PAT E N T S

At a conference held in Austria1, the European Patent Office (EPO; Munich,

Germany), United States Patent andTrademark Office (USPTO; Washington,DC) and Japan Patent Office (JPO; Tokyo,Japan) conducted a comparative study onpatent examination guidelines relating toprotein three-dimensional structure. Thepurpose of the conference was to discuss thepatentability of three types of inventions—those based on ‘information content,’ thosebased on ‘in silico screening methods’, andthose based on ‘materials predicted frominformation’ (e.g., compounds and pharma-cophores designed by the in silico screeningmethods). In each case, the patent officessought answers to the following questions:first, are three-dimensional structural coor-dinate data patent-eligible subject matter;second, do products obtained solely fromthe use of information satisfy the ‘descrip-tion requirements of patent applications’that are required to secure disclosure of aninvention; and third, do in silico screeningmethods using novel protein structuralcoordinate data have novelty and an inven-tive step?

Structure-based drug designStructure-based drug design (SBDD)employs multi-step processes: (1) a hit iden-tification step, which involves the screening

of a large number of compounds that inter-act with the biological target, (2) a lead gen-eration step, which involves the chemicalmodification of a suitable target molecule toimprove chemical characteristics, and (3)lead optimization, which involves the addi-tional modification of the lead compoundsto optimize and produce suitable candidatecompounds. Using the protein structureanalysis, inhibitors selective for cyclooxyge-nase 2 (COX2) are created in the form ofnon-steroid anti-inflammatory drugs(NSAIDs), which has led to the creation ofVioxx by Merck (Rahway, NJ, USA) andCelebrex by Searle/Monsanto (now part ofPfizer; New York). These drugs have becomegreat successes and have generated annualsales of over US$ 4 billion in the year 2000(ref. 2).

In Japan, RIKEN Structural GenomicsInitiatives (RSGI) is analyzing protein struc-tures in collaboration with many pharma-ceutical and biotechnology companies,beginning in December 2003 as a “ProteinPartnership Program3”. Clearly, as SBDDbecomes an increasingly commonplace toolin drug discovery, guidance on the types ofinventions that can be patented is needed.

Patentability of structural coordinatesTable 1 details the seven types of claims thatcan be made on structural data. Accordingto the report from the trilateral comparativestudy, inventions that claim “informationcontents” in the form of a computer modelor data array pertaining to protein three-dimensional structural coordinates (Claim Iin Table 1) are not patent-eligible subjectmatters or statutory inventions as they areconsidered as “mere presentations of infor-mation or abstract ideas.” Thus, applicationsof this type are likely to be rejected by thepatent offices without being examined fornovelty, utility or other requirements.

In Japan, a patentable invention (statu-tory invention) is defined as “a highlyadvanced creation of technical ideas utiliz-ing a law of nature” under Article 2,Paragraph 1 of the Patent Law. Since infor-mation contents are “mere presentations ofinformation,” they are not a creation of atechnical idea and are not regarded as astatutory invention. Similarly, presentationsof information are considered as abstractideas and are thus neither patentable underUS patent law 35 USC §101, nor eligible forpatent protection under Article 52(2)(d) ofthe European Patent Convention (EPC).Therefore, all three patent offices consider“presentation of information” notpatentable, as it is merely a descriptive mate-rial that does not contain physical or tangi-ble embodiment.

Unlike computer programs, which areprotected by patents, an invention that isclaimed as “a computer-readable storagemedium encoded with structural data of aprotein” (Claim II in Table 1) is merely apresentation of information or an abstractidea, and thus its “information contents” arealso not regarded as being eligible for patentprotection or a statutory invention. All threepatent offices require that the software befunctionally interactive with the hardwarefor the purpose of patent protection. Claimsincluding an information storage mediumencoded with protein three-dimensionalstructural coordinate data do not take aform of functional interaction with thecomputer and thus are not considered to bepart of the computing process by the hard-ware. Therefore, these claims do not meetthe requirements for patent-eligible subjectmatter or a statutory invention.

In the past, program inventions wereregarded as “abstract ideas” or “creationsresulting from mental activities” in the samemanner as calculation methods, and were

Itsuki Shimbo is at the Intellectual Property and Technology Transfer Office, RIKEN, 2-1Hirosawa, Wako-shi, Saitama, 351-0198, Japan,Rie Nakajima is at RIKEN Genomic SciencesCenter (GSC), Yokohama, Japan, ShigeyukiYokoyama is at RIKEN GSC & the HarimaInstitute and the University of Tokyo, and KoichiSumikura is at the National Graduate Institutefor Policy Studies (GRIPS), Tokyo, Japan.e-mail: shimbo@postman.riken.go.jp

Patent protection for protein structure analysisItsuki Shimbo, Rie Nakajima, Shigeyuki Yokoyama & Koichi Sumikura

Three national patent offices have consulted on patents that cover protein three-dimensional structural data andpharmacophores, with significant implications for the biotechnology industry.

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not considered to be eligible for patent pro-tection. However, in response to the requestsby the industry, patent protection was estab-lished for computer software-related inven-tions4,5.

In 1996, the USPTO announced its exam-ination guidelines governing computer-related inventions6. In accordance with theguidelines, data structures and computerprograms coupled with or having a func-tional relationship with computer process-ing means are regarded as being eligible forpatent protection. For example, a functionaldata structure that enhances computer pro-cessing efficiency is eligible for patent pro-tection. On the other hand, an inventionthat involves either artistic works (e.g.,music or writing) or simple data arrange-ments being recorded onto a computer stor-

age medium (e.g., a CD) is merely informa-tion (visual or sound) content and does nothave any functional correlation with thecomputer processing means. Such “non-functional information contents” are clearlydistinguished as “abstract ideas” that are notpatent-eligible subject matter7,8.

An EPO decision in a case involving IBMstated that if the processing steps by a pro-gram demonstrate a technical effect that isgreater than the ordinary physical interactionbetween software and hardware, they will notbe excluded from patent eligibility9. Similarto the US case mentioned above, althoughmere information contents are not eligiblefor patent protection, programs and datastructures with technical properties are con-sidered to be eligible for patent protection.

In Japan, the latest computer software

examination guidelines were issued inJanuary 2001 (ref. 10), and an amendmentto the Japan Patent Law was made in the fol-lowing year to add programs to “productinventions” to clarify provisions pertainingto patent protection of program inventions(Article 2, Paragraph 3, Item 1). For a pro-gram to be granted a patent, informationprocessing by software is concretely realizedby using hardware resources (CPU, harddisk, etc.).

In contrast to the USPTO and EPO, theJPO asks for the particular and concretedescription of an information processingmethod where the information processingby software corresponds with the hardwareresources. Therefore, inventions that fallunder Claim III shown in Table 1 are notapplicable to the statutory invention, and

110 VOLUME 22 NUMBER 1 JANUARY 2004 NATURE BIOTECHNOLOGY

Table 1 Examples of claims relating to three-dimensional protein structure

Case Claim description Patentability

Claim I (Information contents claim) None

(Case 1, Claim 2) A data array comprising the atomic coordinates of protein P as set forth in Fig. X which, when acted upon by a

protein modeling algorithm, yields a representation of the three-dimensional structure of protein P.

Claim II (Information contents claim) None

(Case 2, Claim 1) A computer-readable storage medium encoded with the atomic coordinates of protein P as shown in Fig. Y.

Claim III (In silico screening claim) None

(Case 6, Claim 1) A method of identifying compounds that can bind to protein P, comprising the steps of: applying a 3-dimensional

molecular modeling algorithm to the atomic coordinates of protein P shown in Fig. Z to determine the spatial

coordinates of the binding pocket of protein P, and electronically screening the stored spatial coordinates of a set

of candidate compounds against the spatial coordinates of the protein P binding pocket to identify compounds that

can bind to protein P.

Claim IV A method of identifying compounds which can bind to protein P by comparing the 3-dimensional structure of EPO

(Case 7, Claim 1) candidate compounds with the 3-dimensional molecular model shown in Fig. U which comprises the following

steps: (1)..., (2)…, (n)… [The three dimensional molecular model of Fig. U presents the positions of heteroatoms

in the amino acids constituting the binding pocket of protein P (i.e., amino acids 223, 224, …and 384) wherein said

heteroatoms can form hydrogen bonds with hydrogen bonding functional groups in a candidate compound. Steps (1)

through (n) describe a data processing method in which…]

Claim V (Pharmacophore claim) None

(Case 8, Claim 1) A pharmacophore having a spatial arrangement of atoms within a molecule defined by the following formula:

in which A and B both represent an electron donor atom, C represents a carbon atom that is a part of a hydrophobic

group, and the distances represent the distances between the centers of the respective atoms.

Claim VI (Pharmacophore claim) None

(Case 8, Claim 2) An isolated compound or its salt defined by the pharmacophore in claim A.

Claim VII (Protein claim) None

(Case 3, Claim) An isolated and purified protein having the structure defined by the structural coordinates as shown in Fig. V.

In the trilateral comparative study, various claims relating to protein three-dimensional structure were hypothesized, and their abilities to satisfy each patent requirement were assessed. Inthis report, several of those cases have been extracted. The parentheses in the left column of the table enclose the case name used in the trilateral comparative study.

A B

C

1.59+/-0.50 nm

1.33+/-0.25 nm0.95+/-0.25 nm

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information processing methods by com-puter should be specifically described indetail as in Claim IV. This is because “thesaid information processing equipment(machine) or operational method thereofparticularly suitable for the purpose” can bequalified as a “creation of the technical ideasutilizing a law of nature” (Article 2,Paragraph 1).”

Patentability of in silicoscreening methodsIn silico screening methods are computerizedmethods that search for compounds usingthe protein three-dimensional structuraldata that interact with an active site based onthe information obtained from a large-vol-ume compound library (Claim III, IV). Thethree patent offices have different interpreta-tions on these types of screening claims. Incases where a protein function is known andhas industrial applicability, how should thepatentability of an in silico screening methodbe examined? At the USPTO, in silico screen-ing methods are patent-eligible subject mat-ter, as they produce useful, concrete andtangible results11. At the EPO and JPO, thesame methods are also eligible for patentprotection because they have technical char-acteristics and their potential for use in drugscreening. While the three patent offices arein agreement on patent eligibility, they holddifferent views on the assessment of noveltyand inventive step.

With respect to the in silico screeningmethod, the EPO decided that if the proteinthree-dimensional structural coordinatedata have novelty, the method satisfies thenovelty and the inventive step requirements.The inventive step of an in silico screeningmethod is evaluated on the entire invention,including the protein three-dimensionalstructural coordinate data themselves.Although protein three-dimensional struc-tural coordinate data per se are merely pre-sented as information, they are consideredto have a technical effect as long as they areused in an in silico screening method tosearch for compounds. In other words, if theprotein three-dimensional structural coor-dinate data meet the requirements of nov-elty, inventive step and susceptible ofindustrial application, the in silico screeningmethod may be patentable (Claim IV). Ifspatial information of binding pocket is notdetermined (Claim III), it fails to satisfy suf-ficiency of disclosure, as comparable withenablement matter.

This contrasts with the position of theUSPTO and JPO in cases where the algo-rithm of a screening method is commonly

known. They do not consider that suchmethods satisfy the novelty and the inven-tive step requirements, even though the pro-tein three-dimensional structuralcoordinate data may have novelty. As non-functional data used in a known algorithmdo not modify any of the processing steps,and simply changing the data to beprocessed is not beyond the ordinary skill inthe art, the USPTO considers the overallinvention to be obvious under US patentlaw and the JPO considers the invention tolack novelty. In other words, patent examin-ers would evaluate the claims based only onthe technical ideas of the screening method,separating the non-functional data contentsfrom the entire invention. According to theUS guidelines reported in July 2000, aninvention is obvious if the only differencefrom the prior art is the data being stored12.Similar examination guidelines are alsoestablished in Japan. A patent cannot beacquired due to the absence of novelty whena program invention and its technical ele-ments other than the information contentsare already known. However, this does notmean that an in silico screening method perse, is not eligible for patenting. For example,in the case of a newly invented methodcapable of accurately screening compoundsby a computer, a patent can be granted if themethod has novelty and an inventive step.This case merely addresses the finding thatinformation contents alone do not have aneffect on the patentability of screeningclaims in the US and Japan.

Patentability of compounds predicted by computer Pharmacophores are derived based on spa-tial information of protein active sites byanalyzing three-dimensional structures andpredict compounds responsible for desir-able biopharmacological activity.Pharmacophore-type claims describe a spa-tial arrangement of atoms instead of achemical formula (Claim V) or compoundsdefined by a pharmacophore (Claim VI) tocover a large number of compounds. ClaimV, in which a pharmacophore itself isclaimed, is considered to be a mere presen-tation of information, and does not satisfypatent eligibility.

Then do compounds predicted by com-puter meet patentability? For in silicoscreening methods, although bindingbetween a target protein and candidatecompounds can be predicted from a dock-ing study involving molecular dynamics cal-culations, patent examiners would considerthe accuracy of this prediction to be low and

unreliable for granting a patent, due to thelack of in vitro experimental data. Thus, athird person has to conduct undue experi-ments to determine and confirm the bind-ing of the protein with each individualcompound in order to implement the inven-tion. Therefore, this invention likely fails tocomply with the written description andenablement requirements to the extent thatit claims compounds other than thosespecifically made and tested, either in vitroor in vivo.

In Japan, inventions of chemical com-pounds may not satisfy the requirement of astatutory invention when description of anembodiment indicating the utility of thecompound is not adequately given. OneJapanese case involved a lawsuit as towhether an invention was complete or not.Despite the disclosure of a large number ofchemical substance structural formulasrelating to a herbicide, the invention washeld to be incomplete because the disclosureonly provided a small number of workingexamples, and the compounds included didnot demonstrate the prescribed effect13.

Inventions involving compounds pre-dicted by in silico methods are considered tobe incomplete in Japan, and such com-pounds are not patentable if in vivo or invitro experimental examples are not pro-vided. Because they are not adequately sup-ported by examples in the detaileddescriptions, these compounds are also con-sidered not fully satisfying the writtendescription requirement in the US or thesupport requirement of Europe’s EPCArticle 84. To obtain a patent for com-pounds identified using in silico screeningmethods, it is advisable to include some invivo or in vitro experimental examples ofcandidate compounds in the description.

Patent strategies for protein structural analysisSo what is the most effective method toexpress a claim for a specific compound thatis predicted to bind with a specific proteinby computer analysis? One effective strategyis to list all the candidate compounds anddescribe them in the form of a ‘Markush-type claim’. All three patent offices considercompounds presented using a pharma-cophore as not satisfying the clarity require-ment. Furthermore, in the EPO’s viewchemical formulas are described as a generalrule to satisfy the clarity requirement, butonly when a chemical substance cannot berepresented with a chemical formula orname is the identification of the substanceby parameters (i.e., molecular weight, solu-

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bility) allowed14. A Markush-type claimrefers to a form of expression in which twoor more items are alternatively describedand is used to describe a claim in alternativeforms in the case of a plurality of choiceshaving similar properties or functions. Forexample, in the field of chemistry, a group ofcompounds can be broadly protected in themanner of “substitution group R representsA, B or C”. It is alternatively usable fordescribing an invention in the case of a plu-rality of choices having similar properties orfunctions.

Unlike a pharmacophore claim, aMarkush claim clearly describes a concretecompound, and thus, its product can be cre-ated (i.e., how-to-make is understood,thereby it is possible to satisfy the enable-ment and clarity requirement). By indicat-ing working examples for representativecompounds, it is possible to satisfy thedescription requirement of specification.Therefore, the claim can be expanded toinclude compounds with similar properties,which suggests compounds that satisfy thepharmacophore have similar properties.

Moreover, determination of a pharma-cophore, the spatial information of an activesite that binds with a specific compound,allows a large number of compounds thathave been obtained to be broadly described.When pharmacophores are shown togetherwith in vitro or in vivo experimental data ofrepresentative compounds, it brings theassumption that the possibilities as drugcandidates would increase for compoundsnot actually experimented, thereby satisfy-ing the enablement and written descriptionrequirement. Compared to claims derivedonly from an invention with experimentaldata from an in vitro screening method, thisstrategy provides wider range claims andeffectively prevents third parties from cir-cumventing the patented invention.

What types of products should beclaimed? Commonly, the effective way toclaim is when claims are useful for con-sumers. It is appropriate to have claims thatinclude a drug rather than just focusing onan experimental reagent such as an antago-nist. In Japan, when drugs are patented,both the drug test methods and the pharma-cological data must be described, in addi-tion to basic data. If these are not described,a person with ordinary skill in the art will be“unable to use the effective drug”, and there-fore the claim will not satisfy the enable-ment requirement.

It is important to describe specifically themedical components that can be inferred tobe drugs. There have been cases in which

pharmaceutical inventions were held as notsatisfying the enablement requirement inJapan. For example, a patent applicationpertaining to a muscarine-like receptorantagonist with pharmaceutical potential inthe treatment of diseases associated withspontaneous movement of smooth muscledid not satisfy the enablement requirementbecause concrete pharmacological data—ormatters substituted for pharmacologicaldata relating to the drug specifically admin-istered, its dosage and the resulting effects—were not described15.

Whether these pharmacological data canbe added lawfully after the patent applica-tion is a big concern in the patent strategy.All three patent offices do not allow amend-ments to include new matter that exceedsthe matter described in the initial specifica-tion. Allowing amendments involving addi-tional new matters would be unfair to athird party. However, in accordance with thedomestic priority (Japan Patent Law Article41) or the provisional application system(US Patent Law Article 111), pharmacologi-cal data can be added legally and the utilityrequirement can be supplemented.Furthermore, according to the JPO, as longas the pharmacological test methods anddata are described in the initial specificationand a certificate of experiment results con-firming similar pharmacological effects byusing a similar test method is submitted,overcoming refusal decisions may be possi-ble, even if some of the compounds do notsatisfy the enablement requirement.

ConclusionsBiotechnology and pharmaceutical firmsfrequently employ strategies for maintain-ing competitive superiority by claimingproducts such as research tools developed inthe early stages of R&D or pharmaceuticalsthat have yet to be developed. However,granting exclusive rights covering an exces-sively broad range in comparison with thetechnical contribution of the invention isnot likely to be good policy. Patents are notgranted by any of the three patent offices for“reach-through” claims, and the recenttrend is that it is becoming difficult toacquire wide-ranging exclusive rights. Forexample, patents will not be granted if theexperimental data for compounds are pre-dicted only by computer analysis.Inventions described with in vivo or in vitroexperimental results together with proteinstructural information or pharmacophoreswould most likely be as effective as a patentstrategy. With respect to drug inventions,the degree of requirement for experimental

data submission varies among the currentpractices at the three patent offices. Even inthe cases mentioned here, some inventionsthat have been granted a patent in the USare considered to be incomplete in Japan,because of the statutory invention andenablement requirement.

The Trilateral Project Report provides auseful resource for understanding the cur-rent thought at the USPTO, EPO and JPOon the patentability of certain examples ofstructure-based claims. It remains to be seenhow these policies will be applied to newapplications, and whether these policies willultimately be upheld by the courts.Although the differences in assessing patentrequirements among the three patent officesare likely to be minimized in the future, aglobal patent strategy should be establishedbased on the understanding of the differ-ences in the examination standards in eachcountry.

ACKNOWLEDGMENTSWe thank Sheryl R. Silverstein, Takayuki Hirose,Toshio Miyake, and Cora Tsang for advice on thearticle. This work was supported in part by theRIKEN StructuralGenomics/Proteomics Initiative(RSGI), the National Project on Protein Structuraland Functional Analyses, Ministry of Education,Culture, Sports, Science and Technology of Japan.

1. Trilateral Project WM4, Comparative Studies in NewTechnologies. Report on Comparative Study onProtein 3-Dimensional Structure Related Claims,Vienna, Austria, November 4–8, 2002.

2. Flower, R.J. The development of Cox2 inhibitors.Nature Rev. Drug Discov. 2, 179–191 (2003).

3. http://www.rsgi.riken.jp/4. Hultquist, S.J. et al. Patenting bioinformatic inven-

tions: emerging trends in Europe, Nat. Biotechnol.20, 517–518 (2002).

5. Hultquist, S.J. et al. Patenting bioinformatic inven-tions: emerging trends in the United States, Nat.Biotechnol. 20, 743–744 (2002).

6. USPTO. Examination guidelines for computer-relatedinventions, 61 Fed. Reg. 7478 (1996).

7. In re Lowry, 32 F.3d 1579, 1583-4, 32 USPQ2d1031, 1035 (Fed. Cir. 1994).

8. In re Warmerdam, 33 F.3d 1354, 1316, 31USPQ2d1754, 1760 (Fed. Cir. 1994).

9. T 1173/97 (OJ 1999, 609).10. JPO. Examination guidelines for patent and utility

model in Japan, Part VII, Chapter 1 (2001). 11. State Street Bank & Trust Co. vs. Signature Fin.

Group, Inc., 149 F.3d 1368, 47 USPQ 2d 1596(Fed. Cir. 1998).

12. Formulating and communication rejections under 35USC 103 for applications directed to computer-implemented business method inventions, IV. A.Example 12: Rationale reasoned from the differenceis the data being stored (2000).

13. Case of an herbicidal imidazole derivative, TokyoHigh Court, 1990 (Gyo Ke), Decision No. 243(H6.3.22). As comparable case, Case of natriureticpeptide Tokyo High Court, 1998 (Gyo Ke), DecisionNo. 393 (H13.3.15).

14. EPO. Guidelines for examination in the EPO, Part C,Chapter III, 4.7a, June 2000.

15. Case of a muscarine-like receptor antagonist, TokyoHigh Court, 2001 (Gyo Ke), Decision No. 345(H14.10.1). As comparable case, Case of antimeticdrug, Tokyo High Court, 1996 (Gyo Ke), Decision No.201 (H10.10.30).

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