PATENTS

http://biotech.nature.com • AUGUST 2001 • VOLUME 19 • nature biotechnology

Today, molecular biologists possess thetools to clone, sequence, and identify

thousands of potentially useful expressedsequence tags (ESTs) and single nucleotidepolymorphisms (SNPs). Patent officesworldwide are dealing with increasing num-bers of EST and SNP patent applications, butthe route to patent approval is still unclear.In drafting patent specifications, the needfor guidance is perhaps greater than ever.

Last month, we examined the disclosuresrequired to meet the US Patent andTrademark Office’s Revised Utility andWritten Description Examination Guidelines.We also considered the present status of ESTand SNP patenting in the PTO and theenforcement of such patents in the courts1. Wediscussed the need for scientists and patentpractitioners to draft patent specifications thatdisclose functional and structural details suffi-cient to satisfy the utility, written description,and enablement requirements of the patentstatute. Such specifications should allow prac-titioners to draft broader claims and securemeaningful and enforceable patent protectionfor their clients. Here, we examine the directrelationship between the scope of the claimssought by the inventor and the requiredbreadth and detail of the patent specificationto see what protection EST and SNP inven-tions will likely be afforded.

Written descriptionThe scope and content of the written disclo-sure of the patent specification influence thescope of the claims an inventor can obtain aswell as the later interpretation and enforce-ment of those claims in the courts. Duringprosecution of patent applications in thePTO, the examiner measures the scope of theclaims sought against the breadth of the dis-closure in the application. In litigation, thelegal meaning of patent claims is construedby the court in view of the specification, ofwhich the claims are a part, as well as theprosecution history2. The specification is

often considered the best evidence of theinvention actually possessed by the inventorsat the time the application was filed3.

The first part of a patent claim, known asthe preamble, is typically set off from the restof the claim by one of the transitional phras-es “comprising,” “consisting of,” or “consist-ing essentially of.” For instance, an applicantmay claim “An isolated DNA, comprisingSEQ ID NO:1,” where SEQ ID NO:1 mightbe the sequence of an EST or SNP. Thechoice of transitional phrase affects claimscope. “Comprising” means that the claimbroadly covers any DNA sequence that con-tains within it SEQ ID NO:1. However, if theclaim instead used the words “consisting of,”the claim would be much narrower, coveringDNA sequences that contain only SEQ IDNO:1. The phrase “consisting essentially of”

represents a middle ground, in which casethe claim would cover all DNA sequencesthat contain SEQ ID NO:1 plus additionalsequences as long as those sequences do notalter the essential characteristics of SEQ IDNO:1. In examining DNA claims, the PTOlooks, among other things, to the transition-al phrase chosen by the applicant to deter-mine whether the specification contains awritten description that supports the fullscope of the claim under examination.

The PTO recently published its writtendescription guidelines for use in examiningpatent applications4. Four examples fromthese guidelines are of particular relevanceto ESTs and SNPs.

In Example 6, a specification describesSEQ ID NO:1: an isolated 100–base paircDNA fragment of an ORF encoding a cer-tain type of receptor protein expressed in ahuman cancer cell5. The specification defines

a “gene” as including naturally occurringregulatory elements and untranslatedregions and describes methods for cloningthe full-length receptor protein genes. Thespecification also defines a probe as consist-ing of SEQ ID NO:1 and between 5 to 10additional nucleotides on either side of SEQID NO:1. The claim reads, “An isolated genecomprising SEQ ID NO:1.”

Under the new guidelines, this claimwould be rejected for lacking a sufficientwritten description in the specification. SEQID NO:1 lacks the regulatory elements anduntranslated regions required for the dis-closed definition of a “gene.” Furthermore,there is no description of the broader genusof DNA sequences that “comprise” SEQ IDNO:1 (i.e., if the disclosed sequence of thecDNA fragment repeats itself 10 times in thegenome in different contexts, there is nodescription of SEQ ID NO:1 in those con-texts). Based on this specification, the guide-lines recommend claiming “a probe whichconsists essentially of SEQ ID NO:1.”

In this example, the PTO has set up andtoppled a straw man. As an initial matter, it isunnecessary to claim “an isolated gene.” Byso claiming, the prosecuting agent or attor-ney has limited the scope of the claim to agene that, as defined in the specification,must include naturally occurring regulatoryelements and untranslated regions. There isno reason not to simply claim “an isolatedDNA.” Furthermore, prosecuting agents andattorneys generally should not box them-selves in by so narrowly defining terms in thespecification. Typically, a gene should not bedefined in the specification as requiring nat-urally occurring regulatory elements anduntranslated regions unless those elementsare truly critical to the gene’s function anduse. Rather, the gene should be defined interms of its function6.

For instance, in a hypothetical patentspecification, a cDNA comprising thesequence of SEQ ID NO:1 is disclosed. Thespecification then defines a gene as “a DNAsequence comprising a protein-codingsequence and other regulatory elements nec-essary for expressing the protein-codingsequence in a host cell.” Then, by way ofexample, commonly used recombinant

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Patenting expressed sequence tags and single nucleotide polymorphismsThe scope and content of the patent specification is likely to determine the level of protection afforded EST and SNP inventions.

Gerald J. Flattmann and Jonathan M. Kaplan

Gerald J. Flattmann is a partner and JonathanM. Kaplan is a patent agent at Fish & Neave,1251 Avenue of the Americas, New York, NY10020 (gflattmann@fishneave.com).

The patent specification is oftenconsidered the best evidence ofthe invention actually possessedby the inventors at the time theapplication was filed.

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nature biotechnology • VOLUME 19 • AUGUST 2001 • http://biotech.nature.com

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expression systems are provided (mam-malian, insect, yeast, viral, and bacterial), aswell as methods of expression from thegene’s natural position. The PTO or a courtcould read this disclosure and conclude that:(1) the inventors were in possession of theDNA of SEQ ID NO:1; and (2) the inventorsdisclosed methods and compositions forexpressing SEQ ID NO:1 in a variety of ways.Based on this disclosure and definition,therefore, the PTO or a court could reason-ably conclude that the applicant had posses-sion of a broad invention comprising anexpressible SEQ ID NO:1 gene sequence.

Moreover, once a DNA sequence is known,so is the protein sequence it encodes. In theprevious example, the prosecuting agent orattorney should also disclose SEQ ID NO:2 ascomprising the translated protein product ofSEQ ID NO:1. Then claims supported by thewritten description could be drafted to thecloned sequence in every which way imagin-able (i.e., to SEQ ID NO:1, to SEQ ID NO:2,to a DNA sequence that encodes SEQ IDNO:2, to a protein encoded by SEQ ID NO:1,to a vector containing SEQ ID NO:1, to a hostcell that expresses SEQ ID NO:2, to a methodof producing SEQ ID NO:2, etc.).

A note on the use of transitional phrases iswarranted here. The claim in the exampleuses the term “comprising,” the broadest ofthe three commonly used transitional phrasesdescribed above. Generally speaking, thebroader the scope of a claim in an applica-tion, the more likely it will be rejected by anexaminer7. A written description for a broadgenus of DNA sequences containing an iso-lated sequence might adequately justify theuse of “comprising” if it discloses multiplerepresentative examples of that isolatedsequence in different genetic contexts. Such adisclosure would put persons of ordinary skillin the art on notice that the applicant was inpossession of an invention comprising agenus of DNA sequences, including the iso-lated sequence, at the time the applicationwas filed. In most applications, an inventionof such scope is the exception, not the rule.That is not to say that where a single exampleis disclosed, an applicant should not attemptto use the transitional phrase “comprising,”but rather that an applicant in such a situa-tion should be prepared to amend the claimsto use the “consisting of” transitional phrase8.

Example 7 of the synopsis further address-es the use of “comprising” as the transitionalphrase. The specification discloses SEQ IDNO:16 as an EST9. The partial cDNA is fromthe coding sequence of a gene from an infec-tious yeast and hybridizes with its comple-ment in the yeast cell. Its utility is for identifying yeast infections. The exemplifiedclaim reads, “An isolated DNA comprisingSEQ ID NO:16.” As in Example 6 above, the

claim is drawn to a genus, that is, any nucleicacid that contains at least SEQ ID NO:16.The PTO drew the following conclusions:(1) only a partial DNA structure is provided;(2) the claim reads on genes yet to be discov-ered; and (3) there is no correlation of struc-ture to function in the specification that indi-cates that the inventors were in possession ofthe genus of DNAs which comprise SEQ IDNO:16. The guidelines conclude that theclaim as drafted lacks a sufficient writtendescription in the specification.

Again, the rejection is based on the use ofthe “comprising” transitional phrase, whichcauses the claim to read on the entire genusof DNAs that contain SEQ ID NO:16. If thephrase “consisting essentially of” were usedinstead, the claim would be more narrowlydrawn to the minimal sequence disclosed inSEQ ID NO:16 plus any extra sequences thatdo not alter the fundamental properties ofthe sequence. In this form, the PTO wouldbe more likely to allow the claim.

The need to narrow the scope of theclaims as described above could potentially

be avoided by: (1) using the DNA sequenceto clone the full-length gene; and (2) usingcomputer analysis tools to correlate thestructure of the isolated sequence with afunction. A simple BLAST search mightplace an EST or SNP within a family ofimportant proteins and thereby provide thenecessary link between structure and func-tion. Once family members are identified,alignments of the disclosed peptidesequences with those of the other familymembers can be conducted to identifyimportant functional or structural motifsand domains. If the protein family to whichthe EST or SNP belongs proves to be of par-ticular importance, other family membersthat contain the sequence might be identi-fied. Now, the applicant possesses a full-length, isolated DNA sequence that encodesa protein of known function with homologyto a genus of important genes. Disclosure ofthis information in the patent specificationmay constitute an adequate written descrip-tion of a broad genus of DNAs.

Example 9 of the synopsis describes SEQID NO:1 as a single cDNA molecule thatencodes a ligand for an important receptorprotein10. The specification discloses anexample where SEQ ID NO:1 was hybridized

under highly stringent conditions to isolatenucleic acids that encode proteins with simi-lar properties. The hypothetical claim readsas follows: “An isolated nucleic acid thatspecifically hybridizes under highly stringentconditions to the complement of thesequence set forth in SEQ ID NO:1, whereinsaid nucleic acid encodes protein that bindsto a dopamine receptor and stimulatesadenylate cyclase activity.”

The guidelines conclude that there is anadequate written description to support thisclaim. Because the specification disclosed par-ticular highly stringent conditions, the indi-vidual DNA species covered by the claimwould likely be structurally similar to the iso-lated sequence, and a person of skill in the artwould recognize that the applicant was in pos-session of the claimed invention. Moreover,the function of the claimed nucleic acid is spe-cific and identified in the claim itself.

In Example 11 of the synopsis, the specifi-cation describes protein X, a cell surfacereceptor for an adenovirus. Protein X isencoded by the nucleotide sequence of SEQID NO:1, and the polypeptide sequence isshown in SEQ ID NO:2. The invention isdescribed as encompassing alleles of theDNA, including SNPs, but no allelicsequences are provided. The specificationstates that allelic variants of SEQ ID NO:1can be obtained, e.g., by hybridizing SEQ IDNO:1 to a library of DNA sequences fromthe organism that yielded protein X. Theclaims are as follows: (1) an isolated DNAthat encodes protein X (SEQ ID NO:2);(2) an isolated allele of the DNA accordingto claim 1, which allele encodes protein X(SEQ ID NO:2); and (3) an isolated allele ofSEQ ID NO:1.

Because claim 3 is the simplest to dealwith, we discuss it first. The PTO wouldreject claim 3 for lacking a sufficient writtendescription. The claim is not limited todegenerate protein X nucleotide sequences(DNA sequences containing “silent” muta-tions that do not change the encoded aminoacid sequence and are ascertainable by a per-son of ordinary skill in the art). Rather, theclaim covers a very large number of species(e.g., if protein X is encoded by 999nucleotides, the number of permutationscould number in the millions) while thespecification discloses only a single species.The synopsis concludes that the claimedgenus is not supported by the single dis-closed species.

The dispositions of claims 1 and 2 are lessclear. The example correctly describes claim1 as covering a genus of degenerate protein Xsequences and describes claim 2 as coveringa “subgenus” of degenerate protein Xsequences. It concludes, however, that onlyclaim 1 is supported by an adequate written

Generally speaking, the broaderthe scope of a claim in a patentapplication, the more likely it willbe rejected by an examiner.

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PATENTS

http://biotech.nature.com • AUGUST 2001 • VOLUME 19 • nature biotechnology

description, despite the fact that claim 1 cov-ering the genus has broader coverage.

The only material difference between theclaims is that claim 2 recites the word “allele”whereas claim 1 does not. In discussing claim2, the synopsis assumes an “ordinary” mean-ing of the term “allele”: “one of two or morealternate forms of a gene occupying the samelocus in a particular chromosome or linkagestructure and differing from other alleles ofthe locus at one or more mutational sites.”11

Both claims 1 and 2 cover a genus ofDNAs that encode protein X and comprisemultiple species containing silent muta-tions. Insofar as the use of the term “allele”changes the scope of the claim, it relates tothe location of the DNA sequence, not thecomposition of the DNA sequence itself.The take-home message is that practition-ers claiming SNPs should avoid the word“allele.”

EnablementSuppose SEQ ID NO:1 encodes an EST that,by homology, falls within a genus of pro-teins known as XYZ proteases. The specifi-cation discloses the essential characteristicsof XYZ proteases, including functionaldomains, and well-known methods for

expressing such proteins. A claim mightthen be submitted to the PTO as follows:“An isolated DNA encoding an XYZ pro-tease comprising SEQ ID NO:1.” The claimwould likely be enabled by the specificationbecause a person of skill in the art would,without undue experimentation, know howto: (1) isolate SEQ ID NO:1; (2) use SEQ IDNO:1 for expressing the XYZ protease; (3)use SEQ ID NO:1 as a probe; (4) purify theXYZ protease upon expressing SEQ IDNO:1; (5) prepare antibodies to the XYZprotease; (6) develop drugs comprising ortargeting the XYZ protease; and (7) possi-bly use the purified XYZ protease in a bio-chemical reaction. Note that the claimretains the broad “comprising” transitionalphrase.

ConclusionsIn sum, a sufficient written description for abroad EST or SNP claim will depend on thechoice of the transitional phrase, the degreeto which the claimed sequence represents agenus of nucleotide sequences, the ability tocorrelate the structure of the claimedsequence with a function, and the manner inwhich the claim terms are defined in thespecification.

1. Flattmann, G.J. & Kaplan, J.M. Nat. Biotechnol. 19,683–684 (2001).

2. See, generally Markman v. Westview Instruments,Inc., 52 F.3d 967 (Fed. Cir. 1995), aff’d, 517 US 370(US 1996).

3. Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576,1582 (Fed. Cir. 1996).

4. 66 Fed. Reg. 1099 (2001); Synopsis of Applicationof Written Description Guidelines.

5. Synopsis of Application of Written DescriptionGuidelines at 20–22.

6. Structural elements in claims often narrow theirscope. For instance, a claim that recites “a naturalpromoter” is limited to a single structure, the pro-moter found naturally on the chromosome. In con-trast, functional elements may give claims a broaderscope. For example, “a promoter capable of expres-sion” may include a gene’s natural promoter, a dif-ferent promoter from that species, a viral promoter,a bacterial promoter, etc. Claiming with functionallanguage, however, may risk invoking a “means plusfunction” claim construction under 35 USC §112 ¶6.

7. In some instances, however, the PTO will reject amore narrowly drafted claim where the claimedspecies is not supported by the written description.

8. The decision to claim more broadly and wait for arejection to narrow the scope must be made in lightof the recently decided Festo Corp. v. ShoketsuKinzoku Kogyo Kabushiki Co., 234 F.3d 56 (Fed. Cir.2000). In Festo, scope of the doctrine of equivalentswas restricted. The Festo Court held that where anapplicant amends a claim for reasons relating topatentability (e.g., in response to a rejection), theamended element in that claim is entitled to noscope of equivalence.

9. Synopsis of Application of Written DescriptionGuidelines at 23–26.

10. Id at 28–30.11. Id at 34.

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