WASHINGTON _ Is a DNA sequence that encodes aprotein obvious once a partial amino acid sequence hasbeen published, or is otherwise known? Non-obviousness isone of the three major requirements of patentability.This issue was one subject in a forum on BiotechnologyLaw and Policy that took place at George WashingtonUniversity last week. In the eyes of the U.S. Patent andTrademark Office (PTO), gene probe technology hasbecome so sophisticated that a nucleotide sequence isobvious once a portion of a protein (or the nucleotidesequence itself) becomes known, G. Harley Blosser, apartner at the St. Louis law firm, Senniger, Powers, Leavitt& Roedel, told BioWorld.Last November, the Board of Patent Appeals andInterferences of the PTO rejected Jewish Hospital'sapplication to patent a DNA sequence encoding a heparin-binding growth factor based on a ruling that it was obvious.If Jewish Hospital, of St. Louis, loses its appeal, patentingDNA sequences could become much more difficult. OnMay 31, Chiron Corp., of Emeryville, Calif., filed anamicus brief on behalf of the Biotechnology IndustryOrganization, in support of Jewish Hospital. This case, Re.Thomas S. Deuel et. al., was one focus of discussion duringthe forum.An example of non-obviousness might be "apharmaceutical compound that has properties which onewould not expect from its structure," Reid G. Adler,partner, Morrison & Foerster, who moderated the forum,told BioWorld.The patent examiner in the Jewish Hospital case ruled thatthe invention was prima facie obvious, a term and decisionthat places the burden upon the applicant to demonstratenon-obviousness.St. Louis Jewish Hospital likely will have to demonstratethat something besides its sequence per se is non-obvious.In all likelihood, there is nothing special about this DNAsequence as compared to another DNA sequence encodingthe same protein, Adler said.Furthermore, the board's decision said that possession of aprotein sequence provides a reasonable expectation that onecan produce the DNA sequence that encodes the protein."The board seems to be taking judicial notice that having aprotein makes the gene obvious, and puts it in the publicdomain," Adler said."This is analogous to saying that antibiotic compounds areobvious because we know how to culture bacteria andisolate antibiotic molecules, without considering thechemical structure of the antibiotic molecule itself," Adlersaid.However, another legal precedent contradicts the board'sdecision that genes should be obvious from the proteinsequence, and weakens the foundation of the PTO'sposition. In that case, in Re. Graeme I. Bell et. al., scientistsat Chiron filed patent applications for DNA sequencescoding for human insulin-like growth factors (IGF) I and II.In deciding for the applicants, on April 20, 1993, The Courtof Appeals, Federal Circuit ruled that ". . . we do not acceptthis proposition" that "the established relationship in thegenetic code between a nucleic acid and the protein itencodes also makes a gene prima facie obvious over itscorrespondent protein." (The court did leave open,however, the possibility that future technology mightrender the gene obvious from the protein sequence.)The court based this decision in large part on a previouscase which highlighted the fact that the genetic code isdegenerate, Blosser said. Eighteen of the 20 naturallyoccurring amino acids _ all except for methionine andtryptophane _ can be specified by more than one codon(group of three nucleotides that specifies an amino acid).Therefore, although a nucleotide sequence specifies aprotein, an amino acid sequence does not necessarilyspecify a DNA sequence.But the PTO has ignored the Bell decision, because thatwas made not by the full federal circuit, but by a panel ofthree justices from the circuit.Instead, to uphold the notion that nucleotide sequence isobvious, given amino acid sequence, the PTO has reliedupon an earlier decision in which a 1982 textbook was usedas a reference for a technique for obtaining DNA sequencefrom amino acid sequence.The amicus brief supporting the St. Louis Jewish Hospitaldecision argues that the obviousness of DNA molecules, asfor any other chemical, should be judged on the merits ofthe molecules, not simply methods used to obtain them.The brief also states that cloning is not so commonplace aprocedure that one could reasonably expect to succeed infinding DNA that corresponds to any protein of knownsequence.A ruling is expected in the fall. "Deuel is on a hurry-upappeal," said Blosser.What Level Of Efficacy Proves Utility?Also at the forum, patent lawyers discussed an issue whichsome said creates a problem especially for smallbiotechnology firms creating new drugs. To be patentable,a compound must have utility. The question is, what levelof clinical evidence of efficacy is required in order to obtaina patent on a new drug?"Examiners have been acting like the FDA, taking theposition that without clinical data, treatment of diseases isnot believable," Adler said. But for many new compounds,strong evidence of potential efficacy is unavailable. "Thereare not always established animal models that correlate to ahigh degree with what will happen in human trials."That problem threatens to knock out many compoundsbefore they reach clinical trials, said Herbert H. Jervis,assistant patent counsel, SmithKline Beecham. "Patents arecrucial to our industry, and crucial early."Nonetheless, The Court of Claims and Patent Appeals(CCPA) and the Federal Circuit Court of Appeals haveruled more liberally, said Kate H. Murashige, withMorrison & Foerster. In the 1980 case, Nelson v. Bowler,the CCPA accepted as evidence of utility the results of twoin vitro tests relating to blood pressure and smooth musclestimulation respectively. "Knowledge of thepharmacological activity of any compound is obviouslybeneficial to the public," the court stated.Similarly, in 1985, in Cross v. Iizuka, the Federal Circuitheld that the demonstration that the claimed compoundscould inhibit synthesis of thromboxane synthetase wasadequate evidence of utility. The court stated, "Testsevidencing pharmacological activity may manifest apractical utility even though they may not establish aspecific therapeutic use."In the same opinion, the court also stated that "in vitrotesting may establish a practical utility for the compound inquestion.""Successful in vitro testing," the court stated, "will marshalresources and direct the expenditure of effort to further invivo testing of the most potent compounds therebyproviding an immediate benefit to the public . . ." n
-- David Holzman Special To BioWorld Today
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