Patents
 
July 2001 Volume 19 Number 7 pp 683 - 684
 
 
Patenting expressed sequence tags and single nucleotide polymorphisms

Gerald J. Flattmann & Jonathan M. Kaplan
 

Gerald J. Flattmann is a partner and Jonathan M. Kaplan is a patent agent at Fish & Neave, 1251 Avenue of the Americas, New York, NY 10020 (e-mail: gflattmann@fishneave.com).

Although the vast majority of expressed sequence tags (ESTs) and single nucleotide polymorphisms (SNPs) may never prove to be important medically or agriculturally, some could play an important role in drug discovery, food production, or disease prevention and management. Naturally, organizations that identify these sequences want to enjoy the fruits of their efforts by obtaining protection under the patent laws¹. However, meaningful characterization of the identified sequences and their utility for purposes of obtaining patent protection is a monumental task for even the best equipped laboratories.

In the past few years the US Patent and Trademark Office (PTO) has received and continues to receive a steady stream of patent applications for ESTs and SNPs. Regardless of one's stance on the controversial question of whether these isolated sequences should be patentable, the reality is clear: the genomic frontier has been mapped and today's pioneers are eagerly and aggressively staking out what they regard as their territory.

What are the minimal disclosures required for patenting ESTs and SNPs? In this article, the first of a two-part series, we discuss the disclosures required to meet the utility requirement of 35 USC §101 in view of the PTO's recently published Revised Utility Examination Guidelines. We also discuss the written disclosures and teachings required by 35 USC §112. Finally, we consider the present status of EST and SNP patenting in the PTO and the enforcement of such patents in the courts. Next month, we will examine the direct relationship between the scope of the claims sought by the inventor and the required breadth and detail of the patent specification to see what protection EST and SNP inventions will likely be afforded.

The utility requirement
According to 35 USC §101, patentable subject matter comprises any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof. Thus, to be patentable, an invention must have utility. Typically, a naturally occurring substance (such as a gene) is not patentable unless and until it is isolated and purified (i.e., the result of manipulation by humans). The purified substance must also have some greater value than in its natural state². In this legal context, the question of whether ESTs and SNPs are patentable subject matter has been vigorously debated³.

Following a period of public comment, the PTO recently published revised Utility Examination Guidelines⁴. Although these guidelines do not have the force of law, until revised or revoked they will govern the manner in which PTO examiners review the thousands of pending applications on ESTs and SNPs.

Under the guidelines, applicants must assert a utility for the claimed invention that is (1) specific, (2) substantial, and (3) credible. A "specific utility" is one that contrasts with a general utility that would be applicable to the broad class of the invention. For example, a claim to a polynucleotide whose use is disclosed simply as a "gene probe" or "chromosome marker" would not be considered to be specific in the absence of a disclosure of a specific DNA target. A specific utility can more readily be assigned for those ESTs and SNPs that by homology are members of a defined class of genes with known functions. For instance, if an EST represents a gene encoding a protein that is a member of a class of proteases associated with a certain type of cancer, an applicant might successfully assert that the sequence is useful as a target for treating that cancer. In the absence of such a classification, a specific utility will be more difficult to establish.

A "substantial utility" defines a "real-world" use and does not include a mere invitation to conduct further research to identify or reasonably confirm a real-world context of use. Further, a substantial utility does not include so-called "throw-away" utilities, such as using transgenic mice as snake food (unless of course the transgene makes them more nutritious or palatable). One example would be a cloned DNA fragment encoding a protein of unknown function. Despite a description in the specification disclosing the expression of the protein, the DNA lacks a substantial utility because the protein has no real-world use.

"Credible utility" refers to "the reliability of the statement based on the logic and facts that are offered by the applicant to support the assertion of utility" and is assessed from the standpoint of a person of ordinary skill in the art. An assertion that a DNA is useful as a probe, chromosome marker, or forensic or diagnostic marker would be credible; however, such an assertion might fail the "specific" or "substantial" utility tests.

Notwithstanding the "specific, substantial, and credible" tests, applicants are not required to assert a utility if "at any time during the examination, it becomes readily apparent that the claimed invention has a well-established utility." In this situation, patent examiners are not to reject the claim based on lack of utility. The standard here is whether a person of ordinary skill in the art, that is, a biologist or biochemist, would immediately appreciate that the EST or SNP recited in a claim under examination is useful. If so, the claim should not be rejected for lack of utility, regardless of whether that utility is specifically asserted by the applicants in their application.

As an example of a well-established utility, the examiner training materials accompanying the guidelines describe a DNA fragment containing the coding sequence for a protein (known as an open reading frame or ORF). The ORF has 95% homology with a consensus of sequences that define a family of proteins of a known function (DNA ligases). The second most homologous protein is -actin, with a homology of only 50%. On the basis of these homologies, there is little doubt that the ORF encodes a useful protein—a DNA ligase—and, therefore, has a well-established utility.

This example leaves some important questions unresolved. First, consider the situation in which a claimed ORF is 65% homologous to a well-known family of useful proteins and the second best homology is 50%. Will the PTO reject the claim on utility grounds on the basis that there is some question whether the ORF encodes a member of the well-known family? The applicant may need to prove to the PTO that the ORF does in fact encode a specific family member in order to show utility. Second, will the PTO reject a claim to an ORF that clearly belongs to a certain family if the applicant has failed to show a known use for that family? Most likely, the answer is yes. Such a rejection will likely shift the burden back to the applicant to show that members of that family of proteins are in fact useful.

Sufficiency of disclosure
Title 35 of the US Code, §112 requires that the inventor's patent specifications contain a written description of the invention, and of the manner and process of making and using it in such terms as to enable any person skilled in the art to make and use the invention. Thus, there are two distinct statutory requirements of patent specifications: (1) a written description of the invention and (2) an enabling disclosure. The written description requirement takes on special significance in the context of claiming isolated genes that exist in nature. In the landmark Amgen, Inc. v. Chugai Pharmaceutical Co. case⁵, the Court of Appeals for the Federal Circuit held that an inventor typically can distinguish a gene from other biological materials only after it is isolated. The ability to make such a distinction constitutes a conception of the isolated DNA sequence required for an adequate written description at the time an application is filed. It follows that an adequate written description for a claim to an EST or SNP will generally require at least that the sequence be isolated and be shown to differ from previously known sequences.

The Federal Circuit confirmed and amplified its Amgen holding in Fiers v. Revel. In Fiers, the court held that an "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."⁶ Essentially, the court held that an adequate written description of an isolated piece of DNA requires characterization of its sequence. This is generally not a problem for ESTs and SNPs because the claimed invention by nature is a DNA sequence. However, if all that is described in the specification is a DNA fragment comprising an incomplete ORF, subsequently issued claims may be limited to the sequence of that fragment. In sum, based on the Federal Circuit's decisions to date, claims to ESTs and SNPs are likely to be limited to the specific sequences isolated by the inventor and described in the specification.

The requirement that the specification enable a person of skill in the art to practice the invention as claimed is separate from the written description requirement. Generally speaking, the more unpredictable the scientific field—and the Federal Circuit has repeatedly characterized biotechnology as unpredictable—the more detailed the disclosure must be to enable the skilled artisan to practice the invention as claimed. Because single-nucleotide mutations in a DNA sequence can have unpredictable effects on its function, the PTO is less likely to allow broad claims to ESTs and SNPs absent a specification that provides an enabling disclosure of commensurate scope.

Enforcement of patents
The Federal Circuit has yet to issue any significant decisions relating to the patentability of claims directed to ESTs or SNPs. The PTO's practice guidelines, however, generally conform to the Federal Circuit's prior decisions in the biotechnology field. Accordingly, those guidelines may provide a reasonable starting point for predicting how the Federal Circuit and the district courts will assess the scope and validity of EST and SNP claims in litigation.

Other issues unaddressed by the guidelines are not new to patent litigators. For instance, how will defendants fare when accused of infringing EST or SNP claims literally or under the doctrine of equivalents, which permits a finding of infringement if the accused product contains elements that are only "insubstantially different" from elements of the claim? In litigation, the fact finders (i.e., juries or judges) must compare the subject matter of the asserted claims to the accused product or method to determine if the accused product or method contains every element recited in the claim, or its equivalent⁷. A product or process that does not contain one or more limitations of the claim may still be found to infringe under the equitable doctrine of equivalents if it contains elements that represent an "insubstantial difference" from the limitation that is not literally present.

To literally infringe an EST or SNP claim, an accused nucleotide sequence must contain the entire sequence recited in the claim. If, however, the accused nucleotide sequence contains less than the entire sequence, or deviates from that sequence at one or more positions, the court must determine if it infringes the claim under the doctrine of equivalents. That is, the court must construe the asserted claim, compare it with the accused sequence, and determine if the accused sequence is insubstantially different from the claimed sequence. If it is, the accused sequence may be found to infringe the claim under the doctrine of equivalents.

Consider a hypothetical litigation where the plaintiff contends that its SNP-based claim is infringed under the doctrine of equivalents. The claim is directed to a method for diagnosing a disease by probing a patient's chromosomes with SEQ ID NO:1, a SNP of 1,000 base pairs that contains a G C mutation at position 500. The defendant has commercialized a probe based on SEQ ID NO:1, which extends from position 250 to 750, and hence, includes the polymorphism at position 500.

Does the defendant infringe? The court must consider the evidence of record and construe the meaning and scope of the claim as a matter of law (claim construction, the process of determining the scope and the meaning of the claims, is a matter of law to be determined by judges⁸). In construing claims, the courts must consider the intrinsic evidence (i.e., the language of the claim, the disclosure in the specification, and the prosecution history)⁹. Once the claims are construed as a matter of law, the fact finder must compare the claims to the accused product or method to determine if infringement has occurred. If the claim is construed to be limited to use of the 1,000–base pair SNP, the defendant does not literally infringe the claim. However, the fact finder must now conduct an "insubstantial differences" analysis to determine whether the 500–base pair probe that includes the polymorphism at issue still infringes under the doctrine of equivalents. Such analyses are likely to be highly fact-specific and may depend on the particular characteristics and features of the gene sequence, protein family, or polymorphism at issue.

Conclusions
The powerful tools available to today's molecular biologists enable them to clone, sequence, and identify thousands of potentially useful ESTs and SNPs. In seeking patent protection for these sequences, scientists and patent practitioners should attempt to draft patent specifications that disclose functional and structural details sufficient to satisfy the utility, written description, and enablement requirements of the patent statute. If such detailed specifications are provided, practitioners will be able to draft broader claims and secure meaningful and enforceable patent protection for their clients.

REFERENCES

1. Holman, M.A. & Munzer, S.R. 85 Iowa L. Rev. 735, 753-754 (2000).
2. Merck & Co. v. Olin Mathieson Chem. Corp., 253 F.2d 156, 164-165 (4th Cir. 1958). See also Diamond v. Chakrabarty, 447 US 303, 309 (1980)("Congress intended statutory subject matter to 'include anything under the sun that is made by man.'").
3. See, e.g., Harnett, C.J. Risk--Issues In Health & Safety (Spring 1994); Dastgheib-Vinarov, S. Marq. Intell. Prop. L. Rev. 4, 143 (2000); Eisenberg, R.S. Emory L.J. 49, 783 (2000); Auth, D.R. Nat. Biotechnol. 15, 911-912 (1997). | PubMed |
4. 66 Fed. Reg. 1092 (2001), available at http://www.uspto.gov/web/menu/current.html#register. See also Revised Interim Utility Guidelines Training Materials available at http://www.uspto.gov/web/patents/guides.htm; Kowalski, T.J. Nat. Biotechnol. 18, 349-350 (2000). | Article | PubMed |
5. 927 F.2d 1200, 1206 (Fed. Cir. 1991).
6. 984 F.2d 1164, 1170 (Fed. Cir. 1993).
7. See Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 US 17 (1997).
8. Markman v. Westview Instruments, Inc., 517 US 370 (1996).
9. Id.