8Study on the Ways of Protection of
Post-Genome Research Products

In line with the recent progress of post-genome research, patent applications relating to its products arebeing filed in a manner unknown in the past, and it has been desired to promptly establish standards for theirpatentability.
Therefore, this study firstly attempted to clarify technologies subject to patents by reviewing theelementary technologies of protein’s three-dimensional structure analyses and bioinformatics of which are thecore technologies in the post-genome research, in consideration of their application to drug development anddiagnostic methods. Subsequently, with an eyes on the distinctive feature of these technologies; informationand its processing methods, this study extracted and discussed legal issues concerning to major types of claims
likely to be made (including reach-through claims(*1) , function inferential type claims, pharmacophore typeclaims(*2) and virtual screening (in silico screening) type claims), and advised various problems and theirsolutions including the relationship between enablement requirement and the degree of function analysis,
clarity of claims, and the relationship with the examination guidelines of computer software-related
inventions.

Ⅰ Introduction
The research in the field of life sciences ismoving from genome research focusing on the genelevel in the direction of what is called post-genome(following genome analysis) research focusing on
information relating to protein.
Although most of scientific products can beapplied to industrially applicable inventions, in thecase of the life sciences, there are many cases inwhich academic research products in particular are
directly linked to industry, such as a certain protein
which can be used directly as a pharmaceutical.
Thus, many investors for researches in the field oflife sciences expect patent rights to be granted for
those products.
Under these circumstances, since patentapplications relating to post-genome research
products having their characteristics in informationand its processing methods are being filed one after
another, and much more variety of information iscontained in these applications than those in thepast, the handling of which under the Patent Law is
becoming issues. These issues can be specificallydivided into the following three issues.
The first issue is how to handle the“identification” of the products (substances) andmethods utilize the above mentioned information.
The second issue is the extent to which the valueof “inferential” obtained from the information using
bioinformatics technology can be emphasized ascompared with actual experimental results. Finally,
the third issue is how to handle patent applications for

information itself or inventions that can only becharacterized by information.

Ⅱ Protein’s Three-Dimensional Structure
Analyses and Bioinformatics- Products, their Value and Potential 1

Protein’s Three-Dimensional Structure
Analyses Technology and Structural
Proteomics ProjectProteins are only able to demonstrate
their functions as a result of adopting athree-dimensional structure in which a primary
sequence of amino acids is spatially folded over on
itself. Thus, protein’s three-dimensional structure
analyses technology is extremely useful for
inferring the function of that protein. Whenconsidering proteins related to disease, protein’s
three-dimensional structure information leads toelucidation of the molecular mechanism of thedisease, and can be used as basic information thatis directly connected to treatment. Moreover,protein’s three-dimensional structure information
also serves as important information for thedevelopment of pharmaceuticals that regulate thefunction of proteins related to a disease state. In
actuality, together with the formation of theInternational Structural Genomics Organization(ISGO) that has already begun as a result of
numerous public subsidies, numerous venturecorporations, including Structural GenomiX (SGX),(*1) Referring to claims that are described so as to contain all possible products and so forth obtained through the use of basic
research means.
(*2) Pharmacophore typically refers to the representation of the structure characteristics essential for indicating a certain
pharmacological activity using multiple functional groups and their spatial positional relationships.

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Syrrx and Astex, have been established to servein core industries in the field of drug development,
and are beginning to become increasingly active.
At present, the main method for analyzingprotein’s three-dimensional structure is X-ray
crystal structure analyses. The next mostcommonly used method is nuclear magnetic
resonance (NMR). Methods other than these arequite specific, examples of which include electron
beam diffraction, electron microscopy and neutron
beam crystal analyses. In addition, recent progresshas also been made in the area of computerized
three-dimensional structure prediction technology.
Due to the progress of protein’s threedimensional structure analyses technology, although
three-dimensional structure information has beenobtained for numerous proteins, this information is
the result of gathering the individual research
results obtained in accordance with the respective
interests of each research group. On the other
hand, the objective of the genome project is tocomprehensively decipher the entire genetic
repertoire in genomes along with their sequences
irrespective of the interests of individual
researchers. Therefore, if the three-dimensional
structure information of proteins, which are theproducts of these genes, is also similarly covered inan efficient manner independent of individual
research, it will result in the construction of an
extremely useful infrastructure for protein function
research. Consequently, the concept of structuralproteomics is to promote the systematic,
comprehensive and high-throughput determinationof three-dimensional structures in an organizedmanner, and this concept is progressing rapidly
through various international projects.
Examples of important application issues
regardinghigh-throughput
three-dimensional
structure determination include: (1) screening anddesign of bound low molecular weight compounds
having novel functions (such as the search for leadcompounds in new drugs development), (2)modification of the molecular functions of proteinsby amino acid residue substitution (protein
engineering), and (3) elucidation of the effects ofamino acid residue substitution accompanying
cSNPs on phenotype such as disease susceptibility
and drug responsiveness, along with thecontribution to tailor-made treatment based on that.
In addition, examples of potential application
fields to new drugs development using the above
protein’s three-dimensional structure analyses
technology include: (1) inference of molecularfunction in terms of functional genomics, (2) proteinfunction analyses by homology modeling and virtual
screening of drug candidate compounds, (3)searching for lead compounds in new drugs
development, (4) docking studies with metabolic

enzymes and so forth for ADME improvement, (5)modification of protein molecular function by
primarily amino acid residue substitution, (6)elucidation at the molecular level of the effects ofamino acid residue substitution accompanying
cSNPs on phenotype such as disease susceptibility
and drug responsiveness along with thecontribution to tailor-made treatment based on that,(7) design of backup compounds having completely
new structures, and (8) new drug applications.
On the basis of these, in the case of
considering protecting patents of protein’s
three-dimensional structure analyses technology, it
will be necessary to adequate discuss such issues
as (1) the validity of so-called reach-through claims
that claim rights extending to downstream research
products, (2) utility (proof of function) and (3) theneed for protection of three-dimensional structure
information itself (these issues are discussed indetail in the following chapter III mainly from theviewpoint of requirements for patentability).
2

Bioinformatics

Bioinformatics originally referred to laboratory
data management systems for handling DNA or
genome information, tools for analyzing structure
characteristics based on DNA base sequences, andthat database environment. More recently however,bioinformatics has come to be interpreted in a
broader sense, being based on molecular biology,
information processing, statistics and mathematics,
and referring to not only DNA sequence analysis,
but also analytical software for information such as
literature information processing. Moreover, in the
broader sense, there are many cases in which it
refers to the entire spectrum of information
processing involving the analysis of information
relating to biology, medicine and pharmacology,
ranging from protein structure analyses tocompound searches. Thus, its purpose is alsochanging to the efficient organization of vast
amounts and numerous types of biologicalinformation, and the clarification of the biological or
medical significance of that information through its
analyses.
Although researchers have become able toaccess large amounts of information with theestablishment of an information technology (IT)environment, as a result of conversely requiring
information processing abilities that far exceed thelimits of human ability, it has become necessary torely on computers(*3). It is here where bioinformatics
is truly needed, and is also the reason whybioinformatics has grown rapidly over the past ten
years during which large amounts of DNA data
have been analyzed experimentally.
Examples of the characteristics of bioinformatics(*3) T.K. Attwood & D.J. Parry-Smith, Introduction to Bioinformatics (Addison Welsley Longman, Edinburgh Gate, 1999).
● 85 ●IIP Bulletin 2002

include: (1) obtaining of comprehensive analyses
results, (2) easy comparison with other information,(3) public disclosure of a considerably large amountof information (although the undisclosed newest
data of private corporations also exists), (4) additionof integrated annotation, (5) obtaining ofcomprehensive information that links various
databases, and (6) various service and business
forms, including software, hardware, onsite accessand the Internet.
Examples of the elementary technologies ofbioinformatics include: (1) prediction of the generegions and transcription control regions within
all DNA, (2) comparative genome analyses
accompanying function elucidation of the genes ofmodel organisms and laboratory animals, (3)population genetics analysis of DNA using single
nucleotide polymorphisms (SNP), (4) expression ofgenes at the RNA level by DNA chips, gene
networks and gene searching, (5) prediction ofprotein three-dimensional structure from genomes,(6) elucidation of the relationship between ligands
and protein three-dimensional structure, (7)analyses of the interactions between proteins, (8)comprehensive pathway analyses focusing on thecorrelation between substances and biological
functions, and (9) simulation of cell functions
focusing on the time-based changes in the amountsof various proteins. In addition, an example of atechnology considered to be important in the futureis the extent to which information analyses andexperimental analyses, which have each developed
individually, can be fused. Moreover, fusion withnanotechnology is leading to expectations not only
related to simply functions of the living body, buteven to the potential for artificial life through theuse of machines or through the fusion of the living
body and machines.
Important issues that must be confronted bythese elementary technologies include: (1) theestablishment of a database environment capable oforganizing and integrating large amounts of data, (2)improvement of calculation algorithms for achieving
greater efficiency of prediction and analyses of exon
portions and transfer control regions, (3)construction of gene network information systems
for gene expression profile analyses, (4) improvementof calculation techniques and physical models forapplication to configuration structure at themolecular and atomic levels, dynamics simulations
and the molecular orbital method, and (5)introduction of statistical mining techniques for
efficiently obtaining highly accurate results fromlimited clinical data when using population genetics
techniques.
In the case of considering protection of
bioinformatics patents on the basis of these,
although other biological data is to a certain
extent dependent on experimentation, it isnecessary to consider that in the case of

IIP Bulletin 2002

bioinformatics, it has the characteristic of being
unable to distinguish the source of the results(information) obtained, since information processing
is frequently used. In addition, accompanying the
progress of technology, numerous completely
new findings that far exceed the level of common
sense of the past will be discovered or are
expected to be created, in the case of
bioinformatics, when a result is obtained that iscompletely different from anything in the past.
However, it is difficult to determine whether it is
the result of an artificial defect in a computation
model, due to error that enters when making
calculations, or truly a significant, new discovery.
Thus, this will become the issue with respect to
how the ambiguity is to be treated in terms of the
Patent Law.

Ⅲ Discussion of the State ofProtection of Products - Issues
Relating to Requirements forPatentability
ATransforming Products into Claims

1

Claims of Protein’s Three-Dimensional
Structure Information, New Drugs
Development and their Products

In line with the progress of the above-mentioned
protein’s three-dimensional structure analyses
technology, one of the results anticipated byindustry is first the searching for molecules thatbind with target proteins. Namely, this involves
searching for molecules for regulating biological
functions, and with respect to the pharmaceuticalindustry, refers to new drugs development, andmore specifically, to the development of new
enzyme inhibitors as well as the development of
new receptor agonists and antagonists. Secondly,
the progress of protein’s three-dimensional
structure analyses technology is expected tocontribute to the modification of proteins into more
useful molecules. The properties of a protein can bechanged by converting an amino acid at a specificsite or by interchanging the structure of a specificdomain, making it possible to, for example, extend
the half-life of the protein in the body. Thirdly,
another example of the utilization of this technology
involves contributing to the diagnosis andprediction of diseases.
A schematic diagram of the actual manner inwhich new drugs development using protein’s
three-dimensional structure information proceeds
is shown in Fig. 1 from the time a gene is obtained
until a chemical substance in the form of apharmaceutical is developed using the crystal
structure.

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Fig. 1 Flow of Genome Drug Development Research Using Three-Dimensional Structure Information
GenomecDNA (sequence information(primary structure))
HTS compound search (screening)

Protein

Functional
analyses

Functional
analysis

Co-crystallization antagonist(inhibitor)

CrystalThree-dimensional structure
information analyse X-ray/NMR(three-dimensional coordinates)

Three-dimensional structure
information analyses X-ray/NMR(three-dimensional coordinates)

Three-dimensional structure
information analyses Xray/NMR (three-dimensional
coordinates)

Extraction of binding
pocketExtraction of binding
pocketInference of binding
pocketVirtual screening

Assay of biologicalactivity

Co-crystallization agonist(Re-screening) Optical derivation
Assay of biological activity

Correction of binding pocket(Pharmacophore)(Re-screening) Optimal
derivation Assay of biologicalactivity
Correction of binding pocket(Pharmacophore)

Hit compound
Practical antagonist (inhibitor)

In line with the progress of genome-relatedsciences, once the base sequence of a gene is first
determined, the amino acid sequence of thecorresponding protein is estimated followed byfunction analyses of that protein. In the
post-genome era, even under conditions in whichfunction is unknown, since the form (structure) of
the target molecule can be determined, it becomes
possible to focus on those molecules that bind withthat structure, thereby making it possible toderive and focus on more suitable compounds. In
actuality however, there are numerous hurdles tobe overcome. To begin with, at the stage in whichfunction has yet to be adequately determined, astudy must be conducted to determine which
protein is to be the target protein to confirm thatthe target protein is suitable for the purpose oftreatment (also referred to as target validation).
Moreover, even if the target protein has been
determined, there are frequently cases in which
the protein has more than one three-dimensional
structure, at least consisting of that when biologicalactivity is demonstrated and that of a precursor or
inactive form when there is no activity, and thesestructures are often quite different. In addition,
the protein’s three-dimensional structure mayundergo considerable distortion depending on the

Practical agonist

properties of the molecules that bind to the protein.
Thus, even when a certain protein has been
selected and its three-dimensional structure has
been elucidated, this does not immediately signify
the development of a new drug. Drug development
takes considerable time in order to satisfy all
requirements placed on pharmaceuticals relating toa high degree of safety and so forth.
The following provides an introduction to
examples of patent claims that contained protein
three-dimensional structures while focusing
primarily on previously disclosed patents.
(1) Claims relating to a protein crystal itself:
These refer to claims that only specify a“protein sequence or name and its crystal”,
claims that indicate a crystal lattice, namely the
packed state of molecules, and claims that are
represented with parameters obtained from X-ray
crystal diffraction (1/2Q values), three-dimensional
coordinates of results of interpreting diffraction
images and X-ray diffraction images themselves.
(2) Claims describing active sites, or with respect
to binding pockets, amino acid residues involved
with a binding site:
These refer to claims that specify the“coordinates of amino acid residues” or “mutual
distances”, as well as those that use molecules that● 87 ●IIP Bulletin 2002

bind to active sites to specify “molecules having
specific functional groups capable of hydrogenbinding with amino acid residues by indicating
those amino acid residues at the binding site withcoordinates”, “distances between specific functionalgroups of binding molecules” and “allowed spatial
coordinates of a binding pocket”.
(3) Claims that apply the above in the form of “amethod for identifying binding molecules using
structure coordinates”, “a treatment method using
compounds specified with structure coordinates”,“a computer system for displaying molecules thatincorporates three-dimensional structures”, and “amethod for inhibiting enzyme activity characterized
by three-dimensional structure”.
(4) Claims such as “a recording medium capable ofbeing read by a computer for recording atomic
coordinates” and “database that accumulates
compound information”.
(5) Claims relating to compounds which, instead ofanalyzing three-dimensional structure directly,
are specified by synthesizing a large number ofbound molecules (to a specific protein) and thensuperimposing those molecules to derive a
structure (pharmacophore) (a detailed descriptionof the patentability of pharmacophore-type claims isprovided in the following Section B, Part 2 ofChapter III).
(6) Use (treatment agent) claims in which
specification by three-dimensional structure has
been added to structure specification by anextremely broad Markush form.
2

Three-Dimensional Structure Information
anditsApplication
toProtein
Determination and Diagnostic Methods

A portrayal of the relationship between protein
three-dimensional structure and its function can bebroadly classified into c through h of Table 1.

When inferring the function of a protein fromits three-dimensional structure, caution is requiredwith respect to d, e and f in Table 1. In the caseof e, the resulting protein group is inferred to havea similar three-dimensional structure and similarfunction even though the constitutive amino acids
differ. At the present stage, although it is possible
to make a general classification based on thecharacteristics of three-dimensional structure suchas proteins belonging to the super family of serine
proteases and seven transmembrane receptor
proteins, it is difficult to determine their actual
pharmacological function. Moreover, it is also
necessary to consider that it has been recently
shown that proteins cannot be accurately
determined based only on information relating to
the primary structures or three-dimensional
structures, etc. of immature proteins, and that
information including the three-dimensional
structure of the mature protein following
translation is indispensable for determining thefunction of that protein. In addition, in the mannerof f in particular, it is also necessary to consider
that it is possible for proteins to have different
functions despite having similar three-dimensional
structures. Thus, although it is possible to acertain extent to determine a protein from its
three-dimensional structure, verification of that
protein through scientific experimentation is also
important. Furthermore, there are hardly any
proteins known to be applicable to the example ofh in which they have different three-dimensional
structures but demonstrate similar functions.
In addition, since the definition of similarity
between structure and function as previously
discussed in the field of genome science isextremely ambiguous, there is a need for studies on
evaluation criteria for similarity between structureand function in order to evaluate requirements forpatentability of proteins for which function has been

Table 1 Protein Three-Dimensional Structure and Function

Identical

Normalthree-dimensional
structure

Normal functionsc

Abnormal functionsdSimilarthree-dimensional
structure

Similar functionseDifferent functionsfDifferent
three-dimensional
structure

Different functionsg

Similar functionshconstitutive
amino acids

Abnormalthree-dimensional
structure

ProteinDifferent
constitutive
amino acids

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inferred. One area of potential interest is whether
or not it can be treated in the same manner as thesequence homology of genes and proteins.
In recent years, diseases have been
demonstrated to exist that are based on metabolism
being inhibited due to differences in protein’s
three-dimensional structure even though there are
no differences in the constitutive amino acids after
going through the normal protein processing
pathway (conformation diseases). Examples of suchdiseases include Prion disease and Alzheimer’s
disease, and such diseases fall under example ddescribed above.
In the future, it is predicted that conformationdiseases based on the formation of abnormal
three-dimensional structures due to misforming or
the formation of different molecular complexes due
to abnormal association of protein molecules, eventhough protein components are normal, will be
discovered, and that their three-dimensional
information will be accumulated. Examples ofdiagnostic methods that have been developed which
use this three-dimensional information include
positron emission tomography (PET), fluorescent
staining assay, immunoassay and electron microscopic
assay, and their utilization is expected to contributeto preventive medicine. Naturally, new types ofpatent applications are also expected to appear
relating to treatment methods, preventive methods
and diagnostic methods of conformation diseases.
Similar to genetic diagnoses, it is necessary toaccumulate normal three-dimensional structure
information as well as abnormal three-dimensional
structure information of various disease-related
proteins in order to enable diagnosis of protein
three-dimensional structure. The use of thisinformation is expected to lead to the developmentof low molecular weight compounds and protein
chips, etc. that demonstrate affinity for proteins
having abnormal three-dimensional structures.

B

Discussion of Requirements
Patentability of Claimsfor1

Requirements
forPatentability
ofReach-Through Claims and Function
Inferring Claims

New drug development research prior to the
genome era primarily adopted an approach based ona target for which the disease mechanism had been
determined, and screening for compounds having
the potential to become pharmaceuticals wasprimarily carried out through so-called wet
experimental systems both in vitro and in vivo.
However, in the post-genome era, due to theproliferation of bioinformatics technology, theprocess itself of new drug development research
has changed since proteins capable of becoming thetargets of drug development are identified both inlarge quantities and rapidly.
Accompanying this change in the process of
new drug development research, claims of patentapplications in pharmaceutical-related fields havealso clearly undergone a change. In addition topatent applications comprising compound claims ofthe conventional Markush form, a large number ofpatent applications have come to be filed that
describe screening method-specific claims (said tobe a kind of reach-through claim) so as to include allcompounds screened by the use of screening
methods.
Further, patent applications have also come tobe seen that described so-called function inferential
type claims which infer the function of a protein
and so forth based only on its similarity to thesequence or three-dimensional structure of aknown protein, etc.
The following indicates examples of typicalclaims that can be considered in the case of
specifying the three-dimensional structure of anovel receptor protein having the potential of
becoming a target of new drug development,
while also providing a discussion of the patentrequirements of reach-through claims andfunction inferential type claims.
[Examples of Claims]
Claim 1 A receptor R represented by the atomic
coordinates of Fig. 1.
Claim 2 A screening method for a compound
which activates or inhibits the receptor R wherein
the screening is carried out by using the atomic
coordinates of the receptor R represented in Fig. 1
for identifying the compound.
Claim 3 A compound obtained by the screening
method as claimed in claim 2.
Claim 4 A receptor R activator or inhibitor (XXtherapeutic/preventive
agent)
comprisingthe
compound obtained by the screening method asclaimed in claim 2 as an active ingredient.
(1) Novelty
The atomic coordinate data in claim 1 is a“means of specifying a product”, and in the case an
identical three-dimensional structure is not known,claim 1 is considered to have novelty. However, thisnovelty is questioned in the case the protein itself
in the form of receptor R is known by specifying its
amino acid sequence and so forth. In general, as
long as the subject of the claim is a “product” in theform of receptor R, claim 1 is not considered tohave novelty if its three-dimensional structure issimply specified with atomic coordinates.
On the other hand, in the case of analyzing thethree-dimensional structure of a known protein
based on its crystals, novelty can be considered tobe recognized in the case structure differences
between the known state and the analyzed state areclarified by the applicant, and it is clearly shown to
be a different entity.
In addition, it is necessary to create a standard● 89 ●IIP Bulletin 2002

for assessing identity between three-dimensional
structures. This is because, since assay values
naturally change according to the conditions and areaccompanied by error, acknowledgment of therange considered to be substantially identicalpresents an issue, and results having different
levels of analyses accuracy (also referred to as
resolution) present an issue as to whether theyshould be considered to be different in terms of the
Patent Law. In this case, the latter applicant generally
must demonstrate that the three-dimensional
structure relating to the invention of that applicant
has significant structure differences as comparedwith the known three-dimensional structure (of theprior application) even when considering error andconditions.
Since claim 3 is a claim that relates to a novel
substance, it is necessary that it is a claim which
does not include known substances. In the case of a
substance claim that merely specifies only ascreening method, however, there is a highprobability of a known compound being included,
thereby making it difficult to satisfy novelty. Thus,in order for novelty to be acknowledged for claim 3,
other requirements that specify a compound otherthan the screening method are thought to berequired.
(2) Inventive Step
In the case a certain three-dimensional
structure of receptor R is already known, and theclaimed three-dimensional structure of receptor R
is different from that, the inventive step of claim 1
presents an issue. In general, however, since a
person with ordinary skill in the art would not beable to easily obtain a protein having thethree-dimensional structure of claim 1 simply byusing ordinary skill, claim 1 can be determined tohave an inventive step provided the effect obtainedby that protein could not be easily predicted by aperson with ordinary skill in the art.
At present, a three-dimensional structure canbe predicted if there is 25-30% sequence homology.
Thus, in the case there are only substantial
differences in three-dimensional structure information,
it is possible to apply criteria that assess thepredictability of a three-dimensional structure or
the potential for acquiring three-dimensional
structure information by using, for example,
sequence homology between proteins. However, as
is described in the previously mentioned Table 1,since three-dimensional structure information itself
does not unconditionally lead to a specific, concrete
application, adequate examination regarding theapplication of such criteria is required.

With respect to other claims, it seems that
there are more cases where their relationships withenablement requirement, clarity, etc. arequestioned than cases where their inventive steps
are questioned on their own.
(3) Enablement Requirement and Clarity
If utility (industrial applicability, enablement) isfulfilled with respect to claim 1, it will be reasonable
to consider that the utility of claims 2 through 4
would also be fulfilled. With respect to claim 1, thespecific function of receptor R is generally required
to be clarified on the basis of verification orscientific evidence. However, in the case thethree-dimensional structure of receptor R has beenobtained, questions arise concerning the case of
searching a database(*4), comparing with thethree-dimensional structures of other receptors andthen inferring its function. When three-dimensional
structure were attempted to be compared for two
proteins for which homology of their amino acidsequences was not known, it is certain that there
are many cases in which the structures are
extremely similar and molecular functions areconserved(*5). However, as is described in thepreviously mentioned Table 1, it is necessary tonote that just because three-dimensional structures
may be similar, this does not necessarily mean thatfunctions are also similar.
Furthermore, since it is not possible for amethod that identifies agonists or antagonists of a
receptor having unknown functions to satisfy therequirements of utility, in case the utility of claim 1
is not satisfied, the utility of claims 2 through 4 isconsidered not to be satisfied, either.
If the utility of claim 1 is satisfied, and a
description is provided in the specification to an
extent that allows a person with ordinary skill in
the art to obtain receptor R with reproducibility,
then the enabling requirement and clarity are
considered to be satisfied.
With respect to claim 2 and the following
claims, it is considered to be reasonable to refer tothe results of the Trilateral Patent Office
Comparative Research Report on Reach-Through
Claims of November 2001(*6). According to thisreport, although the screening method of claim 2 is
not necessary required through its examples, withrespect to claims 3 and 4, all three patent offices
have indicated that in the case of simply being ascreening method, claims of a specified compoundand an application having that compound for its
active ingredient do not satisfy the enablement
requirement and clarity. Here, as a means of
avoiding reasons for rejection with respect to(*4) An example of a publicly disclosed database is the Protein Data Bank (PDB; http://www.rcsb.org/pdb/). A total of 17,082
structures were registered in this database as of January 15, 2002.
(*5) Shigeyuki Yokoyama: “Kozou Genome Kagaku ga mezasu Mono (Objectives of Structural Genome Science)”, Jikken Igaku(Experimental Medicine), Vol. 19, pp. 930-933 (2001).
(*6) http://www.jpo.go.jp/saikine/tws/report/report_start_page.htm

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enablement and clarity, both the Japanese andEuropean Patent Offices require the claims to be
restricted to compounds of the range described in
the specification. Namely, in contrast to denying thevalidity of reach-through claims themselves thathave been specified with a screening method only,
the US Patent and Trademark Office indicates amethod of avoiding rejection other than claim
restriction. The US Patent and Trademark Officehas stated that it is possible to avoid reasons forrejection with respect to enablement and clarity bysubmitting objective evidence that demonstrates
that a receptor agonist specifically disclosed in thespecification is that which represents the structureof a compound that is detected or identified by theclaimed method. Although it is believed that thesubmission of such objective evidence would not beeasy, it is worth noting that at the US Patent andTrademark Office, that the validity of specified
claims themselves of a screening method only are
not denied, namely there is the possibility ofcompound claims specified with only a screening
method being valid.
2

Patent Requirements of Pharmacophore
ClaimsA pharmacophore refers to an essential
structure characteristic for indicating certain
pharmacological activity, and due to thecharacteristic, drugs are able to interact with target
proteins by a specific mechanism. A pharmacophore
is typically represented by multiple functionalgroups and their spatial positional relationships.
Pharmacophore models of ligands haverecently been determined from the results of X-ray
crystal structure analysis of complexes of target
proteins and ligands, and examples have beenreported of the discovery of leading drug candidate
compounds by screening three-dimensional
databases in silico. The ultimately obtained
chemical substances that are useful as drugs are
one of the important products of genome structurescientific research.
Then, applications have come to be observedthat claim all possible drug candidate compounds
which can be obtained as a result of searching
three-dimensional databases using pharmacophoremodels. These claims are considered to be a type ofreach-through claim (refer to the above Section B
Part 1 of Chapter III), and result in the potential forvarious problems in terms of the Patent Law.
The following indicates probable examples ofclaims based on the discovery of pharmacophoremodels.
(Claim Examples)
Claim 1 A pharmacophore model (and recording

medium on which it is recorded).
Claim 2 A screening method of a drug candidate
molecule using the pharmacophore model.
Claim 3 A compound specified by the pharmacophoremodel (and compound obtained by the screening
method of claim 2).
Claim 4 A compound specified by the combinationof hte pharmacophore model and pharmacologicaleffect (and an agonist/antagonist specified by apharmacophore model).
Claim 5 A composition for treating disease A
containing a compound specified by the pharmacophoremodel.
(1) Patentability of Claims 1 and 2
The advocacy of a highly reliable pharmacophoremodel involves the providing of novel technicalfindings that are useful as a template for screening
or designing a drug candidate molecule. However,from the viewpoint of patentability, the discovery ofa pharmacophore model is that of the causative
relationship between the structure characteristics
of a drug molecule and the pharmacological effect,
and is understood to be the providing of a law ofnature itself or a mere presentation of information
relating to a correlation between structure andfunction. Thus, a pharmacophore model itself (theabove claim 1) is the “creation of a technical idea
utilizing a law of nature”, which is not included in
the concept of an invention in the legal sense. The
transformation of a pharmacophore model into atangible object by recording onto a recording
medium is not still considered to be using a law ofnature, and is therefore understood not to be
included in the concept of an invention in terms of
the Patent Law. Accordingly, an object like that
described in claim 1 is not protected under thecurrent Patent Law.
On the other hand, a screening method of adrug candidate molecule that uses a pharmacophoremodel (claim 2) is recognized to exhibit utilizationof a law of nature, and can be therefore patenter
under the Patent Law. However, novelty is denied
in the case the only difference with a known virtual
screening method is the pharmacophore model(data contents)(*7), and there are also opinions thatsuch methods should not be protected.
(2) Patentability of Claim 3(i) Clarity
It is considered to be relatively easy for a
person with ordinary skill in the art to judge inadvance whether or not a certain specific compound
has physicochemical structure features described in
the claims (multiple functional groups and their
spatial positional relationships), namely whether
or not that compound is contained in the scope ofclaims of a compound specified with a pharmacophoremodel. Thus, with respect to this point, the(*7) “Tokkyo Jitsuyoshinan Shinsa Kijun (Patent and Utility Model Examination Guidelines)” Part VII, Chapter 1, Computer
Software Kanren Hatsumei (Inventions Related to Computer Software), 2.3.6(2).
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description of the claims may be able to be said to
be clear on the basis of claim 3 of the above Section
B Part 1 of Chapter III in which a compound isspecified by a screening method only.
However, the description of a claim has
important significance with respect to comparing
with the prior art on the basis of that description,and examining patent requirements such as novelty
and inventive step. In the case of being specified
with a pharmacophore, it should be noted that acomparison with the prior art is generally very
difficult at the examination stage.
In addition, in the case the specification of acompound is not completed only with thephysicochemical structure characteristics of thecompound itself, but rather is made with themanner of association with the corresponding
target protein by introducing the three-dimensional
structure of the binding pocket and so forth of that
protein, similar to claim 3 of the above Section B
Part 1 of Chapter III in which the compound isspecified with a screening method only, it would be
judged that a person with ordinary skill in the art
would not be able to know in advance whether or
not the specific compound is contained in the scopeof the claim, thereby causing the description of theclaim to lack clarity.
(ii) Enablement Requirement
A compound specified with a pharmacophoremodel can be said to be such that its structure ispartially defined. However, since there is normallyno specification of other portions that are notessential for pharmacological activity, when
considering the entire compound itself, it cannot be
said to be structurally defined. Thus, similar toclaim 3 of the above Section B Part 1 of Chapter III
in which the compound is specified with a screening
method only, whether or not that compound can beproduced and used by a person with ordinary skill
in the art presents a problem.
In contrast to “screening” being an objective
action between the compound and receptor, theobjectivity of the person advocating the screening
can be included in a pharmacophore model. Thus,
some form of support relating to the reliability ofthe pharmacophore model (such as the indication ofexperimental data that clarifies the acquisition
pathway) is considered to be required.
In addition, in the case of being specified by apharmacophore model, there is also the problem
the manner in which it is shown that all compounds
included in claims can be produced. Even if typical
production examples are described in the detailed
description of the invention of the specification forseveral of the compounds included in the claims,
the range of compounds that are confirmed to beable to be produced based on the preparation
examples and the range of compounds represented
by a pharmacophore model will not coincide.
Be noted that the essence of a chemical

IIP Bulletin 2002

substance invention is conventionally considered tobe the providing of a chemical substance that is
novel and useful, or in other words, can be usedindustrially, and in order for the validity of this to berecognized, that compound is confirmed by achemical structure and so forth in the specification,is indicated as being able to be produced, andalthough authentication is not required that is as
severe as in the case of use inventions, thedisclosure of reliable utility (industrial applicability)
is required. As long as an invention is claimed in
the form of a compound (chemical substance), it isconsidered to be reasonable that such requirements
be levied in order to be granted a patent. In cases
where descriptions of examples of actually
producing representative compounds included in
the claims or the intended utility of compounds
having a pharmacophore model that are adequate
for convincing a person with ordinary skill in the art
are not contained at all in the specification, in
addition to the problem of satisfying theenablement requirement, it would be valid to
examine that such an invention would inherently
not be considered to be an invention that can beused industrially.
(iii) Novelty and Inventive Step
In general, since it is difficult to compare
compounds specified by a pharmacophore modelwith compounds specified by a conventional
chemical structure, and there are many cases inwhich applications are filed without adequately
examining whether or not known compounds areincluded, there is an extremely high probability thatknown compounds are included in the scope of theclaims.
(3) Patentability of Claims 4 and 5
With respect to pharmacophore models, aclaim is considered to have patentability if it is likeclaim 5 represented in the form of a so-called use
claim in the manner of “A composition for treating
disease A compising a compound specified by apharmacophore model.” When considering that a
pharmacophore model is found as a result of
discovering a correlation between a certain
structure and pharmacological effect, describing
both structure characteristics and pharmacologicalactivity (use) in the claims in some form is believed
to be appropriate for clarifying the essential portion(technical idea) of the invention and making thescope of rights the scope recognized by theinventor.
On the other hand, specification bypharmacological effect is also thought to be allowedwith respect to claim 4 as well on the premise thatthe compound included in the claims be a novelcompound. At present, if a description of “acompound X having carcinostatic properties” statesthat carcinostatic properties are a uniquecharacteristic of a specific compound X, a
description of “having carcinostatic properties” is● 92 ●

not useful in specifying that substance, and thisclaim is understood to be referring to “compoundX” itself at the examination level(*8). Although acompound specified by a pharmacophore model is
only partially structurally defined, since the overall
structure is not specified (and the essence of thisconversely lies in not deciding the overall
structure), there may be compounds that do nothave the intended pharmacological effect among thewide range of compounds included in the claims.
Thus, the specifying of a specific pharmacologicaleffect may be able to be considered to be useful indemarcating the scope of an invention.
3

Patentability
InventionsofVirtualScreening

The following provides an example of a claimof a virtual screening method (in silico screening
method).
(Claim Example)“A screening method for cancer therapeutic
drug candidates comprising: a step of inputting theatomic coordinates of a specific three-dimensional
shape to first storage means, a step of inputting theatomic coordinates of a candidate compound are
input to second storage means, and a step ofcarrying out the selection of a compound that binds
to a pocket by XXX by YYY means.”
Inventions related to computer software in
Japan are defined as “inventions that require
software for the enablement of the invention” in“Computer Software-related Invention Examination
Guidelines”. According to this definition, in addition
to conventional computer software-related inventions,the inventions of various fields, including businessmodel inventions that include financial methods andbioinformatics inventions that include virtual
screening, are also included in computer
software-related inventions provided they require
software. There are therefore cases in which theabove virtual screening inventions would be judged
to have patentability under the “Computer
Software-related Invention Examination Guidelines”.
According to these Examination Guidelines, inthe case the difference between a claimed invention
and a known cited invention lies only in thecontents of the data, the novelty of the invention is
not acknowledged(*9). In other words, if only thedata contents represented by the atomic

coordinates in the above claim are novel, there is
the possibility of the claim being judged as lacking
novelty.
However, as is described in the above Section
B Parts 1 and 2 of Chapter III, when consideringthat data contents themselves that are represented
by atomic coordinates and so forth are unable toobtain patent protection, there is also the opinion
that the patentability of virtual screening claims
should be recognized in order for a person who has
invested in an analysis of three-dimensional
structure to continue to be able to proceed with
development or obtain a financial return bylicensing to a suitable business partner.
Consequently, it will be necessary to examine thedistinction between virtual screening inventions
worthy of patent protection and those that are notconsidered to be such inventions within the current
legal framework by perceiving the essence of
virtual screening inventions from various
viewpoints, including not only the conventional
approach of expanding the range of protection, butalso with respect to utility (enablement, industrial
applicability), novelty and inventive step(*10).

Ⅳ Conclusion
1

Protein Three-Dimensional Structure
Information and Bioinformatics

In the structural genome project, research
products are aggressively publicity, and structure
information obtained by government institutions isdisclosed six months after that information has
been acquired. The wide-ranging publication ofresearch products itself is also desirable based on
the need for publicity of government institutions.
However, since this structure information has value
as an intellectual property, adequate caution isrequired in the handling of that structure
information.
More specifically, caution is required withrespect to (1) confidentiality until publication of
three-dimensional structure information, (2)handling of the products of function analyses
research using three-dimensional structure
information, and (3) protection of the threedimensional structure information itself as anintellectual property.

(*8) supra note 7 - Examination Guidelines, Part II, Chapter 2, Shinkisei Shinposei (Novelty and Inventive Step), 1.5.2(2)dExample 1.
(*9) supra note 7(*10) A specific proposal regarding this distinction, which states that such a distinction can be made by dividing computer
software-related inventions into inventions whose technical essence utilizes laws of nature and those that do not, by
focusing on the importance of using laws of nature in virtual screening inventions, is described in detail in a report of thisstudy published by the Institute of Intellectual Propertyentitled, “Post Genome Kenkyu Seikabutsu no Hogo no Arikata ni
kansuru Chousakenkyu HoukokushoStudy on the Ways of Protection of Post Genome Research Products”, pp. 130-140,
Institute of Intellectual Property , 2002.

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Although cautions relating to the above (1) and(2) are generally forced to be left to accommodation
through contracts, with respect to (3), it is possible
to attempt to protect three-dimensional structure
information in the form of a trade secret provided
confidential protection is maintained.
In addition, since the requirement ofprotecting three-dimensional structure information
as a trade secret is no longer required to besatisfied after that information has been published,
it may be possible to protect that information in theform of a database. In Japan, although it is possible
to protect information having creativity as a
database (information selection or organizational
structure) under Copyright Law as a copyright,
since databases merely consisting of the collectionof information are not recognized to have creativity
and are not qualified as being copyright, they are
not protected under Copyright Law. However, since
the latter database also has value as a property, it isnecessary to examine legislation for protecting theinformation itself.
With respect to bioinformatics, technology
development is proceeding at a rapid pace, and atpresent it is considered to be difficult to infer thefunctions and three-dimensional structures ofproteins using bioinformatics technology alone forfields where there is currently little accumulationof empirical knowledge in particular. However,since it is becoming easier to infer the functions
and three-dimensional structures of proteins due toprogress in the development of technology, it isnecessary to adequately consider the relationshipbetween requirements for patentability and thisprogress in the development of technology.
2

Problems Relating to Requirements forPatentability(1) Patentability of Proteins Specified with
Atomic Coordinates
It is necessary to adequately examine thevalidity of applying the conventional approach to thepatentability (novelty, inventive step) of proteinsspecified with atomic coordinates.
It is necessary to examine novelty withrespect to c a determination of novelty based on
the difficulty in determining the identity of
three-dimensional structures, and d the approach
to novelty in the case where a protein itself isknown by a primary sequence and so forth.
In addition, it also necessary to sufficiently
examine inventive step with respect to c adetermination of inventive step in the case where
the three-dimensional structure of a protein is novel,d determination requirements for inventive step
including demonstration of safety, differences inpharmacological effects and so forth, and e therelationship with a description requirement ofclaims.

IIP Bulletin 2002

(2) Requirements for Patentability ofCompounds Specified by In Silico
Screening Methods
With respect to the patent requirements ofcompounds specified by in silico screening methods,
in addition to it being necessary to adequately
examine requirements for claim description fromthe viewpoint of clearly eliminating known
compounds and specifying compounds having
specific activity, it will be also necessary toadequately examine the enablement requirement of
the relevant claims when considering requirements
for claim description.
(3) Requirements
forPatentabilityof
Function Inferring and Structure Inferring
ClaimsAmong the requirements for patent relating tofunction inferring or structure inferring claims in
the case of protecting the products of post-genome
research in the form of patents, those requirementsthat present the greatest issues are utility(industrial applicability, enablement) and clarity.
More specifically, it is necessary that adequate
examinations be conducted with respect tonumerous viewpoints including c the standard offunction inferential when determining utility, d
the degree of a use by elucidation of
three-dimensional structure, e the approach toutility within the context of bioinformatics, f therelationship between technical progress, utility andinventive step, and g the relationship between
homology and structure homology with enablement
and clarity. Similarly, it is also necessary to examine
the inventive step of function inferring andstructure inferring claims from various viewpoints.
(4) Patentability of Pharmacophore Claims
Pharmacophore
referstostructure
characteristics required for indicating specificpharmacological activity. In the Patent Law, withrespect to inventions that simply present
information, patentability of them is denied.
Consequently, even if an invention is a screening
method for drug candidate molecules that uses apharmacophore model, in the case where the only
difference with a known virtual screening method is
the pharmacophore model (data contents), there isbelieved to be the possibility of patentability being
denied. However, since it is a fact that data itself inthe form of a pharmacophore model is recognized tohave value as a property, it is necessary to examine
not only the potential for protection based on apatent, but also protection as another intellectual
property.
In addition, since there is also the possibility ofknown compounds and compounds that cannot
actually be made being included in claims ofcompounds having a pharmacophore, it will benecessary to adequately determine the manner inwhich claims are described from the viewpoints ofclarity, enablement and so forth.

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(5) Protection of “Jouhou (Information)”
Since the products of post-genome researchfrequently have the form of “Jouhou (information),”it will be necessary to discuss the protection of“Jouhou (information)” under the Patent Law in the
broad sense.
Since numerous “software” is included in the
products of post-genome research, there are thoseof the opinion that, rather than searching for ways
to protect that software in the form of a “thing” or“process”, it would be reasonable to protect the“Jouhou (information)” itself under the Patent Law
by perceiving it as an intellectual property.
Consequently, it will be necessary to discuss how
the protection of “Jouhou (information)” should befrom a wide range of viewpoints.
More specifically, it will be necessary to
determine the matter of requiring a revision of thesystem in the form of expanding the range ofcoverage of protection under the Patent Law in theform of a medium to long-range issue. However, atleast for the time being, it will be necessary to
conduct further studies in terms of operation,
including the drafting of guidelines and the
production of case studies and so forth with respect
to the manner in which claims are described.
In addition, since the concept of “Jouhou(information)” includes various types of informationsuch as that equivalent to information or knowledge
and that merely equivalent to data, rather thanconsidering general protection of all information, it
will be necessary to conduct specific studies on
how the protection should be in accordance with
the nature of each piece of information.
Furthermore, when discussing the protection of“Jouhou (information)” itself, it will be necessary
to examine the validity of directly applying
practices based on the conventional assumptionsof “hardware” to patent requirements such as“industrial applicability” and “utility.”
Moreover, since the products of post-genome
research are also frequently in the form of“databases,” in addition to examining the present
state and problems associated with protection of“databases” under the Copyright Law andprotection as a “trade secret” under the Unfair
Competition Prevention Law, it will be also
necessary to examine the need for a “database”
protection law.
(6) Issues with Scope of Patent Rights andEnforcement of Patent Rights
There are also issues with respect to the scopeof patent rights and the enforcement of those rights
in the case of protecting the product of
post-genome research with a patent.
For example, since the effect of patent rights
differs between a production process and a simple
process in the Patent Law, depending upon whether
an in silico screening method is considered to be a
production process or a simple process, the effect ofpatent rights (whether or not it extends to a thing)is made different. Although screening methods are
typically considered to be simple processes, when
considered in this way, questions arise regarding
the efficacy of patents of screening methods fromthe viewpoint of enforcement of the rights.
Although it is not necessarily a problem to consider
screening methods to be production processes
from the viewpoints of the nature and effect ofscreening methods, it will be necessary to
determine the scope of patent rights from theviewpoint of effectively exercising those rights withrespect to the ease of establishing infringement
and so forth.
In addition, since there is concern overcreating considerable impairment of research
activities as a result of granting patent protection
when protecting the products of post-genome
research in the form of patents, it will be also
necessary to make a comprehensive determinationfrom various viewpoints regarding problems
relating to the scope of patent rights and theexercising of those rights, including theinterpretation of “experiment and research” definedin Article 69 of the Patent Law.

● 95 ●(Researcher: Kunihisa Masuoka)

IIP Bulletin 2002