The United States Patent Statute requires that in order to be patentable something must be "useful".[6] Modern judicial interpretation of this requirement starts with the 1966 Supreme Court decision in Brenner v. Manson.[7] This case related to a process for production of a specific steroid compound for which no specific utility was disclosed even though utilities were known for other steroids. The Court pointed out that merely producing something that may be the object of scientific research was insufficient to justify the grant of a patent and stated that "[u]nless and until a process is refined and developed to this point - where specific benefit exists in currently available form - there is insufficient justification for permitting an applicant to engross what may prove to be a broad field". In Official Actions examiners typically summarized this decision: "utility must be definite and in currently available form; not merely for further investigation or research".

Another case often cited by examiners in biotechnology patent applications is Nelson v. Bowler.[8] The case focused on whether the products claimed had been shown to have any "practical utility". Examiners tended to seize upon this wording to discount the patentability of biotechnology inventions which do not have a direct therapeutic utility. This is surprising since the data submitted in the case were from "rough screens" which were uncorrelated with actual utility but nevertheless were found to justify patentability because data on "pharmacological activity may manifest a practical utility even though they may not establish a specific therapeutic use".

Ex parte Deuel[9] provides an example of the PTO Board of Patent Appeals and Interferences (Board) use of the "practical utility" test. In this case the claim was for a purified tissue-derived growth factor having defined characteristics. The case came to the Board on the issue of obviousness. The Board, however, on its own accord, noted the specification's lack of a description of how to use the factor. Therefore the claimed factors "could" lack practical utility. Since the application was being returned to the examiner for further prosecution (because the Board had introduced a new ground of rejection), the Board strongly urged the examiner to determine whether a skilled person would have been able to use the claimed growth factor at the date of filing the application.

In Ex parte Aggarwal[10] the Board held that in vivo   data relating to tumor-inhibition in mice showing that a compound was "somewhat active" were insufficient to justify a claim to use of the compound to treat tumors. The Board felt that the examiner had

The Board commented that early filing of patent applications relating to biological uses on humans were permissible but only if, when challenged, the applicant, "can provide evidence showing substantial activity in screening tests customarily used and accepted as predictive of human activity for the type of chemical used."

This test is of no help in situations where there is currently no accepted animal model for the human condition to be treated.

Despite these problems a single accepted utility is sufficient to justify claims to a product per se  so that demonstrating a particular use for a compound (beyond possible use in research) will suffice for this purpose. It is, therefore, sometimes useful when drafting applications where the utility is one on which the PTO routinely takes a tough line, such as treatment of cancer or acquired immune deficiency syndrome, to specify an additional utility in the specification. This practice was endorsed by the Board in Ex parte Hozumi.[11] However, following the decision In re Gottlieb[12] deletion of the unproven utility from the specification had sometimes been required.

It is important that the patent application provides support for fall back positions in the event that objections arise. This may be particularly important in patent applications in the biotechnology arts. For example, it may be useful to include statements relating to the mechanism of action of a drug as well as the broad nature of a disease that may be treated by a drug. In this way, even if one cannot convince the Examiner that the drug is useful for treating the stated disease, one may be successful in arguing that one has at least shown that the drug affects a particular mechanism and establish utility based on this showing. Similarly when the invention is a method of treatment it may be useful to include basis not only for claims to treatment of a disease but also for specific features or aspects thereof in case one can only produce credible experimental data for such limited claims.

Enablement and Sufficiency of Disclosure

35 USC 112 requires inter alia   that a patent specification contain a written description of the invention and the manner and process of making and using it "in such full clear and concise terms as to enable one skilled in the art ... to make and use" the invention.

Case law has made it clear that the requirements for a "written description" and an "enabling disclosure" are separate. For example, where a specification contains sufficient information to enable a skilled chemist to produce a particular compound because it gives detailed information on how to produce analogous compounds but it makes no reference to the compound in question, the "written description" requirement has not been met even though the description may be enabling.

The separateness of the two requirements has been emphasized in the biotechnology area by two cases. Both cases involved interferences in which the count in question related to a strand of DNA. In one case Fiers v. Sugamo[13], the Court of Appeals for the Federal Circuit stated as follows:

In the Fiers case, convention priority was denied to a claim to a DNA sequence coding for a specified protein because of the absence of the actual sequence of the DNA in the priority documents. A similar situation occurred in Fiddes v. Baird[14] where the Board of Appeals stated that "knowledge of amino acid sequence of a protein coupled with the established relationship in the genetic code between a nucleic acid and a protein it encodes would not establish possession of a gene encoding that protein."

Having regard to the enablement requirement itself, two strong themes run through recent cases both at the Board and the Federal Circuit levels namely 1) that the public should not be required to carry out undue experimentation to put an invention into practice and 2) that there must be sufficient enabling disclosure throughout the entire scope of the claim not use in respect of one aspect of it.

The two themes came together in the Federal Circuit Court of Appeals decision In re Wright[15] where the main claim under consideration was:

There was a single example in the specification describing the production of a recombinant vaccine which confers immunity in chickens against the RNA tumor virus Prague Avian Sarcoma virus. The Court pointed out that the relevant date for determining questions of enablement was the filing date of the application and noted that the definition in the claim was extremely broad and would encompass vaccines against the AIDS virus. Since no generally successful vaccine for this purpose has been produced, the Court found that the PTO was correct in its view that the physiological activity of RNA viruses was sufficiently unpredictable that success with one specific recombinant virus vaccine would not have given one of ordinary skill in the art reason to believe that the teaching could be used to produce vaccines for most of the other viruses specified without undue experimentation.

Perhaps the commercially most important biotechnology case to come before the Courts so far is Amgen v. Chugai.[16] In this case both parties had patents relating to human erythropoietin (EPO). Amgen's patent related to producing the material by a recombinant route and included claims that were directed to DNA coding for the final product and cells transformed by said DNA. Chugai's (or more accurately Genetics Institute's) patent related to purified material obtained from natural sources. The District Court had found that each party had infringed claims of the other's patent. On appeal the case turned on the question of enablement in that the Court held that there was no credible evidence that the purified material claimed by Genetics Institute could be produced by the method described and hence the claims of its patent were invalid. However, Amgen did not escape with its patent entirely undamaged. Its generic claim (covering all DNA sequences that code for an amino acid sequence having the same properties as EPO) was held to lack an enabling disclosure. The Court pointed out that for DNA sequences enablement "means disclosing how to make and use enough sequences to justify the grant of the claims sought."

In re Goodman[17], related to production of mammalian peptides in plant cells. The application in question was a continuation of one which had led to the grant of a patent on a specific technique for producing interferon in dicotyledonous plant cells and it was clear that the application was an attempt to obtain protection for the invention in a more generic fashion. The Federal Circuit upheld the enablement rejection at least in part on the basis that those skilled in the art would not have expected genetic transfer techniques that were useful in dicotyledonous plants (the only type of plant exemplified) to be effective in monocotyledonous plants. Thus use of monocotyledonous plants, "if possible at all in 1985, would have required extensive experimentation that would preclude patentability".

In Ex parte Forman[18] the Board considered a claim directed to a class of oral vaccines consisting of hybrid bacteria that were genetically engineered to produce an immunizing effect against both a typhoid bacterial antigen and one other non-typhoid enteric disease. The specification stated that this was accomplished by introducing an antigen for a non typhoid disease into a mutant strain of S.typhi. The final hybrid was deposited with the ATTC. Rejection of the claims was upheld by the Board on the basis that since there was no deposit of the appropriate mutants of S.typhi   one skilled in the art would not be able to obtain the mutants which were necessary for use in the invention and secondly, the techniques required to introduce the antigen were not sufficiently well known and straight forward that at the relevant date (apparently sometime in the early 1980's) one of ordinary skill in the art could predict the results with an adequate degree of certainty. The Board pointed out that in determining whether undue experimentation was required the amount of direction or guidance given in the specification (for example in the present case guidance on how to choose mutants); the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art and the breadth of the claims were all relevant.

In In re Vaeck[19] the Federal Circuit held that a claim to a chimeric gene stated to be "capable of being expressed in cyanobacteria cells" was not properly supported by a specification that showed utility in only a few cyanobacteria because cyanobacteria were a little studied and not fully understood group of organisms comprising over 150 different genera. The court observed that where one was dealing with situations in which results were unpredictable:

Ex parte Maizel[20] posed many of the same issues but in this case the Board focused not so much on the question of experimentation but on the appropriate scope of the claims in light of the enablement set forth in the specification. The claims were to a recombinant DNA vector comprising a DNA sequence coding for a protein having stated properties "or a biologically functional equivalent thereof". The Board concluded that the term "biologically functional equivalent" is so broad as to encompass any protein regardless of its structure that is functionally equivalent to what was specifically described. Such a claim resembled single means claims which are routinely held to be unpatentable in mechanical cases. It would cover all conceivable means to achieve the stated result while the specification only disclosed a specific DNA to achieve this purpose. Therefore the disclosure was clearly not commensurate with the scope of the claim.

In Ex parte Ishizaka[21] the problem words were "effectively homologous" as applied to a stated sequence of nucleotides. On their face the words had a clear meaning. However, the body of the specification indicated that fragments as short as 18 to 20 bases could be used and that the term "effectively homologous" comprised homology of as little as 50%. The Board, therefore, concluded that it could not determine the true scope of the claims not find adequate support for the breadth that the Board inferred might be intended.

On 30th March, 1995 the Court of Appeals for the Federal Circuit issued an opinion criticizing the Patent Office's handling of utility and enablement rejections. In the decision In re Brana[22] the Federal Circuit reversed a Board of Appeals decision upholding the Examiner's rejection of claims directed to 5-nitrobenzodisoquinoline-1, 3-dione compounds for use as antitumor agents. The Federal Circuit noted that the Examiner rejected the applicants' claims under 35 USC 112, first paragraph on the basis that the tests used to determine the utility of the compounds "were not sufficient to establish a reasonable expectation that the claimed compounds had a practical utility (i.e. tumor activity in humans)". Although the Examiner did not reject the claims as lacking utility he did note that a rejection under 35 USC 101 could have been made.

The applicants' specification disclosed that the claimed compounds were superior antitumor agents as compared to prior art compounds that had antitumor activity. The compounds were tested using in vivo  animal tumor models that are used by the U.S. National Cancer Institute to determine whether a compound should be selected for further study.

The Federal Circuit pointed out that it considered the issue before it (what must the applicant prove regarding the practical utility or usefulness of the invention for which patent protection is sought) to be well-settled and noted the issuance of the Commissioner's new utility guidelines which summarized the law in this area (see below). In finding that the Examiner had not established the prima facie burden of establishing that one of ordinary skill in the art would reasonably doubt the asserted utility, the Federal Circuit considered that the asserted utility of treating tumors was believable and that the prior art showed that structurally similar compounds had antitumor activity. The Federal Circuit added that even if the Examiner had met the prima facie burden, the evidence that the applicants submitted including data showing antitumor activity against standard in vivo tumor models was sufficient to rebut the rejection.

The Federal Circuit also emphasized that the standards for establishing utility for patentability purposes are lower than those required to obtain "government approval to market a particular drug for human consumption".

This decision reflects the sentiment that the standard for establishing utility of compound per se claims is lower than for method of treatment claims. Nevertheless, given the facts in this case, if the Federal Circuit had to consider the utility of method of treatment claims the same result may have been reached due to the applicant's reliance on animal tumor models that are standards in the art.

Obviousness in the biotechnology field

The leading cases relating to obviousness in the biotechnology patent field are the Federal Circuit's decisions Hybritech Inc. v. Monoclonal Antibodies Inc.[23] and In re O'Farrell.[24] In both cases it was asserted that, for a claim to be rejected on the ground of obviousness, the prior art must have pointed towards what was being claimed and those skilled in the art must, on considering the prior art have felt that there was a reasonable expectation of success in following the pointers. Furthermore, as pointed out in, for example, In re Dillon[25] the obviousness analysis may be broken into two parts, first a consideration of whether the invention as claimed is prima facie obvious and if it is, whether there are any surprising results or other factors that might rebut the prima facie  finding.

Application of these basic rules to particular situations, however, can be difficult. In the Hybritech case it was found that an immunometric assay which differed from the prior art by employing monoclonal antibodies bound to a solid carrier (i.e. a so-called sandwich) was patentable despite predictions of the utility of monoclonal antibodies and the fact that sandwich assays were known for polyclonal antibodies. The evidence showed that when monoclonal sandwich assay kits were introduced those skilled in the art were skeptical about their reliability so that their success was not reasonably expected by those skilled in the art.

In re O'Farrell, on the other hand, the Court although rejecting as a standard of determining obviousness the idea that something could be held unpatentable because it was merely "obvious to try" found that claims directed to producing particular proteins in a transformed species of bacteria were obvious. No evidence in the case showed that those skilled in the art would have doubted that a hint in the prior disclosure would have led to a useful means for producing proteins. Although the applicants argued that the field was unpredictable, the Court was not convinced and specifically pointed out that "obviousness does not require absolute predictability of success, merely a reasonable expectation of success."

An important recent decision on the question of obviousness was that of the Federal Circuit in the case of In re Bell.[26] The claim in question was for DNA sequences encoding insulin-like growth (hIGF).

The prior art involved two publications disclosing amino acid sequences corresponding to specific nucleotide sequences set out in the claim. Other art taught means of isolating genes for which at least a short amino acid sequence of the encoded protein was known by preparing a nucleotide probe corresponding to that known amino acid sequence and using this to isolate the gene of interest. The Examiner held the claims to be obvious on the ground that it would have been obvious "albeit tedious" to prepare appropriate probes and from this obtain the appropriate gene. The Federal Circuit disagreed. The Court commented

It was calculated that there were 1036 different nucleotide sequences that might correspond to the amino acid sequence in question. The Court cautioned that its view was "not to say that a gene is never rendered obvious when the amino acid sequence of its coded protein is known" but that was not the situation in the present case. The art in question suggested use of only a short probe and the applicants apparently had to choose a longer probe in order to obtain the gene in question and thus had taken a step contrary to the prior art teaching. Thus, what the applicants had done was not obvious. To some extent this decision is, contrary to the earlier Board decisions in Ex parte Hudson,[27] and in Ex parte Movva.[28]

The Board gave some indication of its attitude toward the Court's decision in Bell in its own decision in Ex parte Deuel.[29] The claims were directed to purified and isolated DNA sequences coding for heparin binding growth factors. The cited art showed accurate but partial amino acid sequences for bovine and rat versions of the factor including the N-terminal portion and a general technique for using oligonucleotide probes for isolating DNA coding for a particular protein where the N-terminal sequence is known. The Board characterized the issue before it as "whether or not knowledge of the partial amino acid sequence of a protein, in conjunction with a reference indicating a general method of cloning, renders the invention as a whole i.e. the gene prima facie   obvious". Having concluded that the Bell decision was based on the fact that the reference dealing with the probes had taught away from the claimed invention and finding no such teaching again in the present case, the Board held that the degeneracy of the genetic code did not itself preclude a finding of prima facie   obviousness.

This attitude of the Board was reflected in other areas. As an indication of the general tendency of the USPTO to retreat from rigorous positions on issues such as obviousness the USPTO reaction to In re Baird[30] case is interesting. The Federal Circuit Court held that a disclosure of a generic formula encompassing more than one hundred million different diphenols only one of which was the claimed compound could not render that claimed compound obvious.

Following this decision the USPTO distributed in 1994 a directive to Examiners instructing them to disregard this decision in making prima facie obviousness determinations on claims to specific compounds encompassed by a prior art generic disclosure. This attitude of the USPTO had been criticized in other applications to the Federal Circuit Court as indicating an arbitrary attitude of the USPTO to the decisions of the Court. On March 28, 1995 the Patent Office then announced that they were withdrawing this March 1994 Notice and the Examiners were being directed to determine the patentability of claims to a species within a prior art genus on a case-by case basis in relation to the facts.

On the same date, March 28, 1995, the Court of Appeals for the Federal Circuit reversed the Deuel [31] decision. It considered the rejection of the claims for specified cDNA sequences and the claims that generally defined all DNA sequences coding for a specified protein. The issue before the court was "whether the combination of a prior art reference teaching a method of gene cloning, together with a reference disclosing a partial amino acid sequence of a protein, may render DNA and cDNA molecules encoding the protein prima facie  obvious under [35 USC]103?" The Federal Circuit in reversing the Board's decision reaffirmed the principle of In re Bell "that the existence of a general method of isolating cDNA or DNA molecules is essentially irrelevant to the question whether specific molecules themselves would have been obvious, in the absence of other prior art that suggests the claimed DNA's". The Federal Circuit noted that the primary reference disclosed a partial amino acid sequence of heparin-binding brain mitogens (HBBMs) that were isolated from human and bovine brain tissue. There was, however, no disclosure of DNA or cDNA coding for the HBBMs. The Federal Circuit stated that the existence of art disclosing a protein and a technique that can be used to determine the DNA sequence coding for that protein does not make obvious the specific claimed DNA sequence coding for that protein. Due to the redundancy of the genetic code the disclosure of a partial protein sequence does not suggest a particular DNA sequence coding for the protein. "The 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". The Federal Court did state that a different result might occur if the prior art disclosed a small and simple protein so that all DNA coding for that protein would be obvious.

The Federal Circuit also reversed the obviousness rejection of the claims for all DNA sequences coding for the specified proteins. However, this rejection would probably have been upheld if the cited art had disclosed the entire amino acid sequence of the heparin binding growth factor rather than the partial sequence disclosed in the primary reference. The Federal Circuit did comment that the claims to all DNA sequences coding for a protein may not be enabled because the specification only described how to obtain the specific cDNA sequences and did not describe how to obtain all the DNA sequences coding for the specified proteins.

New Utility Guidelines

Following the PTO's review of biotechnology practice, noted in the earlier section of this part of the paper there was a public hearing at which witnesses testified that the examiners in the biotechnology group were requiring, in many cases, the submission of clinical data in order to overcome a lack of utility rejection under 35 USC 101 even for compound per se  claims. Such rejections led to difficulty for many applicants because without a patent or the likelihood of obtaining a patent, an applicant could not raise the funds to conduct clinical trials and without clinical trials the applicant could not obtain a patent. Witnesses also testified that there should be a presumption of utility, that predictability should be the standard for establishing utility and that the establishment of safety and effectiveness should be left to appropriate regulatory agencies such as the U.S. Food and Drug Administration. Thereafter the U.S. Commissioner of Patents announced that in view of what had been said at the hearing there was to be a change in PTO policy at least on the question of the utility required to establish patentability.

In his initial announcement to the press of the change of policy, the Commissioner indicated that the PTO would no longer require the submission of clinical data before granting a patent on a biotechnology product and stated "While drug makers will still have to show the potential usefulness of new biotechnology products, they can satisfy the requirement by submitting any kind of evidence to demonstrate that their claims are credible" and that the "examiners will no longer impose unrealistic and unattainable evidentiary requirements on patent applicants."

Proposed Utility Examination Guidelines were published for public comment in the Federal Register[32] on January 3, 1995. It is expected that new guidelines on obviousness, enablement and the written description requirement will be forthcoming.

It perhaps should be noted that the original draft Guidelines were mentioned favorably in the In re Brana case discussed earlier. In March 1995 in the 6th Edition of the Manual of Patent Examining Procedure (MPEP) Sect. 608.01(p) there was a revision of the Utility Examination Guidelines. However, further revisions are to be effected following the In re Brana case and the USPTO Biotechnology Group are awaiting (at the time of writing this article - June 1995) the final new utility guidelines.

However, this section of the MPEP does contain amended utility guidelines which have been amplified to provide examples of approved procedures for reviewing utility statements in a different context as well as providing a discussion of the pertinent case law. In particular the Section discusses the handling of evidentiary materials, the correlation between evidence and asserted utility and the significance of issues such as the meaning of "real world value".

In particular it is specified that, when the treatment of disease conditions is supported by data by in vitro  and animal testing, this is sufficient to support human therapeutic utility. Clinical data should rarely be necessary to establish such utility.

Additional training materials are also being developed by the Patent Office to implement the above materials.

The burden on the Examiner is to accept as true credible statements unless "one of ordinary skill in the art would have rational basis to doubt the truth of such statements."

Thus a procedure which the Examiner must follow to determine utility is set out as:

Thus the burden is on the Examiner to support the case for rejection which must be properly grounded on evidence and sound reasoning. Evidence by a recognized expert would be sufficient to rebut a rejection.

The test is perhaps rather double negative but is essentially:

The present and proposed revisions of the MPEP do not completely remove all of the possible problems but do discourage unreasonable positions being taken by Examiners; clearly some issues may still exist. For example, concern has been expressed as to the "expressed sequence tag" applications filed by the U.S. National Institutes of Heath involving utility of nucleotide sequences encoding polypeptides.

Clearly the results will be to reduce the burden on applicants but it remains to be seen whether the examiners will follow these requirements.

With luck the major problems relating to utility requirements for inventions in the field of biotechnology will soon be behind us. Problems still remain on what is or is not a sufficient disclosure for enablement purposes, an issue closely related to the problem of determining the date of invention. Indeed some U.K. applicants claim that the "burden" has shifted to this area although this seems to be anecdotal. In the area of obviousness analysis, at least in the case of inventions relating to recombinant DNA technology, the guidelines as to what is to be regarded as prima facie   obvious are becoming reasonably clear.

Conclusion

It can be seen that the U.S. has removed some of the discrimination against foreign applicants inherent in the old practice of only accepting, as proof of date of inventions, events in the United States. There also has been some harmonization to international norms in relation to the term of the patent. Nevertheless in relation to other issues such as the protection of the first to invent as distinct from first to file, the U.S. continues to divert from international norms. Insofar as the practice of examining patent applications in the field of biotechnology this has still not been totally assimilated to the standards applied in other areas of technology but is moving closer.