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Patent Prosecution and Enforcement in Pharmacogenomics

By Nusrat Khaleeli and Dennis Fernandez

Nov 15, 2005 | Pharmacogenomics stems from a related field, pharmacogenetics, and the two terms are often used interchangeably. Pharmacogenetics is the decades-old study of differences in drug absorption, metabolism, elimination, or response and then examines a few candidate genes for variations underlying the observed phenotypes. In contrast, pharmacogenomics casts a wider net to capture complicated patterns of genetic variation and attempts to correlate these patterns to different drug response phenotypes [1].

The most prevalent genetic variations in the human genome are single nucleotide polymorphisms (SNPs), which are single-base-pair differences that occur in 1 percent of the human population [2] on average every 1.91 kb. The human SNP map shows 1.42 million differences, a majority of which occur in coding regions [3]. Variations in the disease-causing genes, drug targets, or the enzymes that metabolize drugs influence the drug’s potency and efficacy. Pharmacogenomics studies how these sequence differences affect the ways in which people respond to drugs.

The promise of pharmacogenomics is that it is possible to design clinical trials for target patient populations having the genotypes that are likely to respond to a drug under investigation and thus may reduce clinical trial costs and speed up FDA approval processes [4]. Also, genetic differences between patients explain why some patients but not others suffer from harmful drug side effects. Therefore, it may lead to identifying patients that are likely to suffer adverse effects from the drugs [4].

Challenges to PGX Patents
The tools available to researchers involved in pharmacogenomics studies are viewed as patentable. These include reagents, kits, chips, microarrays, instrumentation, devices used for genetic tests, algorithms for searching and sequence alignments, and database technology. Certain proteins may also fall under the tool category if they can be used as probes to identify other biomolecules or small molecules.

Patenting methods that aid in the acquisition of pharmacogenomic data such as screening and genotyping methods is standard practice. Further, methods used in the diagnosis and treatment of subjects based on pharmacogenomic knowledge are also patentable. Interestingly, methods for managing complex data from pharmacogenomic studies — such as a method for integrating clinical, diagnostic, genomic, and therapeutic data — are patentable. Finally, methods for pharmacogenomics-based clinical trial design meet the criteria for patentability.

The composition of isolated nucleic acid sequence, isolated protein, and small molecules can be claimed. However, there are particular challenges to the prosecution of patents claiming composition resulted from pharmacogenomics research, such as meeting the enablement and written description requirements.

The U.S. Patent and Trademark Office amended its guidelines in January 2001 to require that a patentable subject matter have specific, substantial, and credible utility. The addition of the substantiality requirement means that patent claims that require considerable research by a person of ordinary skill in the art to determine the function of a molecule are likely to be rejected. The motivation for the requirement is to reduce claims that expand the scope of the invention beyond the functions and utility described in the specifications.

In its most simplified interpretation, the utility rule demands that each claim pertain to products that have a clear use and benefit to human society. For example, one has not shown utility if one claims a nucleic acid sequence that may be used as a gene probe, a primer in PCR, a chromosome marker, or an antigen generator, since such utility is applicable to virtually any nucleic acid sequence. However, if the function of the gene is known and its utility is understood then claiming the DNA, as a gene probe, would be valid. Further, if the gene function is known and the utility is accepted then a homologous DNA sequence would comply with the utility requirements and could be claimed. Even if a portion of this homologous gene was previously published as an expressed sequence tag, the patenting of this homologous gene still complies with the novelty requirement. While a SNP or a nucleic acid sequence containing such a variation cannot be claimed, if the variation proved useful as a marker for a disease state or for drug metabolism then the composition could be claimed.

The written description requirement is the greatest hurdle for patenting of composition. In an age where “describing a method of preparing a cDNA or even describing the protein that the cDNA encodes...does not necessarily describe the cDNA itself,” one can be sure that the written description requirement is very strictly enforced [5].

The European Patent Office also has specific laws pertaining to biotechnology patents, described in the EU Biotechnology Directive of July 1998 and the European Patent Convention (EPC) of 1999. For instance, Article 53(a) of the EPC states that “European patents shall not be granted in respect of...inventions the publication or exploitation of which would be contrary to ‘ordre public’ or morality” [6], and Rule 23d (d) excludes “processes for modifying the genetic identity of animals which are likely to cause them suffering without any substantial medical benefit to man or animal, and also animals resulting from such processes” [7]. Thus, patents that cover genetically modified animals, for example, that do not specify or imply medical benefits, can be rejected by the EPO or challenged in an Opposition, a procedure in which any person may oppose a granted European patent within nine months from publication.

Exceptions to the Rule
Some exemptions to infringement under the U.S. patent law might be relevant to enforcing pharmacogenomics patents. The research exemption is designed to protect actions performed “for amusement, to satisfy idle curiosity, and for strictly philosophical inquiry.” As seen in the case of Madey v. Duke University, the experimental use defense is not valid if the activity furthered the “legitimate business objectives” of the alleged infringer whether or not a profit was made. This defense is “very narrow and strictly limited” [5].

35 USC 271 (e)(1) creates another exemption that provides that it is not an act of infringement to use a patented invention solely for uses “reasonably related” to the generation of information likely to be relevant to FDA approval of a product. This exemption may be applied in the case of business methods, devices, research tools, and even chemical entities. The recent U.S. Supreme Court case Merck v. Integra Life Sciences made it clear that the exemption is broad enough to cover “experimentation on [patented] drugs that are not ultimately the subject matter of an FDA submission” or “use of patented compounds in experiments that are not ultimately submitted to the FDA” [8]. In this case, the defendants used patented peptides as positive controls in screening to find candidates for an FDA filing. The Court held that such activity was within the safe harbor protection of 35 USC 271 (e)(1). Thus, one might argue that use of patented SNPs or other composition in experimentation associated with FDA filings, such as to determine responsive population for a drug, is not infringement under 35 USC 271 (e)(1).

Furthermore, groups involved in developing pharmacogenomic research tools and methods should be aware of the Housey decision passed by the district court of Delaware. In accordance with this decision, one can elude U.S. protection on patented screening methods by performing the research work outside the United States. Once the screening is completed and a useful product is found, the Housey decision permits the information to be brought back into the United States for further testing and development into a commercial product [5].

The challenges to pharmacogenomics patents are still evolving. Because of their direct application to biological life on earth, pharmacogenomics and genomics patents are subject to intense scrutiny by the various patent offices. As the technology develops, however, one impedance to the biotech patent process, namely the need for more cross-technically educated patent examiners and counsel, will eventually become less of a burden. Knowledge of the challenges to the pharmacogenomics patent process will lead to more skillful prosecution and more rapid innovation overall.

1          Constans, E. “Making medicine personal,” The Scientist 16, 44-50; 2002.
2          Henry, C.E. “Pharmacogenomics,” Chem Eng News 79, 37-42; 2001.
3          The International SNP Map Working Group. “A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms,” Nature 409, 928-33; 2001.
4           Overend-Freeman, E. “Maximizing R&D productivity: getting more bang for your R&D buck,” Datamonitor Report.
5           Warburg, R.J. et al. “Patentability and maximum protection of intellectual property in proteomics and genomics,” Pharmacogenomics 4, 81-90; 2003.
6          European Patent Convention: Part II Ch.I Article 53(a).
7           Implementing Regulations to the Convention on the Grant of European Patents: Part II Ch. IV Rule 23d(d).
8          Merck v. Integra Life Sciences, 125 S.Ct. 2372 (2005).

Dennis Fernandez is managing partner, and Nusrat Khaleeli is an intern, at Fernandez & Associates. E-mail:

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