An Inventor’s Guide to Patenting Polynucleotide Inventions

19 Biotechnology Law Report 155Number 2 (April 2000)Mary Ann Liebert, Inc.

{BLR 3071} Nonobviousne ss - Patentability - Polynucleotides.

An Inventor’s Guide to Patenting Polynucleotide Inventions1

PETER J. DEHLINGER and MICHAEL T. GABRIK

155

INTRODUCTION

Not all polynucleotide inventions are alike. Un-fortunately, by treating them alike, inventors may

miss opportunities for broad patent protection, and thecourts may apply inapt standards of patentability. It isuseful, therefore, for inventors to understand the na-ture of their polynucleotide inventions, as a guide toclaiming their inventions and mustering arguments forpatentability during patent prosecution. This paperprovides a guide to the four major invention types ofpolynucleotide inventions: (1) chemical compound,(2) molecular probe, (3) set of instructions, and (4)computational elements. Each type has unique char-acteristics that allow inventors to recognize and prop-erly classify their polynucleotide inventions. The pa-per illustrates each invention type with examples,sample claims, and arguments that an inventor can of-fer to support patentability and broad claim scope.

BACKGROUND

The evolution of life on earth is intimately tiedto polynucleotides and the variety of roles they play.Two of these roles may have led to the evolution ofearly forms of enzymes: the ability to replicate bybase-directed polymerization and the ability to formthree-dimensional electronic structures capable ofcatalyzing chemical reactions.2

As self-replicating polynucleotides became orga-nized into cellular and multicellular structures,polynucleotides were enlisted as the instruction setsfor coordinating cell replication and gene expres-sion. In this role, polynucleotides also became thecomputational elements of life, combining and re-

arranging information strings to form new pheno-typic variations required for natural selection.

Not surprisingly, DNA-sequence inventions made“by the hand of man” tend to exploit the same polynu-cleotide roles found in nature. Among the first andmost important type of polynucleotide invention is agene, or coding sequence, of a protein.3 In this role,the polynucleotide functions as an instruction set fordirecting expression of a desired protein under the con-trol of a biological “machine.” The same polynu-cleotide may also function as a molecular probe foridentifying a complementary polynucleotide se-quence. Polynucleotide enzymes and binding agentsthat function purely as chemical compounds are re-ceiving increasing patent attention,4 as are sets of DNAsequences, including sequence libraries and arrays,that function essentially as computational elements.

The different personalities of polynucleotideswould seem to require different guidelines govern-ing the issues of patentability5 and claim scope.6 Thebasis of nonobviousne ss for a polynucleotide en-zyme that has unpredictable properties should be

1©1999 Peter J. Dehlinger and Michael T. Gabrik, Dehlinger& Associates, Palo Alto, CaliforniaAll rights reserved.2M. Amarzguioui and H. Prydz, Cell Mol Life Sci 54(11):1175-1202 (1998); J. A. Martinez Gimenez, G. T. Saez, and R. T.Seisdedos, J Theor Biol 194(4):485-490 (1998); P. E. Leon, JMol Evol 47(2):122-126 (1998).3To date, there are well over 2500 U.S. patents that claim cod-ing sequences for polypeptides.4S. D. Jayasena, Clin Chem 45(9)1628-1650 (1999); and M. Fa-mulok, Curr Opin Struct Biol 9(3):324-329 (1999).5“Patentability” here refers to statutory standards of novelty andnonobviousness (or inventive step). 6Claim scope refers to the breadth of “embodiments” that aclaim covers and is determined in the U.S. largely by the statu-tory requirements, under 35 U.S.C. §112, first paragraph, thata claim be commensurate in scope with the enablement pro-vided in the specification and within the written description ofthe invention in the specification.

Peter J. Dehlinger and Michael T. Gabrik practice with the firmDehlinger & Associates in Palo Alto, CA.

different from that for a DNA probe, which hashighly predictable properties. The informationneeded to support broad claim scope for a codingsequence, which functions as a set of instructionsfor a given-sequence protein, should be differentfrom that needed to support a polynucleotide thatcan be claimed functionally; e.g., as part of a com-putational device.

This paper examines four basic types of polynu-cleotide inventions7 and the defining characteristicsof each. Depending on its structural characteristicsand the function it performs, a polynucleotide in-vention may be considered as a chemical compound,a probe, a set of instructions, or one of a set of com-putational elements. With each type of invention,we present examples that illustrate the patentingstandards that should apply and strategies for opti-mizing claim scope. In most cases, a polynucleotideinvention may be classed in more than one way, al-lowing multiple claim presentations and patentingstrategies.

POLYNUCLEOTIDE AS A CHEMICAL COMPOUND

An underlying theme in chemical patent practiceis the notion of unpredictability in compound orcomposition inventions. The unpredictable featuremay reside in the compound’s chemical reactivity,its catalytic activity, or its interaction with othercompounds or with biological systems. The com-pound’s properties are unpredictable because theycannot be determined from existing scientific tools;e.g., quantum mechanical calculations, X-ray struc-ture, or molecular modeling. Characteristics of a chemical compound invention

Polynucleotide inventions that have unpre-dictable molecular properties are likely candidatesfor “chemical compound” inventions. More gener-ally, a polynucleotide invention should be treated asa chemical compound if:

(1) The polynucleotide has unpredictable chemicalproperties or interacts with other molecules orliving systems in an unpredictable way;

(2) The unpredictable properties are related to theelectronic or spatial characteristics that the mol-ecule has or adopts when interacting with othermolecules or systems; and

(3) The effect of a given chemical modification ofthe compound may or may not be predictable,depending on whether the modification is ex-pected to alter critical electronic and spatial fea-tures of the compound.

As examples, one could mention ribozymes(polyribonucleotide enzymes), DNA or RNA ap-tamers having specific binding or enzymic activi-ties, and antisense molecules that rely on unexpectedmolecular properties; e.g., the ability to cross cellmembranes, for their activity.

Note that the unexpected property must reside inthe polynucleotide compound itself, not an indirecteffect of the polynucleotide. A polynucleotide cod-ing sequence that functions in a predictable way toencode a given protein should be treated as an in-struction set (see below) rather than a chemical com-pound, even though the properties of the encodedprotein may be unpredictable. Similarly, an oligonu-cleotide probe that functions in a predictable way tobind to a complementary target sequence (see be-low) should be treated as a probe rather than a chem-ical compound, even though the use of the probemay lead to a nonobvious biologic result.

Example of polynucleotide chemical compound:aptamer-binding agent

An inventor screens a large RNA aptamer libraryand selects from this library a novel RNA bindingagent capable of binding to and inhibiting HIV pro-tease. The molecule is intended for use in gene ther-apy, for inhibiting HIV infection of cells that havebeen transformed to produce the RNA agent by genetranscription.

The compound clearly meets the three criteria ofa chemical-compound invention. First, the interac-tion of the molecule with HIV protease could nothave been predicted from the molecule’s base se-quence. Second, the molecule’s interaction withHIV protease is related to the electronic or spatialcharacteristics or both that the molecule adoptswhen interacting with the protease. Third, the effectof chemical modifications; e.g., base substitutions ,

156 Biotechnology Law Report � Volume 19, Number 2

7The term “polynucleotide” is intended here to encom pass anypolymer of nucleotide bases, including DNA, RNA, and analogsthereof, such as any of a variety of antisense analogs havingmodified backbone bases.

on protease binding activity would be difficult topredict without structure/activity data.

With this analysis in hand, the inventor wouldlogically draft a compound claim of the form: Acompound capable of binding to and inhibiting pro-tease activity, comprising a ribodeoxynucleotidehaving the sequence identified by sequence A (thesequence of the claimed compound).

Patentability. The inventor’s first task will beto establish that the invention is patentable; that is,both novel and nonobvious over the prior art. Thecompound will be novel if the sequence itself isnovel, a straightforward inquiry. To establishnonobviousne ss, the inventor must show that thecompound’s claimed protease-binding activitycould not have been predicted from the prior art.Unless the prior art discloses an RNA protease-bind-ing agent with a close sequence homology, the casefor unpredictable properties is quite clear.

As a general rule, claiming a polynucleotide in-vention as a molecular compound will simplify theinventor’s task of establishing nonobviousne ss: theinventor merely has to show that the advantageousproperties of the claimed polynucleotide sequenceare not predictable from the compound’s base se-quence.

Claim scope. Ideally, the inventor would like toclaim the molecular compound in a way that wouldprevent others from easily designing around theclaim. To this end, the claim might be expanded toread: A compound capable of binding to and in-hibiting protease activity, comprising a ri-bodeoxynucleotide having the sequence A, andstructural modifications of the sequence which pre-serve the protease-inhibitory activity of the com-pound .

In order to support the broadened claim, the ac-companying specification must comply with twoadditional requirements known in U.S. patent prac-tice as the “enablement” and “written description”requirements. The first requirement is met if theinvention, as broadly claimed, can be practicedwithout undue experimentation, in light of theguidance provided in the specification. This re-quirement tends to be more exacting for polynu-cleotide chemical compounds than for other in-vention types we will examine, precisely becausethe relation between structure and function tendsto be unpredictable.

Nonetheless, there are strategies available to theinventor for broadening a polynucleotide chemical-compound invention. Certain features of a polynu-cleotide chemical compound, such as the effect ofbase-pairing or loop formation on secondary struc-ture, can be reasonably predicted. In many cases,adding one or more bases to the termini of the com-pound, or modifying one or more bases with chem-ical moieties such as polyethylene glycol chains,will be well tolerated. The inventor will want to con-sider a variety of structural modifications that canbe predicted to leave the compound’s properties rel-atively unaffected. These general modificationsshould be described in the patent specification togive support to the claim language “and structuralmodifications of the sequence which preserve theprotease-inhibitory activity of the compound .”

The written description requirement is met, for aclaimed chemical compound, only if the specifica-tion discloses the structural features of the claimedcompound in a way that allows the compound to bedistinguished over the prior art. It is not enough tomerely describe the function of the compound or themethod by which it can be obtained.8 In practicalterms, the written description requirement will re-quire that the patent specification disclose at least aportion of the nucleotide sequence of the claimedcompound. This will be true for both narrow andbroadened compound claims.

POLYNUCLEOTIDE AS A PROBE

A polynucleotide probe contains a sequence ofbases; e.g., 8 to 20 bases, that can bind by Watson-Crick base pairing to the bases in a complementarytarget polynucleotide sequence. The sole functionof the probe is to identify the target sequence andform a base-paired duplex between itself and target.

Characteristics of a polynucleotide probe

Unlike a polynucleotide that functions as a mol-ecular compound, where compound activity is de-

Biotechnology Law Report � Volume 19, Number 2 157

8Amgen, Inc. v. Chugai Pharmaceutica l Co. Ltd., 927 F.2d1200, 18 USPQ2d 1016 (Fed. Cir. 1991); Fiers v. Revel, 984F.2d 1164, 25 USPQ2d 1601 (Fed. Cir. 1993); and Regents ofthe University of California v. Eli Lilly & Co., 119 F.3d 1559,43 USPQ2d 1398 (Fed. Cir. 1997).

termined largely by secondary or tertiary structure,a probe’s ability to hybridize with a complementarypolynucleotide sequence resides entirely in the pri-mary base sequence. Moreover, this activity ishighly predictable.

Examples of molecular probes include fragmentsof genomic DNA; cDNA and cDNA fragments suchas gene fragments, expressed sequence tags (EST’s),sequence-tagged sites (STSs); RNA fragments; syn-thetic oligonucleotides; e.g., for use as PCR primers;and oligonucleotide analogs, typically associatedwith antisense molecules.

Example: SNP probe

An inventor finds an SNP (single-nucleotidepolymorphism) that is diagnostic of a predispositiontoward drug resistance to a chemotherapeutic agent.The inventor synthesizes a probe designed to rec-ognize the SNP, for use as a diagnostic reagent todetect chemotherapy patients who are likely to showa predisposition to drug resistance.

Because the probe (1) functions by forming abase-specific duplex with a target region of genomicDNA; (2) is able to find the target region out a largepool of different sequences; e.g., the entire genome,and (3) has a predictable, sequence-specific activ-ity, the compound should be treated for patentabil-ity as a polynucleotide probe. As such, it can beclaimed in the form: A polynucleotide probe havingthe sequence identified by sequence B (the sequenceof the probe).

Patentability. The novelty requirement mayimpose a lower limit on the number of bases thatthe claimed probe can have. If the probe has fewerthan 10 to 12 bases, the claimed sequence is likelyto be found in a polynucleotide sequence database.

Assuming the sequence is novel, the inventormust find some basis for nonobviousne ss. Becausethe activity of the compound in hybridizing with agiven target sequence is highly predictable, the in-ventor will have to look beyond the actual proper-ties of the compound to establish nonobviousne ss.In most cases, the source of nonobviousne ss will befound in the ability of the probe to produce a nonob-vious result through its binding to a target comple-mentary sequence. In the present example, thenonobvious result is the ability to screen individu-als for a nonobvious phenotype, in this case, a pre-disposition to drug resistance. Other nonobvious re-

sults might include the use of the probe to isolate anonobvious gene, the use of the probe to find anonobvious genotype, or the use of an antisenseprobe to inhibit a cellular function in a nonobviousway.

Can nonobviousne ss ever reside in the probe’snucleotide sequence per se? It is logical to ask thisquestion because the particular sequence of anyprobe selected from a large number of different-se-quence probes is unpredictable. This logic, in fact,was applied in two court cases, where a given hu-man coding sequence was found nonobvious solelyon the basis of the fact that the sequence could nothave been predicted from the large number of pos-sible sequences.9 However, there is little legal jus-tification for this view. A better view is that theprobe’s sequence per se is an identifying descriptorof the probe, not a property on which patentabilitycan be based.

Claim scope. In the SNP-probe example, the in-ventor would like to obtain a claim that is broadenough to cover any probe that would hybridize withthe target SNP region. Fortunately, probe binding toa complementary-sequence target is highly pre-dictable and relatively independent of polynu-cleotide backbone structure, base substitutions andmismatches at certain positions, and chemical mod-ifications at probe ends. Therefore, the inventor isfree to define a polynucleotide probe quite broadlyand protect, in essence, every polynucleotide andpolynucleotide analog that can be predicted to hy-bridize with the target sequence under specified hy-bridization conditions.

With this in mind, the inventor may attempt tobroaden her patent rights with a claim of the form:A polynucleotide or polynucleotide analog that se-lectively hybridizes to a target polynucleotide se-quence B’ under [defined] hybridization conditions .

The claim can be enabled because the inventorcan offer ample guidance in the patent specificationas to the types and sequences of probes that wouldmeet the functional limitation set out in the claim.The written description requirement for the claimshould be easily met, because the patent specifica-tion would clearly define the nature of the probe


9In re Bell, 991 F.2d 781, 26 USPQ2d 1529 (Fed. Cir. 1993)and In re Deuel, 51 F.3d 1552, 34USPQ2d 1210 (Fed. Cir.1995). See text accompanying note 12, infra.

composition being claimed, given the specified tar-get sequence B’.

The reader will appreciate that claiming apolynucleotide as a probe, even if the polynu-cleotide’s primary function is not as a probe, mayallow the inventor to obtain broader claim scopethan would otherwise be available. As an example,consider the aptamer polynucleotide invention dis-cussed above. To recast this invention as a polynu-cleotide probe, the inventor would identify somenovel portion of the aptamer sequence that has ademonstrated utility; e.g., use as a reagent for im-mobilizing the aptamer on a solid support. Aprobe-composition claim covering this portionmight read something like: A polynucleotide probedefined by sequence C (the novel segment from thetotal aptamer sequence).

This claim should be patentable over the prior art,because it is both novel and has the nonobviousproperty of being able to bind to and immobilize apreviously unknown, and nonobvious, aptamer mol-ecule. At the same time, the scope of the probeclaim is considerably broader than that of the ap-tamer-compound claim in two respects:

(1) The claimed sequence is presumably shorterthan the total aptamer sequence and thereforeless restrictive;

(2) The claimed sequence will admit substantiallymore variation in base modifications and addi-tions and backbone structure without loss of theprobe binding activity.

This strategy is sufficiently important that it de-serves mentioning as a special claim-strategy rule:the scope of protection in a polynucleotide chemi-cal-compound invention may be broadened by re-casting the invention as a polynucleotide probe, as-suming the probe can be shown to have somedemonstrated utility; e.g., as a binding agent for thechemical compound.

POLYNUCLEOTIDE AS A SET OF INSTRUCTIONS

Certain coding and regulatory regions of thegenome of a living cell function as a set of instruc-tions that are executed by cellular machinery to con-trol the operation of the cell, just as the instructions

embodied in software are executed by hardware togovern the operation of the host computer.

In the case of software, many different instruc-tion sets or modules act individually or in groupsto coordinate the operation of the computer’s com-ponents and control allocation of the computer’sresources. Such instruction sets also direct thecomputer hardware to perform various tasks suchas processing, networking, and input/output func-tions. Similarly, polynucleotide sequences in thegenome of an organism serve as the instructions tocoordinate many different but interrelated cell ac-tivities.

Although the actual functions performed by thecomputer and cell are, of course, quite different, theunderlying similarity between computer code andgenetic code is the programming and control theyexert on their respective hosts. In light of this sim-ilarity, it would seem appropriate to address thequestion: when does a polynucleotide qualify as aset of instructions?

Under the case law developed for computer-re-lated inventions, a software-driven algorithm is sub-ject to patent protection when it transforms the hostcomputer to produce “a useful, concrete and tangi-ble result.”10 According to this standard, a polynu-cleotide is an instruction set (and potentiallypatentable as such) when its base sequence has auseful coding function; e.g., when it codes for a par-ticular polypeptide or protein or when it controls orregulates a biochemical process.

As is the case for a software instruction set, theproperties of a polynucleotide instruction set arebased on (1) the output generated by the host, (2)the underlying processing performed by the host, or(3) the specific interaction between the code and thehost machinery. These properties are important inascertaining the patentability of a polynucleotide asan instruction set. Not only do such properties pro-vide arguments for distinguishing a particularpolynucleotide over other known and closely relatedpolynucleotides, but they also provide a basis forexpanding potential claim scope.Characteristics of a polynucleotide as an instructionset.


10State Street Bank & Trust Co. v. Signature Financial Group,Inc., 149 F.3d 1368; 47 USPQ2d 1596 (Fed. Cir. 1998)

By analogy to computer software, a polynu-cleotide invention should be treated as an instruc-tion set if it meets the following criteria:

1) The polynucleotide directs a cellular process ina series of steps performed by the cell under thedirection of the polynucleotide;

(2) The instructions are “read” by biological struc-tures; e.g., proteins or ribosomes, that may exe-cute the instruction directly or through one ormore secondary structures;

(3) The instructions are specified by one or moreparticular sequences;

(4) From the code, it can be predicted how the in-structions will be executed.11

Example: coding sequence for novel protein

An inventor isolates a previously unknow n pro-tein and uses a standard informatics program to gen-erate coding sequences that are codon optimized foreach of a variety of expression hosts, including bac-teria, yeast, human cells, and plant cells.

The inventor believes that these new coding se-quences all meet the criteria for an “instruction set.”They are made up of a string of codons that are readin a sequential manner by the host cell to direct thesynthesis of the protein whose amino acid sequenceis dictated by the sequence of codons.

The inventor therefore proposes a claim of theform: A DNA sequence that encodes a protein thathas (a) a [specified protein] activity, and (b) a pro-tein sequence substantially identical to amino acidsequence D. The claim generally corresponds to asoftware claim covering any readily implementedsoftware for achieving a specific result.

Patentability. The manner in which the codingsequence is read and processed, as an instruction set,is unlikely to be novel. Therefore, the patentabilityof a claimed coding sequence, as an instruction set,will almost certainly rest on the novel and nonob-vious result produced by the coding sequence - theprotein produced. As long as the results producedby the instruction set are novel and nonobvious, theclaim should be found patentable.

Claim scope. Because any of the large numberof degenerate coding sequences for a given proteincan be predicted to function as an instruction set ina given biologic host, it is reasonable to believe that

the claimed polynucleotide coding sequence is en-abled for any of the large number of degenerate cod-ing sequences for the specified protein. Further, itis reasonable to believe that one skilled in the artcan make “neutral” sequence modifications to theprotein without significantly altering the activity ofthe protein, so the coding sequence should encom-pass the corresponding modifications to the codingsequence as well.

The written description requirement for the claimshould be met by stating in the specification that theinvention includes the coding sequences for the iso-lated protein. This should be sufficient even if noactual coding sequences are given in the specifica-tion. One skilled in the art, aware of the sequenceand activity of the encoded protein, would readilyappreciate the nature of the invention being claimed.

An alternative (or additional) type of instructionset claim, which may give the inventor even broaderclaim scope, would take the form: A DNA sequencewhich hybridizes to a DNA sequence E (a codingsequence for the novel protein) under [specified hy-bridization] conditions, and which encodes a pro-tein having a [specified] activity.

This claim is actually a hybrid instructionset/molecular probe claim in that the claimed se-quences are probes that hybridize with a single spec-ified polynucleotide instruction set (sequence E) andare also instruction sets that encode the functionallyclaimed protein. The claim is less restrictive thanthe first instruction set claim in that the encoded pro-tein is claimed functionally rather than claimed byits sequence and thus encompasses a broader rangeof encoded proteins. The limitation that the codingsequence hybridizes with at least one specified cod-ing sequence is necessary for meeting the writtendescription requirement. A comparable softwareclaim would cover a specified set of instructions ex-ecutable by a computer to produce a desired func-tionally specified result and all other sets of in-structions that bear a close resemblance to thespecified instruction set.

The instruction set/molecular probe claim is en-abled if the patent specification provides reasonableguidance on how one would generate operable cod-


11However, certain regulatory regions of a coding sequence,while not altering the basic code execution process, may func-tion in an unpredictable way; e.g., by increasing the rate or ex-pression level of translation.

ing sequences that should hybridize to sequence Eand encode the functionally defined protein. Thewritten description requirement for the claim is metbecause all of the claimed coding sequences are ei-ther described by an actual sequence or by a distin-guishing physical property—namely, the ability tohybridize to the specified sequence.

Like computer/software inventions, coding se-quences tend to be claimed in a variety of settingsand modes of operation. For example, a coding se-quence can also be claimed as part of a suitable ex-pression vector, with the coding sequence identifiedas set forth above or possibly in relationship to thevector. The coding sequence may also be claimedin combination with a host expression system. In thecomputer/software area, these claims would corre-spond to claims directed to a suitable computationaldevice such as a computer or other processor-con-trolled device embodying a program of instructionsexecutable by the computer or device. Claimingcoding sequences and instruction sets as part of thedevices in which they function does not broadenclaim scope but may provide certain advantages tothe patent owner in calculating damages in an in-fringement action.

Perhaps the broadest type of claim that the in-ventor can fashion from an instruction set is a trueprobe claim that covers a relatively short, but novel,segment of the coding sequence. Such a probe claimwould have the same fundamental two advantagesover an instruction set that it has over a molecularcompound:

(1) The claimed probe sequence may be shorter (inthis case, much shorter) than the actual codingsequence, and is therefore less restrictive, in thesense that any coding sequence that also con-tains the probe sequence would be covered bythe claim; and

(2) The claimed sequence will admit substantiallymore variation in base modifications and addi-tions and backbone structure without loss of theprobe binding activity.

Is the probe claim patentable? It is if the probesequence that is selected is novel and if the in-ventor can show a nonobvio us use of the sequence,such as in isolating a novel, nonobviou s gene se-quence or in quantitating the expression of thenovel gene in certain disease states, or in identify-

ing mutations in the gene within the region of theprobe sequence.

We now have a second claim strategy worth not-ing: The scope of protection in a polynucleotide in-struction set invention may be broadened by re-casting the invention as a polynucleotide probe,assuming the probe can be shown to have somedemonstrated utility; e.g., as a tool for detecting thepresence, level, or integrity of the novel gene thatincludes the probe sequence.

Recasting a polynucleotide instruction set as aprobe should also be useful when the inventor isprecluded from claiming a novel coding sequenceas an instruction set, as illustrated in the next ex-ample.

Example: coding sequence of a known protein

Here, the inventor, using amino acid sequencedata relating to a known human protein, prepares aset of degenerate DNA probes for isolating the geneof the known protein. Following standard gene-iso-lation and cloning methods, the inventor is suc-cessful in isolating the human gene that encodes theknown protein.

From all appearances, the invention has the char-acteristics of an “instruction set.” It is made up ofcertain regulatory elements and a string of codonsthat are read in a sequential manner, by the host cell,to direct the synthesis of a protein whose amino acidsequence is dictated by the sequence of codons.

The problem facing this inventor is that the re-sults produced by executing the instruction set—theknown protein—is neither novel nor nonobvious.Because the coding sequence instructions areprocessed in a well-known manner, the inventormay have no viable arguments for establishing thecoding sequence as a nonobvious instruction set.12

From the section above, a logical alternative typeof claim would be one directed to a probe compo-sition containing a novel portion of the coding se-quence. This claim has the advantages of providingbroad claim scope, as discussed in the exampleabove. The most challenging issue facing the in-


12As mentioned above, two court cases— In re Bell, supra note9 and In re Deuel, supra note 9—have suggested that nonob-viousness may be found in the unpredictability of the codingsequence per se. The inventor may therefore advance this ar-gument, although its legal justification is dubious.

ventor will be nonobviousne ss. As above, the in-ventor may be able to point to the ability of the probeto detect the presence, level, or integrity of the novelgene that includes the probe sequence. If the nonob-viousness hurdle can be cleared, the inventor willhave converted a narrow coding sequence claim ofmarginal patentability into a relatively broad probeclaim.

The inventor should not rule out the possibilitythat the coding sequence may be claimed as a mol-ecular compound. Here, we treat the coding se-quence as a selection invention in which the inven-tor has selected from a large set of disclosedcompounds (in this case, all possible coding se-quences of a given protein), one sequence that hasa unique, unsuggested property (other than the se-quence per se). It is unlikely that a unique, unsug-gested property will be found for most coding se-quences, so this approach has limited use.

POLYNUCLEOTIDE AS COMPUTATIONAL ELEMENT

In nature, DNA computation is done by a genetic“algorithm” that generates new combinations ofgenes by recombination and low rates of genetic mu-tations, selects those genotypes that show highestnatural fitness, and repeats the steps continually tomeet changing environmental conditions. In the re-search laboratory, several variations on this themeare used to generate new inventions or information.

One well known example, known as phage dis-play, exploits the ability of bacteriophage to expressheterologous coding sequences on their coat pro-teins, where the expressed, heterologous polypep-tides can be screened for their binding affinity to aselected target. The phage are constructed with alarge number of different, heterologous coding re-gions, yielding a large library of surface-expressedpolypeptides for binding selection.13 Combinatoriallibraries of immunoglobulin genes14 or DNA cod-ing regions produced by gene shuffling15 representother approaches in which a library of polynu-cleotides is used to generate a library of expressedpolypeptides and the polypeptides are screened fordesired binding or other properties.

In another general approach, libraries of DNA orRNA aptamer oligonucleotides are screened directlyfor desired molecular properties, such as analyte-specific binding or substrate-specific enzymic reac-

tions. Here,the DNA components serve as both thecomputational elements and the end result.16

Arrays of oligonucleotides on a substrate carryout computational steps by forming target-bindingpatterns that can be used to calculate or determineinformation about the sequence or levels of a targetnucleotide.17

Finally, DNA computational elements can be ma-nipulated enzymatically to solve certain types ofcomplex problems that can be represented as stringsof elements.18

Expressed in their most generic terms, all fourtypes of DNA computational “devices” mentionedabove (and the one utilized in nature as well) typi-cally employ the following elements or features:

(1) A set of polynucleotides that serve as the com-putational input;

(2) A computational step in which the set of polynu-cleotides are processed; e.g., as coding se-quences, binding agents, or enzyme substrates;

(3) An analytical step in which the results of thecomputational step are analyzed; and

(4) A desired result (invention or information) thatfollows from the analytical step.

Depending on the nature of the invention, nov-elty and nonobviousne ss could rest on any one ormore of the four features; that is, the characteristicsor arrangement of the set of polynucleotides used asthe computational input, the way the set isprocessed, the way the processed set is analyzed, orthe computational result. In addition, patentability


13K. Johnsson and L. Ge, Curr Top Microbiol Immunol 243:87-105 (1999); S. Gupta, K. Arora, A. Sampath, S. Khurana, S. S.Singh, A. Gupta and V. K. Chaudhary, Biotechniques27(2):328-330,33 2-334 (1999); and R. C. Ladner, Q J Nucl Med43(2):119-124 (1999).14D. B. Rubinstein, P. Leblanc, D. G. Wright, T. Guillaume, A.Strotchevoi and M. Boosalis, Mol Immunol 35(14-15):955-964(1998); Y. L. Yip, N. J. Hawkins, M. A. Clark and R. L. Ward,Immunotechno logy 3(3):195-203 (1997); and A. Kakinuma, S.Portolano, G. Chazenbalk, B. Rapoport and S. M. McLachlan,Autoimmunity 25(2):73-84 (1997).15P. D. Kaplan, Q. Ouyang and D.S. Thaler, J Theor Biol188(3):333-341 (1997); and P. Casali and E. W. Schettino, CurrTop Microbiol Immunol 210:167-179 (1996).16fn. 4 ibid.17U.S. patent nos. 5,861,242; 5,858,659; 5,837,832; 5,800,992;5,905,024; and 5,780,232.18L. M. Adleman, “Molecular Computation of Solutions toCombinatoria l Problems,” Science 266:1021-1024 (1994).

may also reside in the way the device is formed. Theinventor will want to present claims to each indi-vidual feature that will support patentability.

It is also useful to consider claiming the combi-nation of elements as they function in a computa-tional device. The combination of elements is likelyto provide arguments for patentability that are notavailable for the individual elements. For example,a set of oligonucleotides that function as the inputin a computational device may not be novel whenclaimed alone, but could be patentable based on (1)the manner in which the set of is processed; (2) themanner in which the processed elements are ana-lyzed; or (3) the result obtainable by the device.

Claiming the elements of the device as a combi-nation of elements may also allow some of the in-dividual elements to be claimed more broadly thanotherwise possible. For example, the set of polynu-cleotides making up the input of the device wouldhave to be claimed structurally, as a single-elementclaim. (The element of a single-element claim can-not be defined functionally, because then one isclaiming every possible invention for achieving thatfunction, including inventions not yet made. Thisconstraint does not apply to multielement claims).However, if claimed as part of a multi-element de-vice, the set of polynucleotides might be definedfunctionally, such as:

� A set of polynucleotides containing more ofmore compounds capable of binding to apolypeptide target;

� A position-addressable array of oligonu-cleotides capable of forming a unique bindingpatterns with different-sequence target polynu-cleotides; or

� A set of oligonucleotides that can be enzymat-ically linked to represent all possible combina-tions of events represented by the individualoligonucleotides in the set.

The reader will recognize each of these sets or ar-rays or oligonucleotides as one that has been em-ployed in prior-art DNA computational devices andtherefore one that must rely on specific structuralfeatures for patentability. On the other hand, if thedevice employs a novel processing step, or analyt-ical step, or achieves a novel result, the set itselfmay be defined functionally in broad terms. Ofcourse, one will still want to seek patent protectionof the set of polynucleotides, if the set or any of itsindividual members meet the requirements forpatentability.

CONCLUSIONS

Polynucleotide sequence inventions are not allalike. Depending on the function a DNA sequenceinvention performs and its characteristics as a mol-ecular entity, the invention may be classed as a mol-ecular compound, a probe, a set of instructions, orone of a set of computational elements. These in-vention types correspond roughly to the roles thatpolynucleotides play in nature.

This paper outlines the characteristics of the fourinvention types, as a guide to inventors for classi-fying their DNA sequence inventions into one ormore types. In general, the inventors should classifytheir inventions into as many types as possible, aseach type offers particular advantages in terms ofmeeting the requirements for nonobviousne ss, en-ablement, or written description. A recurrent strat-egy, as applied to molecular compounds and cod-ing sequences, is to attempt to find novel sequenceswithin the polynucleotides that can be indepen-dently claimed as a probe. A basic strategy forclaiming sets of polynucleotides that function ascomputational elements is to claim the set as part ofa computational device.


Documents

An Inventor’s Guide to Patenting Polynucleotide Inventions