomenon is still unclear.
According to the classification by physiological and biochemical characteristics and by Gram staining, bacteria can be classified as follows, for example (Reference 4, pp. 78-80).
(a) Photosynthesis bacteria;
(b) Gram-negative heterotrophic aerobic bacteria;
(c) Autotrophic chemosynthetic bacteria;
(d) Gram-negative facultative anaerobic bacteria;
(e) Gram-negative anaerobic bacteria;
(f) Gram-positive bacteria that do not generate spores;
(g) Gram-positive bacteria that generate spores;
(i) Rickettsia and chlamydia;
(j) Mycoplasma; and
(k) Superthermoresistant bacteria
III. Classification of Microorganisms: Molecular Biological Method
Recently, in addition to the classical method described above, molecular biological methods are used in classifying microorganisms, thanks to the advancement of the molecular biology.
In the molecular biological methods for classifying microorganisms, the following classifying indicators are used, for example:
Classifying indicator: nucleic acid
- DNA probe;
- rRNA gene sequence;
- RFLP (Restriction Fragment Length Polymorphism);
- G+C content of DNA; and
- DNA-DNA homology.
Classifying indicator: bacteria cell components other than nucleic acid
- Fatty acid bacteria cell component;
- Cell wall component;
- Electrophoretic pattern of enzymes;
- Electrophoretic pattern of protein of all bacteria cells.
Each of the classifying indicators above, except isoprenoidquinone as a target molecule, can be used to identify species. Especially, RFP, enzymes, and electrophoretic pattern of protein of all bacteria cells are effective in identifying strains , which are subordinate to species (Reference 5, p. 4, Fig. 1.1).
Among the classifying indicators above, mainly used is the rRNA gene sequence, especially the gene sequence of 16S rRNA. The 16S rRNA is an rRNA that constitutes 30S semiparticles among ribosome elementary particles. The 16S rRNA is very useful as an indicator, because nearly all microorganisms have the 16S rRNA, the size of the 16S rRNA does not significantly differ among species, and the 16S rRNA is phylogenetically preserved.
Recently, the complete genome sequences of various organisms have been determined.
Accordingly, the use of genome data will drastically improve classification techniques for microorganisms.
For example, among the complete genome sequences of microorganisms, determined are Hemophilas influenzae (1995), Saccharomyces cerevisiae (1996), E. coli (1997), bacteria of Bacillus genus, and the like.
The genome mappings for these microorganisms have been carried out only at those research institutes having wide-scale equipment.
In the late 1990's, the shot-gun method was introduced as a sequence determination method, and the DNA sequencers of multi-capillary-type came into practical use. For these reasons, it became possible to carry out sequence determinations with smaller equipment. As a result, genome mappings for bacteria of Streptomyces genus, Corynebacterium glutamicum , bacteria of Aspergillus genus, and the like have been completed, or are in progress (Reference 6).
IV. Classification of Inventions on Microorganisms
It is believed that, among microorganisms existing in the natural world, artificially isolated and scientifically recognized microorganisms are very few. Therefore, it can be assumed that there are many novel microorganisms that are still unknown. In this respect, it is meaningful to make patent applications for inventions on microorganisms.
Inventions on microorganisms can be roughly classified into the following two types:
(1) Inventions that create novel organisms by using genetic recombination and the like
e.g. Transduce, into bacteria A , a gene for trait b obtained from an organism B , so as to obtain a novel bacteria A' that express the trait b .
(2) Inventions of novel systems by using newly found microorganisms obtained from the natural world
e.g. A system that efficiently and safely decomposes waste materials by using novel bacteria C obtained by screening from the soil of a certain location.
In an invention of type (1), in most cases it is possible to describe, in the specification, the process of creating the novel microorganism (bacteria A' in the example above) so that a third person can reproduce the microorganism.
Therefore, it is not necessary to deposit the microorganism, as long as a third person can easily obtain the microorganism that is to be the base (bacteria A in the example above).
On the other hand, in an invention of type (2), the most important point of the invention is the newly found microorganism itself (bacteria C in the example above). No matter how specific the description, in the specification, of the process for finding the newly found microorganism, it does not mean that a third person can obtain the microorganism. Therefore, it is necessary to deposit the microorganism in cases where applications are to be made for the inventions of type (2).
The inventions of type (2) can be further classified into the following two types:
(2-1) Inventions in which metabolic products of microorganisms play the key role for the work of the system
e.g. A system that efficiently and safely decomposes waste materials in which a special kind of enzymes c produced by bacteria C play the key role for the decomposition of the waste materials.
(2-2) Inventions in which the microorganisms themselves play the key role for the work of the system
e.g. A genetic transformation system including novel bacteria D and a vector for exclusive use for the bacteria D .
In an invention of type (2-2), the bacteria D themselves are the most significant feature of the invention. In an invention of type (2-1), on the other hand, the bacteria C are not necessarily the most significant feature of the invention. In this case, if it is possible to identify the special kind of enzymes c produced by the bacteria C and the gene that codes the enzymes c , it is apparently more advantageous, in making a patent application, to emphasize that the gene and protein, which are materials, are the most significant features of the invention. Therefore, in an invention of type (2-1) among inventions on microorganisms, it is preferable to treat a gene and a protein as a main part of the invention, and to treat a microorganism as a subordinate invention.
V. Classification of Microorganisms and Patentability
If the microorganism is treated as a main part of the invention in the invention of type (2-1), the following problems may arise:
If the system using the bacteria C, for example, is treated as a main part of the invention of type (2-1), it is highly likely that a microorganism other than the bacteria C that is similar to the bacteria C does not, in effect, fall into the scope of the patent right.
Moreover, even if it is sufficient to obtain a right that only covers the bacteria C, there is a possibility that the right is not sufficiently effective, if the microorganism, which is a life form, is treated as the most significant feature of the invention, as opposed to the case where materials such as genes and proteins are treated as features of the invention. This is deeply linked to the problem of classification and identification of microorganisms.
The molecular biological methods described in chapter III may look superior to the classical classification method described in chapter II. In practice, however, the molecular biological methods are not perfect; they have respective drawbacks. Specifically, taking as an example the technique that uses the 16S rRNA gene sequence as a classifying indicator, there is not always a correlation between an identical 16S rRNA gene sequence and similarity in scientific characteristics.
In other words, there are cases where scientific characteristics such as appearances (shapes), physiological and biochemical characteristics, or Gram staining results are significantly different, while there is a high-level homology in gene sequences. Furthermore, it is believed that there is no correlation between the 16S rRNA gene sequence and the DNA-DNA homology.
Therefore, even the homology of 16S rRNA gene sequence, which is currently a principal classifying indicator, cannot be a decisive indicator for identifying species and genus. The same is true in identifying strains, which are subordinate to species.
As described above, it is very difficult to judge whether or not a microorganism that is said to be newly found is truly novel. Therefore, taking the above-described system using the bacteria C as an example, the novelty of the bacteria C is questionable if the enzymes c produced by the bacteria C are not specified, and bacteria E that belong to the same species as the bacteria C and that is capable of decomposing waste materials have been known.
In this case, it is necessary to prove the novelty and utility of the specific strain of the bacteria C.
Moreover, proteins such as enzymes are not always produced under the same conditions; they heavily depend, for example, on the environment in which microorganisms grow up. Therefore, even if the scientific characteristics of microorganisms are seemingly different, this cannot be a proof that the microorganisms are different as strains. To take a more extreme case as an example, it is possible that molecular biological methods are used as a ground for denying the novelty of a microorganism.
For example, suppose that a patent application is made for the invention of the above-described system using the bacteria C, and the rRNA gene sequence of the bacteria C is specified in the specification. And suppose that it is known that the bacteria C is capable of decomposing waste materials, but it is not known that this decomposition is caused by the enzymes c. Here, suppose that, at the time of application of this invention, there are known bacteria F that belong to the same species as the bacteria C and that are apparently different as a strain, judging from their physiological and biochemical characteristics. If the bacteria F are studied after the application and it is found that the 16S rRNA gene sequence of the bacteria F is homologous to that of the bacteria C, and that the bacteria F produce the enzymes c under certain conditions, the patentability of the invention of the system using the bacteria C is highly questionable.
In contrast, if specific enzymes produced by bacteria C and genes and a system using the same are treated as the main part of the invention, instead of a system using bacteria C, the most significant feature of the invention are genes and proteins, which are materials. As a result, uncertainty is significantly reduced as compared with the case where a microorganism is treated as the most significant feature of the invention.
For example, in the example above, by identifying the amino-acid sequence and gene sequence of the enzymes c before the study of the bacteria F progresses, it is possible to prevent the patentability of the invention from being seriously affected, even if it is found later that the bacteria F and the bacteria C are the same strain.
Therefore, in making a patent application for an invention on a microorganism and that is classified as the type (2-1), it should be avoided, as long as possible, to treat the microorganism as the most significant feature of the invention. Needless to say, even in the case of an invention of specific enzymes produced by bacteria C and genes, it is preferable to deposit the bacteria C, in order to meet the enablement requirement. However, in the case of an invention on a microorganism, it is necessary to reconsider whether or not the feature of the invention is really the microorganism itself.
1. International Patent Organism Depositary at National Institute of Advanced Industrial Science and Technology, Depositing and Furnishing Patent Organisms: A User's Guidebook (Tokkyo seibutsu kitaku bunjo gyoumu riyou no tebiki), in Japanese (2000).
2. HIRASHIMA, Yoshihiro, The Dictionary for Naming Nomenclatures of Organisms (Seibutsu gakumei meimeihou jiten), n Japanese (Heibonsha, 1994).
3. Society for the Study of Deposit of Patent Microorganisms ed., Deposit of Patent Microorganisms Q&A (Tokkyo biseibutsu kitaku Q&A), in Japanese (Hatsumei Kyoukai, 1993).
4. YAMANAKA, Takeo, Introduction to Microbiology (Biseibutsugaku he no izanai), in Japanese (Baifukan, 2001).
5. Kenichiro SUZUKI, Akira HIRAISHI, and Akira YOKOTA, Experimental Techniques for the Classification and Identification of Microorganisms
(Biseibutsu no bunrui doutei jikken hou), in Japanese (Springer-Verlag Tokyo, 2001).
6. "The Study of Genomes of Usable Organisms: Current Status," in Chemistry and Biology (Kagaku to Seibutsu), vol. 40, no. 7 (2002) to vol. 41, No. 1 (2003), serial articles in Japanese.