Are Oligonucleotide Primers and Probes Prima Facie Obvious over Larger Prior Art Nucleic Acids?

Article excerpt

I. INTRODUCTION

While the Court of Appeals for the Federal Circuit [hereinafter CAFC] has decided that large nucleic acid sequences are nonobvious when the prior art teaches only shorter sequences, the converse question remains unaddressed, i.e. whether small nucleic acid sequences are obvious in view of the larger nucleic acid sequences that comprise them? This Comment approaches the question of "prima facie obviousness" in these smaller sequences through two hypothetical patent claims that are drawn to nucleic acid oligonucleotides. This Comment will analyze seven common prior art situations, as applied to the two hypothetical patent claims, to determine whether for each prior art situation the hypothetical claims are prima facie obvious in light of the relevant case law.

II. BACKGROUND

As the pace of advancement in biotechnology increases exponentially and the databases which store nucleic acid sequences double every year, (1) increasingly complex issues of intellectual property leave the laboratory and enter the courtroom. Nucleic acid sequences serve as a resource for the bioinformatics researcher and molecular biologist alike to design new tests and assays. (2) Some tests have been designed to diagnose diseased patients and identify the specific organism suspected of causing the symptoms, thereby leading to a specific treatment. (3) Another test has been designed to identify genetic mutations in a pig that cause enhanced litter size. The test allows farmers to select pigs with increased fecundity, which can in turn lead to reduced farm costs. (4) These tests rely on the use of small pieces of deoxyribonucleic acid (DNA), oligonucleotides, which are termed either "primers" or "probes," depending upon their use. (5)

Probes and primers are pieces of DNA which contain specific information encoded by the four nucleotide base codes, A, C, G, T (Adenine, Guanine, Cytosine, or Thymidine). (6) Probes interact with other pieces of DNA in a hybridization reaction, wherein a specific probe with a specific sequence of nucleotides will interact with a complementary sequence in a target nucleic acid. (7) Primers are a subset of probes with the further capacity to be extended in length by addition of nucleotides in a sequence-specific manner in a catalytic process employing a DNA polymerase enzyme. (8)

This Comment will address the question of whether and when oligonucleotide probes and primers are obvious under a variety of prior art situations. Figure 1 discloses the seven different nucleotide prior art situations that will be used. These sample claims will be analyzed under current case law to yield conclusions regarding the prima facie obviousness of the exemplary claims. Embedded in the CAFC case law are three approaches that are used to address the obviousness of DNA-based claims. These approaches are based upon (i) chemical case law, decisions that existed prior to the biotechnology revolution which interpret oligonucleotide claims from a chemical composition perspective; (ii) genus-species type case law, which approaches the obviousness of oligonucleotide claims as individual species in relation to the genus from which they derive; and (iii) some recent biotechnology-specific case law that is focused on issues regarding the obviousness and possession of biotechnological inventions. These three approaches will be individually applied in analyzing the level of obviousness in the exemplary claims.

III. OBVIOUSNESS ANALYSIS

A. Basic Principles

The statutory language in the Patent Act that addresses obviousness provides the starting point in analyzing the nature of each of the seven situations provided in Figure 1. The applicable section is 35 U.S.C. [section] 103(a), which states in significant part,

[a] patent may not be obtained though the invention is not

identically disclosed or described as set forth in section

102 of this title, if the differences between the subject

matter sought to be patented and the prior art are such

that the subject matter as a whole would have been obvious

at the time the invention was made to a person having ordinary

skill in the art to which said subject matter pertains.

Patentability shall not be negatived by the manner in which

the invention was made. (9)

The Supreme Court analyzed the statute in Graham v. John Deere Co. and developed the following analysis for determining whether a claim was nonobvious over the relevant prior art:

Under [section] 103, the scope and content of the prior art

are to be determined; differences between the prior art and

the claims at issue are to be ascertained; and the level of

ordinary skill in the pertinent art resolved. Against this

background, the obviousness or nonobviousness of the

subject matter is determined. (10)

It is the relationship of the Graham analytical factors that guides the prima facie obviousness determination. Obviousness is determined by focusing on whether the individual of ordinary skill in the art, when analyzing the relevant prior art, would have found the differences between that prior art and the patent claims at issue to be obvious. (11) Each of the three factors, along with any evidence of secondary considerations, must be weighed as a whole to make the prima facie obviousness determination. (12) The first inquiry identified by the Supreme Court involves characterizing the prior art. (13)

B. Prior Art

The first of the Graham factors addresses the scope and content of the prior art. In the oligonucleotide context, a significant body of prior art exists which discusses the parameters and objectives involved in the selection of oligonucleotides that function as probes and primers. (14) A specific example is the Hogan et al. teaching probe selection, which provides for specific identifications in bacterial ribosomal RNAs. It states,

Once the variable regions are identified, the sequences are

aligned to reveal areas of maximum homology or 'match'. At

this point, the sequences are examined to identify potential

probe regions. Two important objectives in designing a probe

are to maximize homology to the target sequence(s) (greater

than 90% homology is recommended) and to minimize homology

to non-target sequence(s) (less than 90% homology to

non-targets is recommended). (15)

There are, in fact, many Internet Web sites that provide free downloadable software to aid in the selection of primers drawn from genetic data recorded in a spreadsheet. (16) Other sites will freely permit primer selection using Web based applications. (17) Thus, the prior art is replete with guidance and information necessary to permit the ordinary artisan in the field of nucleic acid detection to design primers and probes.

Figure 1 illustrates seven hypothetical oligonucleotides compared against relevant prior art sequences. In each of the examples given, there are two parameters which vary: the sequence itself, and the length of the sequence. It is the interaction of these two parameters, in conjunction with the prior art and the proper legal analysis, that determines the obviousness of any particular nucleic acid sequence. The first hypothetical situation shown is where the oligonucleotide has no homology with any known prior art sequence whatsoever, as exemplified in Panel A. The second situation is where the oligonucleotide is perfectly complementary to a prior art oligonucleotide of identical length and sequence, as shown in Panel B. The vertical lines between the bases represent a convention that the nucleotide bases in the code are identical. Where there are no vertical lines, the nucleotide bases are divergent or have a mismatched nucleotide base. The third situation is where the entire sequence from which the oligonucleotide is derived is known in the prior art, as shown in Panel C. The fourth situation is where, not only is the entire sequence from which the oligonucleotide derived known in the prior art, but there is another oligonucleotide from the same sequence in the prior art as well, as shown in Panel D. The fifth situation is where, not only is the entire sequence from which the oligonucleotide derived known in the prior art, but there is an overlapping oligonucleotide in the prior art as well, as shown in Panel E. The sixth situation is where the prior art sequence from which the oligonucleotide is derived has a mismatch or different nucleotide with the oligonucleotide, as shown in Panel F. The seventh situation is where the oligonucleotide is longer than the prior art sequence, as shown in Panel G. These seven hypothetical situations, which epitomize the most common prior art that is available in oligonucleotide cases, represent the prior art which will be further analyzed in this Comment.

C. Claims Analysis-Anticipation and Nonobviousness

The second Graham factor involves analyzing the differences between the prior art and the claims at issue. Two separate claims are considered in the obviousness inquiry for the sample sequences in the figure. The only difference between the claims is the "transitional" phrase. Claim 1 uses the open language phrase "comprising" whereas Claim 2 uses the closed language phrase "consisting of." (18) The hypothetical claims state:

Claim 1, an isolated oligonucleotide comprising GCAGAGTACTATCGATG, and Claim 2, an isolated oligonucleotide consisting of GGCAGAGTACTATCGATG. The sequence disclosed in the claims is the sequence represented by the oligonucleotide in Figure 1.

In analyzing the seven situations in the figure against Claims 1 and 2, two of the situations are immediately resolved for either claim. Since there is no prior art in Panel A, there can be no analysis of the differences, thus the claims are considered "nonobvious." The obviousness analysis begins with an inquiry into the scope and content of the prior art. (19) If this first inquiry reveals no prior art which can be applied to the claims--because the differences between any prior art and the claims are too significant for any of the prior art to be applicable--then the claims are necessarily "nonobvious."

[FIGURE 1 OMITTED]

Panel B shows a situation where a single prior art reference meets the exact limitations of the claimed invention, thus the claims are considered "anticipated." (20) In this instance, the nonobviousness inquiry is short-circuited since the claims lack "novelty" under 35 U.S.C. [section] 102. When a claim is "anticipated," no question of obviousness is present since the obviousness inquiry only begins if the claim itself is novel over the prior art. A mere modification of the prior art may render a claim obvious. (21)

Further, analyzing Panels C-E with regard to Claim 1 can be simplified. In each case the reasonable interpretation of the open term "comprising" permits the presence of the additional sequence attached to the ends of the specific oligonucleotide. (22) Therefore, in Panels C-E, there are also no differences between the prior art and the oligonucleotide, rendering Claim 1 anticipated by the prior art. Claim 2, however, is not anticipated by the prior art in Panels C-E, since there are differences between the prior art and the claim. These panels will be analyzed later under the relevant case law.

The third Graham element, the level of ordinary skill in the art, is addressed by

[f]actors that may be considered in determining level of

ordinary skill in the art include (1) the educational

level of the inventor; (2) type of problems encountered

in the art; (3) prior art solutions to those problems; (4)

rapidity with which innovations are made; (5)

sophistication of the technology; and (6) educational

level of active workers in the field. (23)

It is assumed for the purposes of this Comment that the educational level of the inventor and active worker in the DNA diagnostics field is a Ph.D. with several years of postdoctoral experience. The problems and prior art solutions are also at the highest level of sophistication with innovation itself proceeding at a very rapid rate. The level of ordinary skill in this art is therefore extremely high, and the third Graham element will ordinarily favor a finding of obviousness. In analyzing the prima facie obviousness of the prior art situations of Panels F and G as applied to Claim 1, and Panels C-G as applied to Claim 2, the case law has approached the prima facie obviousness inquiry in several ways: some oligonucleotide cases analogize oligonucleotides to chemical analogues and apply chemical case law; a second approach is to apply genus-species case law, which states that small nucleic acid pieces are "species" of a larger "genus" suggested by the full length sequence; third, the reasoning in recent biotechnological case law regarding anticipation and written description of nucleic acids has occasionally been applied to oligonucleotides.

V. CHEMICAL CASE LAW

In early chemical cases, chemical entities were prima facie obvious if the claimed compound was "structurally" obvious over a prior art reference. (24) The Court of Customs and Patent Appeals [hereinafter CCPA] began from the premise that "in order to be patentable, novel members of a homologous series of chemical compounds must possess some unobvious or unexpected beneficial properties not possessed by a homologous compound disclosed in the prior art." (25) Chemical entities which were homologous to prior art entities were prima facie obvious until the applicant rebutted this obviousness with an evidentiary showing. (26) The CCPA addressed the showing necessary to rebut the prima facie case of obviousness in In re Papesch, where the CCPA found that an applicant who showed that a novel compound possessed anti-inflammatory properties, which were not present in a homologous prior art compound, had rebutted the case of prima facie obviousness. (27) Regarding the assumption that homologues (28) are identical in properties, the CCPA noted that "[a]n assumed similarity based on a comparison of formulae must give way to evidence that the assumption is erroneous." (29) When the CAFC took up this issue en banc in In re Dillon, the court stated,

This court, in reconsidering this case in banc [sic],

reaffirms that structural similarity between claimed

and prior art subject matter, proved by combining

references or otherwise, where the prior art gives

reason or motivation to make the claimed compositions,

creates a prima facie case of obviousness, and that

the burden (and opportunity) then falls on an applicant

to rebut that prima facie case. (30)

The CAFC found in Dillon that the triorthoesters and the tetraorthoesters were equivalent, and that the addition of the single carbon did not alter the properties of the chemical. (31) The CAFC clarified that a prima facie case for obviousness of chemical compounds requires only teachings of the composition by combination of prior art references with concomitant motivation present to combine the prior art references. No requirement exists, however, for the prior art to suggest the same utility as that of the inventor. (32)

This contrasts with the statement of the CAFC in In re Grabiak that "[u]pon review of this history, we have concluded that generalization should be avoided insofar as specific chemical structures are alleged to be prima facie obvious one from the other." (33) In that statement, and in later cases, such as In re Jones, specific motivation to make the change in the chemical structure seems to be required. (34) The CAFC appears to be moving from a requirement of "motivation to make the compound" to a requirement of "motivation to make the specific change which results in the new compound." In part, this may be due to a belief that the unpredictability of the chemical arts should be reflected in the prima facie obviousness analysis. (35)

One application of the chemical case law to a biotechnological invention is found in In re Mayne, where the CAFC analyzed the obviousness of a modified protein. The relevant prior art consisted of a primary reference which taught the making of fusion proteins, a secondary reference which taught the specific cleavage sites in fusion proteins, and another secondary reference which taught a number of chemical cleavage sites which shared some structural similarity with the claimed compound. (36) Once the CAFC found that there were structural similarities sufficient to form a prima facie case, the CAFC reviewed the evidence of secondary considerations. (37) The CAFC found that the evidence presented failed to support a determination of unexpected results. (38) As a result, this case would support a rule that modifications to nucleic acids or proteins, where the general modification is suggested by a prior art reference, are prima facie obvious in the absence of secondary considerations.

A. Chemical Case Law Applied to Claim 1

As noted previously, the two significant parameters in evaluating oligonucleotide claims are the oligonucleotide sequence and the oligonucleotide length. In Panel F, the two sequences are essentially identical, with the exception of a single mismatch between the oligonucleotide and the prior art sequence. It is this similarity which makes the oligonucleotide a homologue of the prior art sequence. The chemical case law will be applied next to determine whether the level of homology renders the claimed oligonucleotide prima facie obvious.

The homology in the sequence is based upon the fact that each of the nucleic acid bases are arguably homologous to each other. As shown in Figure 2, the Thymine and Cytosine bases only differ in the placement of a methyl group. (39)

[FIGURE 2 OMITTED]

To argue that the bases are homologous, the proponent would note that Thymine and Cytosine are both present in essentially all DNA sequences and that they belong to a class of organic compounds which differ from one another in fixed locations by one substitution of an amine (40) for a carbonyl group (41) and one methyl group. (42) Replacing a Thymine base for a Cytosine base, in an 18 nucleotide oligonucleotide, composed of hundreds of atoms, would affect the hybridization properties of the oligonucleotide. (43) This mismatch would cause a ten degree reduction in Tm, (44) as analyzed by the oligonucleotide properties calculator. (45) This means that the mismatched oligonucleotide would hybridize with a reasonable degree of specificity. (46) Given the express statement by the Dillon court that structural similarity is sufficient to provide a prima facie case of obviousness, the court might support a finding of obviousness of the oligonucleotide in Panel F in view of the prior art shown. (47)

The decision in Ex parte Anderson might also support a finding of prima facie obviousness. In that case, the Board of Patent Appeals and Interferences affirmed a rejection of a nucleic acid sequence that differed from another nucleic acid sequence due to an allelic variation, which resulted in one different amino acid in the resultant protein. (48) Such a molecular modification may be sufficient for establishing obviousness. (49) The oligonucleotide in Panel F would be prima facie obvious in light of the structural similarities it shares with the prior art, despite the mismatched base, because the base is "chemically" homologous.

The case depicted in Panel F is not as good as the case in In re Mayne, however, where there was essentially an express suggestion in the prior art of the particular amino acid that should replace its homologous amino acid. (50) In the example, no specific teaching is present to suggest which, if any, homologous nucleotides should be altered in the prior art nucleic acid which would result in formation of the claimed oligonucleotide. If it were directly applied to the example, Mayne would likely result in a finding that Claim 1 is nonobvious.

The CAFC made the strong statement in In re Jones that

[c]onspicuously missing from this record is any evidence,

other than the PTO's speculation (if it be called evidence)

that one of ordinary skill in the herbicidal art would have

been motivated to make the modifications of the prior art

salts necessary to arrive at the claimed 2-(2'-aminoethoxy)

ethanol salt. (51)

Following Jones, a change of one homologue for another, in the absence of particular motivation for the particular change, would lead to a conclusion of nonobviousness. This motivational problem is central in Panel F, because there is no reason to alter the particular nucleotide at that particular position in the oligonucleotide to create the altered oligonucleotide. As the case law has progressed, the motivation question appears to have become the central issue. Even in Dillon, the CAFC seemed to imply a requirement for "motivation to make the change." In the instant example, no motivation exists other than a generic observation that alteration of a single nucleotide in the oligonucleotide would modestly alter the properties if present. (52) Therefore, applying the analysis of Jones to Claim 1, using the prior art situation of Panel F would very likely result in a finding that the claim is nonobvious over the prior art.

Applying the reasoning of Dillon and Jones to Panel G, there are substantial differences between the oligonucleotide and the prior art. As the prior art sequence is shorter than the oligonucleotide, there is no teaching of the full length of the oligonucleotide in the prior art. Further, there is no suggestion or motivation to fill in the missing nucleotides into the prior art of Panel G, thus the oligonucleotide would likely be found nonobvious over the prior art of Panel G. (53) It would appear then that deficiencies in the prior art teachings regarding the sequence and length of the oligonucleotide mitigate against a finding of prima facie obviousness for the sequence shown in Panels G.

B. Chemical Case law Applied to Claim 2

In regards to Claim 2--where the oligonucleotide is claimed using the closed language phrase "consisting of"--the anticipation and nonobvious determinations made regarding Panels A and B remain the same as the determination for Claim 1. This is because the prior art deficiency still renders Claim 2 nonobvious in view of Panel A, while Claim 2 is anticipated in view of the prior art of Panel B. The analysis of Panels F and G, while tending toward nonobviousness, remain substantially the same as above, since the central issue in each of those panels is the absence of teaching an alteration of a particular nucleotide or nucleotides in the prior art. The motivation to select a particular oligonucleotide from the larger sequence is that ordinarily a practitioner will first review the prior art to identify desirable locations for oligonucleotides. (54)

Panels C, D, and E represent increasing levels of structural similarity between the prior art and the claimed oligonucleotide. In Panel C, the full length sequence has a region of complete identity, where every nucleotide perfectly matches between the prior art oligonucleotide and the hypothetical oligonucleotide of Claim 2, and the prior art differs only in the length of the sequence. In Panel D, the prior art not only has the region of complete identity with the oligonucleotide, but there the prior art teaches of a functionally homologous oligonucleotide as well. (55) In Panel E, the prior art has the region of complete identity, and the functionally homologous oligonucleotide in the prior art substantially overlaps the claimed oligonucleotide, to share a substantial region of complete identity.

In analyzing Panels C, D, and E, besides the prior art sequence shown in Figure 1, two other types of prior art must be considered. To begin with, prior art abounds on modes of selection of primers and probes from larger sequences. This prior art in part, provides the ordinary practitioner with the ability to select smaller sequences from larger, known prior art sequences. Abundant prior art also exists that provides motivation to select primers from larger sequences, such as that in the Mullis patent. (56)

Applying this prior art tableau and the chemical case law to Panel C, the only difference between the prior art and the oligonucleotide is the extended length of the prior art relative to the oligonucleotide. As noted above, there is prior art which would direct the selection of primers from larger sequences and there is prior art which would motivate such a selection, for example, in order to amplify the sequence of interest. (57) Applying the chemical case law, In re Dillon in particular, a prima facie case of obviousness seems to emerge. In Dillon, the CAFC found that the triorthoesters and the tetraorthoesters were equivalent, and that the addition of the single carbon did not alter the properties of the chemical. The situation in Panel C presents the converse; (58) there is a deletion of nucleotides from the prior art polynucleotide which is necessary to render the oligonucleotide obvious.

An ordinary practitioner in biotechnology is aware that any version of the prior art polynucleotide which comprises the claimed oligonucleotide would function to hybridize to the same target molecule. (59) The issue, therefore, is whether there is motivation to shorten the particular oligonucleotide claimed to the specific sequence given. Generic motivation to shorten the polynucleotide may be provided by the earlier references, such as Mullis, which desire shorter nucleic acids in order to perform the polymerase chain reaction. (60) The bent of the chemical case law suggests that a functional and structural homologue is sufficient for a prima facie case of obviousness. Therefore, case law appears to support the obviousness of the oligonucleotide in Panel C, based on the prior art polynucleotide and earlier prior art references. (61)

Panels D and E represent situations in which the motivation to make the oligonucleotide is enhanced. In Panel D, for example, a homologous prior art oligonucleotide provides express motivation for the detection of the prior art sequence by hybridization or amplification analysis. (62) While the analysis of this Panel is similar to Panel C, the presence of the homologous oligonucleotide in Panel D demonstrates that the ordinary practitioner tends to design oligonucleotides of reduced length, relative to the full length prior art sequence, and provide a functional homologue to the claimed oligonucleotide. The case for obviousness in Panel D is stronger than in Panel C, due to the presence of the prior art homologous oligonucleotide. Panel E represents a scenario where the prior art is nearly identical and the oligonucleotide is arguably obvious, but not anticipated. The prior art teaches not only the full length polynucleotide from which the oligonucleotide is derived, but also teaches an overlapping oligonucleotide. The presence of the overlapping oligonucleotide arguably directs the ordinary practitioner to a particular part of the prior art polynucleotide, therefore reducing the amount of variability in the sequence that must be motivated by the prior art polynucleotide. This represents the strongest case of prima facie obviousness under the chemical case law because there is "functional" homology and "structural" similarity with identical utility in the prior art, as compared to the claimed oligonucleotide.

This case is closest to the situation in Mayne, where there was express suggestion of the possible alternative enterokinase cleavage sites, (63) and the CAFC found selection of one site relative to another enterokinase cleavage site prima facie obvious. (64) Therefore, as the prior art increases in motivation in Panels C-E, it is increasingly likely that a court would find the claimed oligonucleotide prima facie obvious over the increasingly close prior art.

VI. GENUS-SPECIES CASE LAW

A different approach to the question of obviousness, as applied to Claims 1 and 2 and in light of the prior art, is to view the question as the selection of a species from a larger genus. The original position of the CCPA on genus-species issues is expressed in In re Susi. In this case, the CCPA wrote "[a]ppellant is essentially in the position of one who argues that the selection of a relatively small subgenus from a genus disclosed in the prior art would have been unobvious at the time of his invention to one skilled in the art." (65) The CCPA determined that selection of a species from a genus, absent a showing of unexpected results, was prima facie obvious. (66)

The CAFC applied the same reasoning in Merck & Co. v. Biocraft Laboratories, Inc., where selection of a particular compound out of 1200 possible prior art compounds in the prior art genus was determined to be obvious. (67) The obviousness in that case was based both on the structural similarity of the different compounds and upon the CAFC's understanding that each and every compound in the genus would have been expected to function. (68) The CAFC noted that "any of the 1200 disclosed combinations will produce a diuretic formulation with desirable sodium and potassium eliminating properties." (69)

The CAFC cited In re O'Farrell for the proposition that such a selection of particular species from a prior art genus was not "obvious to try," but rather that there was a reasonable expectation of success. (70) Two types of error are identified as "obvious to try" in O'Farrell, the first being that,

[i]n some cases, what would have been "obvious to try"

would have been to vary all parameters or try each of

numerous possible choices until one possibly arrived at

a successful result, where the prior art gave either no

indication of which parameters were critical or no

direction as to which of many possible choices is

likely to be successful. (71)

The second type of error is "to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance." (72) The CAFC noted that neither type of error applied in Merck, where the prior art reference "instructs the artisan that any of the 1200 disclosed combinations will produce a diuretic formulation with desirable sodium and potassium eliminating properties." (73) That is, where every member of the genus would be expected to achieve success, there is a reasonable expectation of success.

The CAFC, when given cases where the genus was substantially larger, has stepped away from the bright line rule of Susi that species are prima facie obvious where the genus was in the prior art. (74) The genus in In re Baird was estimated to encompass more than 100 million different compounds and selection of a single compound from this genus was required for the rejection. (75) The CAFC found that given the large size of the genus, the reference did not render the claimed invention obvious. (76) The CAFC extended this reasoning into the biotechnology domain in In re Bell, where the court noted,

Bell has argued without contradiction that the Rinderknecht

amino acid sequences could be coded for by more than [10.sup.36]

different nucleotide sequences, only a few of which are the

human sequences that Bell now claims. Therefore, given the

nearly infinite number of possibilities suggested by the

prior art, and the failure of the cited prior art to

suggest which of those possibilities is the human

sequence, the claimed sequences would not have been

obvious. (77)

While the court may wish to avoid a bright line test, it is fairly clear that, as the number of species in a genus increases, two distinct thresholds are crossed: anticipation and obviousness.

Professor Adelman, a scholar at the George Washington University School of Law, identifies six tests which courts have used to analyze whether a species claim is anticipated by a genus disclosure. (78) The tests include,

(1) The number of compounds embraced by the most specific

prior art description; (2) The degree of structural

similarity between the compounds of that group; (3) The

number of properties shared by compounds of that group; (4)

Whether the properties of the claimed compounds are the same

as, consistent with or diametrically opposite to the

properties disclosed in the prior art; (5) The number of

parameters that can be varied among the most specifically

described group of prior art compounds; and (6) Whether

the claimed materials are physical mixtures or the product

of chemical reactions. (79)

These same factors can serve as a guide for the obviousness determination, since the same elements that animate the anticipation determination regarding genus-species situation will impact the obviousness determination. In particular, the element of motivation or suggestion to combine, which is necessary for an obviousness rejection, will be significantly impacted by whether the factors above suggest the claimed materials are closely or distantly related. For example, in a small genus where each species can be immediately envisaged, a species may be legally anticipated by the genus. (80) As the number of species rises, for instance, the 1200 species being permitted under the facts of Merck, the species may be rendered obvious by the genus. (81) When the number of species reaches stratospheric heights, as in Bell ([10.sup.36] different species) or in Baird (millions of species), the species is not obvious from the teaching of the genus. (82)

A. Genus-Species Case law Applied to Claim 1

In applying genus-species case law to Claim 1, Panels A-E are treated identically to the chemical analysis described above. Applying the six-factor Adelman tests (83) to oligonucleotides, several of the factors are shared in common by all oligonucleotides including those described in Figure 1. Regarding the third factor--the number of properties shared by compounds in the genus--all oligonucleotides share a number of structural properties; oligonucleotides are carbohydrate polymers composed of the same four monomeric species which are capable of hybridization to complementary sequences. These sequences are ordinarily found in a duplex helical form whose exact properties are determined by the precise order and ratio of the monomeric components. (84) The only properties not necessarily shared by oligonucleotides are those due to differing sequences which result in different targets for duplex formation.

Both the prior art and the claimed oligonucleotide share the same chemical properties with regard to the fourth factor--the relationship of the properties of the claimed compounds to the prior art. Any differences in properties are solely related to the different specific sequences of the oligonucleotide and the prior art polynucleotide which would result in different target sequences for complementary hybridization. Finally, applying the sixth factor--whether the compounds are mixtures or products of chemical reactions--the oligonucleotides may be the product of chemical reactions, but they are compounds, not mixtures.

Panel F presents the case where a single nucleotide is changed from the prior art. Applying the first factor, the prior art embraces a single compound. The Mullis patent may be relied upon to teach that sequence variations function for the polymerase chain reaction [hereinafter PCR] primers and perfect matches are not required. Therefore, as Mullis directs, "the primer sequence need not reflect the exact sequence of the template." (85) In the present example, the Mullis patent is combined with the prior art polynucleotide of Panel F to create a genus of single base pair mismatches.

While the figure is illustrative, prior art nucleic acid sequences can range from the relatively short 67 nucleotide sequence shown in Figure 1, to thousands or even millions of nucleotides, depending upon the prior art reference. (86) To determine the number of possible probe sequences, the length of probes must be multiplied by 3 to yield the number of probes with single mismatches. Since there are four nucleotides, A, C, G, and T and since every position has one of these four bases already, at each position there are three different possible mismatches. For example, if an A is in position 1, it can be changed only to a C, a G, or a T to form a mismatch. To calculate the total number of possible single mismatches in a oligonucleotide of a given length, the calculation involves multiplying the number of possible positional mismatches at positions 1 to the end of the oligonucleotide, by the number of possible different probes at each position, which will ordinarily be three since there are only three alternate nucleotide bases. This calculation determines the number of possible probes. Assuming the prior art sequence shown in Figure 1, if factor 1 is applied to 67 nucleotides, with 66 of the nucleotides held constant and only one nucleotide permitted to change at a time, there are 3 times 67 members of the genus (or 201) single point mutations in the prior art sequence.

A normal probe range includes lengths of 15 to 25 nucleotides, and is also the preferred range for many genetic applications and PCRs. (87) For 18 mer (partial) probes, there are 49 possible probes of the 67 nucleotide prior art polynucleotide sequence. (88) For the full probe range of 15 to 25, adding the number of possible probes for every member of the range of probe lengths from 15 to 25, there are 465 possible probes. Multiplying 465 by 3 to determine the total number of probes with single mismatches yields the total number of single mismatch probes: 1395, including mismatched probes.

Factor 2 leads to the conclusion that some of the members of the group of 1395 possible mismatched probes have substantial structural similarity in a purely chemical sense, but information-wise are very different. For example, while two probes which overlap except for one nucleotide or which differ by a mismatch are structurally nearly identical, two non-overlapping probes may have completely unrelated sequences, but identical chemical compositions.

Factor 5 indicates that the two parameters concerning the particular sequence and particular length of a group of prior art compounds are variable. Considering these factors as a whole in view of Merck, one could argue that a single point mutation in a short 67 nucleotide prior art sequence would be prima facie obvious since it represents selection of 1 compound out of 1395 compounds, all of which would have identical hybridization properties. (89) However, as the length of the sequence increases beyond 67 nucleotides and the number of mismatches increases beyond a single mismatch, the number of compounds in the genus will rapidly rise to numbers closer to those in the Baird decision rather than the small genus found in Merck. (90) Thus, longer sequences with more mismatches are likely to be nonobvious, based upon the application of the Adelman factors.

In Panel G, the number of species is much larger, and the fact pattern is more like the situation in Bell. The size of the genus in Panel G would be the four possible nucleotides held to the 11th power. Further, there is no assurance that any large portion of this genus would function to specifically detect any particular sequence.

Applying factor 2 is slightly counterintuitive, since every larger sequence would encompass the 7 nucleotides in the prior art, meaning that there would be some identical structure in the entire genus of 4,194,304 oligonucleotides--four possible nucleotides held to the 11th power. However, the vast majority of the genus would not function in a manner homologous to the claimed oligonucleotide.

Factor 5 relates the two variable parameters of sequence and length. Considered in their entirety, these factors appear to place analysis of obviousness for Panel G closer to Bell than to Merck particularly given the absence of a reasonable expectation that each member of the genus would be functionally homologous. (91) Therefore, the analysis in Bell would render the oligonucleotide in Panel G nonobvious.

B. Genus-Species Case Law Applied to Claim 2

In Claim 2 the oligonucleotide is claimed using the closed language phrase, "consisting of." As above, the anticipation and nonobvious determinations made regarding Panels A and B remain the same. The analysis of Panel G is nearly identical to the analysis above for Claim 1, since the concern in Panel G is the absence of implicit teaching of the 11 missing nucleotides. The use of "comprising" within the claim does not enter the analysis. Panels F, C, D, and E, respectively, show decreasing sizes of the possible structural genus. There is also abundant prior art that suggests how to make primers and probes from larger sequences, as well as equally abundant prior art that teaches the means necessary to make such prior art.

One last element, relevant because of the CAFC's holding in Merck--the genus is obvious when each member would be expected to function--is evidence that each oligonucleotide would be expected to function. (92) There is prior art that has tested every possible complementary oligonucleotide, including lengths ranging from monomers, (93) to 17 nucleotides, to a 122 nucleotide sequence, for the ability to hybridize, and found that DNA hybridized to most of the array. (94) This prior art supports the kind of "equivalence" that the CAFC relied upon in Merck.

Another area with abundant prior art is sequencing by hybridization, where every oligonucleotide of a certain size is synthesized on a micro array and hybridized to the target sequence. (95) Such arrays have been made and tested with oligonucleotides that have each of the 65,536 different oligonucleotides in 8-nucleotide lengths. (96) Based upon the hybridization pattern, the sequence of the target can be determined by a methodology that relies upon the functional equivalence of hybridization of every oligonucleotide on the array. (97)

The analysis and conclusions are the same under Adelman factors 3, 4, and 6 for Panels C-F with Claim 2 as they were for Panels C-F with Claim 1. With Claim 2, factor 5 though, differs between Panels C-F. In Panel F, the parameters that vary are the length of the oligonucleotide and the sequence of the oligonucleotide. Whereas, Panel C has the same two parameters, but because no sequence mismatches are permitted, there is less variability found within the sequence of the oligonucleotide. Panels D and E both have changes in the sequence of the oligonucleotide; however, since both also have prior art oligonucleotides of 18 nucleotides in length, that parameter is expressly taught by the prior art references. Panel E also has a reduction in the variability in the sequence parameter since the prior art oligonucleotide suggests a particular region of the prior art polynucleotide.

Factor 2 analyzes structural similarity, and in this instance there is abundant chemical structural similarity. However, the information content imposed by the specific arrangement of the nucleotides indicates that, except for Panel E, there is no structurally similar oligonucleotide. Panel E has an oligonucleotide which overlaps 14 nucleotides out of 18 total nucleotides, yielding close to 78% homology. (98)

Finally, factor 1 shows a decreasing genus size from Panel F to Panels C through E, respectively. In parentheses next to the number calculated for the prior art in Figure 1 is a number based on a prior art sequence of 5000 nucleotides in length. The number in parentheses shows the calculated genus size, not just for the hypothetical small sequence, but also a size that is more relevant to the typical real-life situation that would exist in the prior art, where the prior art sequences would be larger than the sequence in Figure 1. The number in parentheses represents a calculation for the more common prior art situation, where the sequence is 5000 nucleotides in length. Panel F has 1395 (164,340) oligonucleotide species which fall within its genus claim, given a prior art teaching of oligonucleotide lengths between 15 and 25 nucleotides, as taught by Mullis. (99) Panel C has a genus size of 465 (54,780) oligonucleotide probes, given a prior art sequence 67 nucleotides in length and permitting the oligonucleotide length to vary between 15 and 25 nucleotides. Panel D has a prior art oligonucleotide which teaches a length of 18 nucleotides. Therefore, the number of 18 nucleotide length oligonucleotides in a 67 nucleotide sequence would be 49 (4,982). While Panel D also teaches a preferred location, this teaching does not teach a method estranged from locating the oligonucleotide at other positions, but simply teaches a single preferred embodiment of a method to arrive at an 8-nucleotide sequence. (100) Panel E has an overlapping prior art oligonucleotide which also teaches the 18 nucleotide length, so if the claimed oligonucleotide is directed to that length and an overlapping region, only 35 (35) species are present in the genus of oligonucleotides suggested by the prior art.

Evaluating the Adelman factors with regard to the precise factual pattern given in the panels, the situations posed in Figure 1 appear to be closer to the court's determination of obviousness in Merck than to the decisions in Baird or Bell, which found the sequences nonobvious. In each of these cases the number of species is relatively low and the prior art would expect every member of the species to function in a predictable and identical manner, just like the diuretic compositions in Merck. (101) Because the prior art teaches an equivalence among 65,536 different oligonucleotides, even the higher numbers of species shown in parentheses for a genus of oligonucleotides which hybridize to a 5000-nucleotide prior art sequence might be found prima facie obvious. The fact patterns of Panels D and E, with 4982 and 35 different species members respectively, each comprise a genus that is sufficiently small, sufficiently homogenous, and whose expected function is likely to fall within the scope of Merck; particularly since each of the other Adelman factors would support a finding of prima facie obviousness. Panel C is still a relatively small genus, compared to the millions of different sequences in Baird or the immense exponential numbers in Bell. Panel F begins to approach a genus size more comparable to that in Baird and further faces the issue that the precise sequence is not taught in such a way that several of the other Adelman factors oppose an obviousness determination. Thus, based upon this analysis using the Adelman factors, Panels D and E would be strongly expected to yield a result of obviousness, Panel C would likely result in a determination of obviousness, and Panel F would likely be found nonobvious.

VII.BIOTECHNOLOGY CASE LAW

The CAFC has approached the issue of the obviousness of DNA with an amalgamation of chemical case law and genus-species case law, with several novel twists. The decisions have been somewhat controversial. (102) The CAFC also has two lines of case law dealing with obviousness and written description of DNA sequences. The first line of case law deals with the obviousness of large DNA sequences, given less than complete information regarding the nucleotide sequence, and the second lineage deals with what constitutes a written description of a DNA sequence to support claims under the first paragraph of 35 U.S.C. [section] 112.

The first lineage begins with Amgen, where the CAFC determined that a gene is not conceived until its sequence is known and defined. (103) The next case is Bell, where the USPTO rejected a claim drawn to nucleic acids which encoded the human insulin growth factor protein as obvious in light of two references. (104) The first reference taught the amino acid sequence of the protein and the second taught a method of isolation of nucleic acids using probes designed with the protein's amino acid sequence. (105) The CAFC argued that there would be [10.sup.36] possible sequences for the nucleic acid sequence and that this very large genus rendered the claim nonobvious. (106)

In Deuel, the CAFC focused on the extremely large genus sizes of isolated cDNA sequences, (107) where the prior art has no specific defined sequence. That decision indicates that reliance upon methods which are generically capable of isolating the genes, without more, is insufficient. (108) The CAFC further stated, "[w]hat cannot be contemplated or conceived cannot be obvious." (109) While the court did not elucidate this statement, routine knowledge of the issues involved in cloning genes using partial protein sequences can identify some of the problems with which the CAFC was concerned. Using a partial protein sequence and the appropriate cDNA library, screening could identify the full-length gene of interest, or screening could identify alternate splice variants, alternate genes, or artifacts. (110) Finally, in performing the screening, the sequence of the entire gene cannot be known. It is only this specific, defined nucleotide sequence however, that will likely be referred to as not "contemplated" or "conceived."

The second lineage of cases, which involve the written description requirement, is logically consistent with Deuel. Written description cases are relevant to the determination of the prima facie obviousness of primers over larger nucleic acid sequences, since that which is not described cannot be obvious. (111) Beginning with Fiers v. Revel, the CAFC imposed the requirement that the written description of a nucleic acid requires the sequence of the nucleic acid. (112) As the CAFC stated "[a]n adequate written description of a DNA requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it; what is required is a description of the DNA itself." (113) The CAFC reaffirmed this position in Regents of Univ. of California v. Eli Lilly, stating "a fortiori, a description that does not render a claimed invention obvious does not sufficiently describe that invention for purposes of [section] 112, [paragraph] 1." (114) The CAFC recently noted in Enzo Biochem v. Gen-Probe that the subject matter of the claims "is similarly defined only by the function of the claimed probes," which does not identify the chemical structure of the probes themselves. (115) These cases are consistent with Deuel since, whether a particular nucleic acid sequence is found to be obvious or described, the CAFC has required that the particular nucleic acid sequence be known. In these situations, the CAFC finds it insufficient to argue that one could get the sequence through mere routine practices. However, no court has addressed the situation at issue in this Comment: where an entire particular sequence is known, and the alleged invention lies in the selection of a small, defined segment of that particular defined and known sequence.

A. Biotechnology Case law Applied to Claim 1

Panel F represents the mismatch situation where the prior art does not teach one of the nucleotides of the claimed oligonucleotide. This lack of teaching constitutes a lack of written description of the particular oligonucleotide. No possible selection of a primer which is identical to the prior art sequence can result in the claimed oligonucleotide. There are generic methods to screen and sequence a number of allelic variants of the prior art sequence, (116) one of which might turn out to comprise the sequence of the claimed oligonucleotide. (117) However, the CAFC in Deuel indicates that a general method of isolating allelic variants would not render the claimed, specific oligonucleotide obvious. (118) Therefore, the oligonucleotide situation in Panel F would likely be nonobvious under the prior art.

Panel G of is similar to Panel F, but with less prior art. Panel G is directly analogous to the situation in Deuel, where the prior art sequence was used to screen a library which, given sufficient experimentation, would have resulted in the claimed oligonucleotide. However, the CAFC suggests that the inability to conceive in advance which nucleotides will be attached to the prior art sequence producing the claimed oligonucleotide renders the claimed oligonucleotide nonobvious. (119) This is consistent with the written description decisions, since there is no written description of the oligonucleotide in the prior art and an oligonucleotide which has not been described cannot be obvious. Therefore, the oligonucleotide in Panel G is also nonobvious over the prior art.

B. Biotechnology Case Law Applied to Claim 2

The anticipation and nonobvious determinations made regarding Panels A and B remain the same as in the chemical and genus-species analysis of Claim 2. Further, the analysis of Panels F and G is identical to that given for Claim 1. As before, Panels C-E represent situations in which the prior art gives increasing motivation to the selection of the specific oligonucleotide. Unlike the case in Lilly, the prior art sequence from which the oligonucleotide is derived is completely known and described. That is, the complete sequence of the oligonucleotide is found in the prior art and a claim to every 18-nucleotide primer from the prior art sequence would be properly described and encompass the claimed oligonucleotide.

In Deuel, the CAFC had three separate concerns regarding the obviousness of the DNA sequences. (120) The first concern was a huge genus size. (121) As discussed in the genus-species analysis, the genus size in probe selection is significantly smaller than that for back-translation of proteins into genes. Instead of a genus comprising [10.sup.36] species, the number of species even in a large 5000 nucleotide sequence genus will be less than 55,000, as calculated by the method discussed in the genus-species analysis. The largest genus for a particular example, such as Panel C, would comprise 465 members. The genus size would be smaller in Panels D and E, since there is less variability between the prior art and the hypothetically claimed oligonucleotide in those panels; the sequences are closer in length and position. Panel E, which teaches a particular probe size and suggests a particular preferred oligonucleotide location which overlaps the location of the hypothetical probe, permits very little variability which significantly reduces the genus size. Thus, the situation with regard to genus size in Claim 2 in the prior art situations of Panels C-E is unlike the genus size in Deuel. The genus sizes in these panels are many factors smaller than those at issue in Deuel.

The second concern in Deuel was that the prior art lacked the specific, defined sequence which was the subject of the claim. (122) In the current case, however, the prior art in Panel C comprises the specific, defined sequence. The prior art in Panels D and E not only comprise the specific, defined sequence, but further suggests particular sized oligonucleotides and particular locations that are especially of interest. This suggestion results from the fact than an ordinary practitioner is likely to first review the prior art for desirable locations for oligonucleotides and use such prior art locations as the starting point for oligonucleotide design.

The only case in which preexisting sequence was present was Mayne, where substitution of a known cleavage site with a particular amino acid sequence into a fusion protein was deemed obvious. In the present fact pattern, the expected functional equivalence of every member species of the genus of probes suggests the homologous oligonucleotides will be functional. (123) This suggestion, combined with the ability of a computer or scientist to completely define each and every species member solely through the prior art, supports prima facie obviousness of the oligonucleotides. There is greater suggestion of obviousness in Panels D and E, where there is an express homologue present on the same prior art sequence to suggest alternate compounds. These presumptions of obviousness would be rebuttable, however, under the logic of In re Papesch. (124)

The third issue presented by Deuel is that of whether a compound can be defined by the process of identification. The CAFC has stated that "[t]he fact that one can conceive a general process in advance for preparing an undefined compound does not mean that a claimed specific compound was precisely envisioned and therefore obvious." (125) While the fact patterns of Panels C-E have a claimed oligonucleotide, which may be deemed an undefined compound in some sense, the lack of definition is of an entirely different type and magnitude than that referred to and intended by the court in Deuel. In Deuel, no nucleic acid sequence was known in the prior art. The entire process and method cited for the rejection were devoted to isolating and sequencing unknown nucleic acids in order to identify the particular nucleic acid sequence of interest. (126) This is in direct contrast to the current fact pattern, where the entire nucleic acid sequence is known in the prior art, and Panels D and E, where oligonucleotide homologues, drawn to the particular prior art sequence and target sequence, are known in the prior art. Further distinguishing the oligonucleotide primer and probe situation from the situation in Deuel is the nearly 100% expectation of success in probe identification. (127) There is also prior art which shows that essentially every probe is expected to hybridize to its complementary DNA target. (128)

Therefore, analysis of the fact patterns in Panels C-G, using the biotechnology case law, supports the position that where the prior art does not teach the sequence of the oligonucleotide--as in Panels F and G--the oligonucleotide is nonobvious. Where the prior art teaches the nucleotide sequence from which the oligonucleotide is derived--combined with the substantial skill in the prior art in selecting oligonucleotides and the prior art demonstrating the functional equivalence and expectation of success of every oligonucleotide in hybridization reactions--it can be reasonably concluded that the oligonucleotides are prima facie obvious.

VIII. CONCLUSION

Courts should analyze nucleic acid claims using a combination of the three analytical approaches presented. The ideal analysis would analyze the issue of equivalence, the central element found in chemical cases, by applying the genus-species cutoffs. That is, equivalence would depend on the size of the genus, the relationship of the species to the genus, and the fundamental nature of the species. Finally, the court would recognize that in biotechnology, the fundamental nature of the species termed oligonucleotides is as carriers of biological information.

Applying these principles to oligonucleotides, courts should find specific oligonucleotide probes and primers prima facie obvious, when the prior art provides the complete sequence from which these probes are drawn. That is, when the invention is solely based upon routine selection of a small DNA piece from a larger prior art sequence of DNA, the invention should be deemed prima facie obvious in the absence of any secondary considerations. Whether applying the chemical case law such as Mayne, the genus-species case law of Merck, or the biotechnology case law in Deuel, each supports the obviousness of primers and probes where the prior art teaches the entire sequence. When the prior art does not teach the sequence, this same set of case law support a finding of nonobviousness.

(1.) David S. Roos, Bioinformatics-Trying to Swim in a Sea of Data, 291 SCI. 1260 (2001).

(2.) See Sylvia J. Spengler, Bioinformatics in the Information Age, 287 SCI. 1221 (2000).

(3). See U.S. Patent No. 6,214,583 (issued April 10, 2001).

(4.) See U.S. Patent No. 5,939,264 (issued August 17, 1999).

(5.) See BENJAMIN LEWIN, GENES V 633-656 (Oxford University Press 1994).

(6.) See id. at 633.

(7.) See id. at 644.

(8.) See Optimization of PCRs, PCR PROTOCOLS A GUIDE TO METHODS AND APPLICATIONS 9-10 (Michael A. Innis et al. eds., Harcourt Brace Jovanovich 1990).

(9.) 35 U.S.C. [section] 103(a) (2000).

(10.) Graham v. John Deere Co., 383 U.S. 1, 17 (1966). Certiorari was granted in two related patent infringement appeals from the Eighth Circuit Court of Appeals, 333 F.2d 529, and 336 F.2d 110. The Court, held that the provisions in the Patent Act pertaining to nonpatentability due to obviousness were intended to codify judicial precedent, and that the general level of innovation necessary to sustain patentability remains the same. The patents at issue were invalid due to obviousness of subject matter. Id.

(11.) See id. at 19.

(12.) Id.

(13.) Id.

(14.) See, e.g., K. Agarwal et al., A General Method for Detection and Characterization of an mRNA Using an Oglionucleotide Probe, 256 J. BIOLOGICAL CHEMISTRY 1023 (1981); A. Sharrocks, The Design of Primers for PCR, PCR TECH.: CURRENT INNOVATIONS 5-11 (H.G. Griffin & A.M. Griffin eds., 1994).

(15.) WO 87/03009, 12-13 (1987).

(16.) Steven Strain & Jerry G. Chmielewski, ROCK: A Spreadsheet-Based Program of the Generation and Analysis of Random Oligonucleotide Primers Used in PCR, at http://www.sru.edu/depts/artsci/bio/rock.htm (last revised June 13, 2001).

(17.) Medical Research Council, Welcome to the Genome Web Primer Design, at http://www.hgmp.mrc.ac.uk/GenomeWeb/nuc-primer.html (last visited November 24, 2002).

(18.) See MANUAL OF PATENT EXAMINING PROCEDURE [section] 2111.03 (8th ed. 2001).

(19.) Graham v. John Deere Co., 383 U.S. 1, 17 (1966).

(20.) MARTIN J. ADELMAN ET AL. CASES AND MATERIALS ON PATENT LAW 389 (1998).

(21.) See MANUAL OF PATENT EXAMINING PROCEDURE [section] 706.02 (8th ed. 2001).

(22.) See MANUAL OF PATENT EXAMINING PROCEDURE [section] 2111.01 (8th ed. 2001).

(23.) Environmental Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983), cert. denied, 464 U.S. 1043 (1984).

(24.) See Philippe Ducor, Recombinant Products and Nonobviousness: A Typology, 13 SANTA CLARA COMPUTER & HIGH TECH. L.J. 1, 19 (1997).

(25.) In re Hass, 141 F.2d 122, 128 (C.C.P.A. 1944).

(26.) See In re Henze, 181 F.2d 196 (C.C.P.A. 1950).

(27.) See In re Papesch, 315 F.2d 381, 391 (C.C.P.A. 1963).

(28.) A chemical homolog is defined as "[b]elonging to or being a series of organic compounds, each successive member of which differs from the preceding member by a constant increment." WEBSTER'S II NEW RIVERSIDE UNIVERSITY DICTIONARY 589 (Houghton Mifflin Co. 1984).

(29.) In re Papesch, 315 F.2d at 391.

(30.) In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (emphasis added).

(31.) See id. at 693.

(32.) Id.

(33.) In re Grabiak, 769 F.2d 729, 733 (Fed. Cir. 1985) (emphasis added).

(34.) See In re Jones, 958 F.2d 347, 351 (Fed. Cir. 1992).

(35.) See William Marsillo, How Chemical Nomenclature Confused the Courts, 6 U. BALT. INTELL. PROP. L.J. 29, 30 (1997).

(36.) See In re Mayne, 104 F.3d 1339, 1343 (Fed. Cir. 1997).

(37.) See id. at 1343-44.

(38.) See id. at 1344.

(39.) A methyl group is a carbon atom linked to three hydrogen atoms. GEOFFREY ZUBAY, BIOCHEMISTRY 45 (Prentice Hall 1983); see also John Brabson & Adrienne Enfield, Nucleic Acid Structure, at http://mills.edu/RESEARCH/FUTURES/JOHNB/structurefunction/707.html (last modified November 14, 1997).

(40.) An amine group is a nitrogen atom linked to two hydrogen atoms. See BIOCHEMISTRY supra note 39, at 326.

(41.) A carbonyl group is a carbon atom linked by a double bond to an oxygen atom. Id. at 37.

(42.) See Brabson & Enfield, supra note 39.

(43.) See Ulrich Melcher, Molecular Genetics (last updated May 28, 2001), at http://opbs.okstate.edu/~melcher/MG/MGW1/MG11120.html.

(44.) Tm is the melting temperature or the temperature at which 50% of a given oligonucleotide is hybridized to its complementary strand. See GENES V, supra note 5, at 112- 14.

(45.) BASIC SCIENCES AT NORTHWESTERN UNIVERSITY MEDICAL SCHOOL (2002), available at http://www.basic.nwu.edu/biotools/oligocalc.html.

(46.) Id.

(47.) See In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990).

(48.) See Ex parte Anderson, 30 U.S.P.Q.2d 1866 (BPAI 1994).

(49.) See Ducor, supra note 24, at 48.

(50.) See In re Mayne, 104 F.3d 1339, 1343 (Fed. Cir. 1997).

(51.) In re Jones, 958 F.2d 347, 351 (Fed. Cir. 1992) (emphasis added).

(52.) See Dillon, 919 F.2d at 693.

(53.) See Jones, 958 F.2d at 351.

(54.) See WO 87/03009, 12-13 (1987).

(55.) A functionally homologous oligonucleotide is an oligonucleotide that differs in structure from the reference oligonucleotide, but is capable of performing the same function as the reference oligonucleotide. For example, two oligonucleotides which can both detect the same region in a gene of a disease causing organism would be functionally homologous. See NEW RIVERSIDE DICTIONARY, supra note 28, at 589.

(56.) See U.S. Patent No. 4,683,202 (issued July 28, 1987).

(57.) See Sharrocks, supra note 14.

(58.) See In re Dillon, 919 F.2d 688, 693 (Fed. Cir. 1990).

(59.) Natalie Milner et al., Selecting Effective Antisense Reagents on Combinatorial Oligonucleotide Arrays, 15 NATURE BIOTECHNOLOGY 537 (1997).

(60.) U.S. Patent No. 4,683,202 (issued July 28, 1987).

(61.) See Dillon, 919 F.2d at 693.

(62.) Hybridization is the process of annealing two nucleic acid strands to form the Watson-Crick duplex structure. Nucleic acid amplification refers to methodologies by which the amount of certain nucleic acids are increased in a sample by biotechnological processes. See GENES V, supra note 5, at 1244.

(63.) Site through which the upper intestinal mucosa enzyme enterokinase converts inactive trypsogen into the digestive enzyme trypsin. AM. HERITAGE DICTIONARY. 745 (3d ed. 1996).

(64.) See In re Mayne, 104 F.3d 1339, 1342 (Fed. Cir. 1997).

(65.) In re Susi, 440 F.2d 442, 445 (C.C.P.A. 1970).

(66.) See id. at 445.

(67.) See Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).

(68.) See id. at 807.

(69.) Id.

(70.) Id.

(71.) In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988).

(72.) Id. at 903.

(73.) Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).

(74.) See Julie A. Hokans, In Re Baird: A New Approach to Obviousness of Chemical Compounds Introduction, 29 U.C. DAVIS L. REV. 197, 215 (1995).

(75.) See In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994).

(76.) See id. at 383.

(77.) In re Bell, 991 F.2d 781, 784 (Fed. Cir. 1993).

(78.) MARTIN J. ADELMAN, PATENT LAW PERSPECTIVES [section] 2.2[4] (2d ed. 2000).

(79.) Id.

(80.) See In re Schaumann, 572 F.2d 312 (C.C.P.A. 1978).

(81.) See Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).

(82.) See e.g., In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994); In re Bell, 991 F.2d 781, 784 (Fed. Cir. 1993).

(83.) See PATENT LAW PERSPECTIVES, supra note 78.

(84.) See GEOFFREY ZUBAY, BIOCHEMISTRY 665-679 (Prentice Hall 1983).

(85.) U.S. Patent No. 4,683,202 (issued July 28, 1997).

(86.) See e.g. Elizabeth Pennisi, Microbial Genomes Come Tumbling In, 277 SCI. 1433 (1997).

(87.) See U.S. Patent No. 4,683,202 (issued July 28, 1997).

(88.) This result is reached by subtracting the probe length, here 18 nucleotides, from the target sequence length, here 67 nucleotides, to result in a determination that there are 49 different contiguous 18 mer probes which are fully complementary to the 67 nucleotide prior art oligonucleotide.

(89.) See Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989).

(90.) Id. at 807; see also In re Baird, 16 F.3d 380, 382 (Fed. Cir. 1994).

(91.) See In re Bell, 991 F.2d 781, 784 (Fed. Cir. 1993); See Merck & Co., 874 F.2d at 807.

(92.) See Merck & Co. 874 F.2d at 807.

(93.) A monomer is a single unit which can be combined with other monomers to form a polymer, for example, a nucleotide is a monomer which, when combined with other nucleotides, forms an oligonucleotide. See BIOCHEMISTRY supra note 84, at 667.

(94.) Milner, supra note 59. 59

(95.) See U.S. Patent No. 5,525,464 (issued June 11, 1996).

(96.) Id.

(97.) Id.

(98.) See D. Wen et al., Erythropoietin Structure-Function Relationships: High Degree of Sequence Homology Among Mammals, 82 BLOOD 1507.

(99.) See U.S. Patent No. 4,683,202 (issued July 28, 1997).

(100.) See MANUAL OF PATENT EXAMINING PROCEDURE [section] 2123 (7th ed. 2000).

(101.) See Merck & Co. v. Biocraft Laboratories, Inc., 874 F.2d 807 (Fed.Cir. 1989).

(102.) See Jeffrey Dillen, Comment, DNA Patentability-Anything but Obvious, 1997 WIS. L. REV. 1023, 1045 (1997).

(103.) See Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 1206 (Fed. Cir. 1991).

(104.) See In re Bell, 991 F.2d 781, 782 (Fed. Cir. 1993).

(105.) See id. at 783.

(106.) See id. at 784-85.

(107.) cDNA is a DNA copy of an mRNA generated by a reverse transcriptase. See GENES V, supra note 5, at 1237.

(108.) See In re Deuel, 51 F.3d 1552, 1559 (Fed. Cir. 1995).

(109.) Id. at 1558.

(110.) See e.g. M. Mladinic et al, 'Specific' Oligonucleotides Often Recognize More Than One Gene: The Limits of in Situ Hybridization Applied to Gaba Receptors, 98 J.NEUROSCIENCE METHODS 33 (2000).

(111.) See In re Deuel, 51 F.3d 1552, 1559 (Fed. Cir. 1995).

(112.) See Fiers v. Revel, 984 F.2d 1164, 1169-70 (Fed. Cir. 1991).

(113.) Id. at 1170.

(114.) Regents of Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559 (Fed. Cir. 1993).

(115.) Enzo Biochem, Inc. v. Gen-Probe Inc., 2002 U.S. App. LEXIS 5642, at *1020 (Fed. Cir. Apr. 2, 2002).

(116.) Allelic variants are naturally occurring mutations in a gene which represents differences between individuals. See GENES V supra note 5, at 1244.

(117.) See L. Larsen et al., High Throughput Mutation Screening by Automated Capillary Electrophoresis, 3 COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING 393 (2000).

(118.) See In re Deuel, 51 F.3d 1552, 1554 (Fed. Cir. 1995).

(119.) See id. at 1558.

(120.) See id. at 1555.

(121.) See id. at 1559.

(122.) Id.

(123.) See In re Deuel, 51 F.3d 1552, 1558 (Fed. Cir. 1995).

(124.) See In re Papesch, 315 F.2d 381, 391 (C.C.P.A. 1963).

(125.) In re Deuel, 51 F.3d at 1559.

(126.) See id. at 1556.

(127.) See U.S. Patent No. 5,525,464 (issued June 11, 1996).

(128.) See Milner, supra note 59.

Jeffery Fredman ([dagger])

([dagger]) Jeffery Fredman is currently a Primary Examiner for the USPTO, and J.D. candidate at The George Washington University Law School. He holds a Ph.D. in Biochemistry from the University of Alabama at Birmingham. The opinions expressed in this Comment are solely those of the author, but are derived from his experiences as a scientist and a patent examiner.

Oops!

An unknown error has occurred. Please click the button below to reload the page. If the problem persists, please try again in a little while.