Clades, classifications, and claims: evolution of organisms and their nomenclature in life science patents

Clades, classifications, and claims: evolution of organisms and their nomenclature in life science patents

ABSTRACT

Organisms are complex biological entities that are less easily defined by specific structures or sequences than molecules, nucleic acids, and antibodies. Nor are they necessarily fixed in time or reproducible by repeatable methods, given their capacity for replication and mutation. Like organisms themselves, names and classifications also change over time as scientists better understand extant biodiversity. Taxonomy is the field of evolutionary biology concerned with classifying, naming, and identifying organisms, while phylogenetics concerns organisms' evolutionary history and relatedness. Here, I review the challenges evolution poses for patentees, using the examples of evolving influenza viruses and bacterial classifications, and Federal Circuit decisions relevant each issue. I conclude that careful consideration of organisms' evolutionary histories and the systematics underlying their classification in specification drafting allows patentees to: (i) mitigate the impact of scientific disagreement (such as the 'species problem' in microbiology) in claim construction; (ii) limit the effects of changing classifications on infringement analysis; (iii) describe generic categories of related organisms to encompass later-arising ones; and (iv) bolster compliance with the written description and enablement requirements of thirty-five U.S.C. section one hundred twelve (a). Accordingly, patentees might address the challenges that evolutionary uncertainty poses for organism-centered patents by embracing these areas of evolutionary biology.

I. INTRODUCTION

The evolutionary history and relatedness of organisms are central to the working of many inventions in biotechnology. Prophylactic vaccines, for example, use pathogens or their components to induce adaptive immune responses, thereby reducing the risk of infection by closely related pathogens. The breadth of protection afforded by a particular vaccine component is pathogen-dependent-the same measles vaccine, containing a single strain of measles virus, has been in use for over fifty years, whereas seasonal influenza vaccines contain components from multiple viruses of different lineages and are updated regularly to account for viral evolution. Other inventions, such as live biotherapeutic products, direct-fed microbials, and postbiotics, harness utility of microorganisms and metabolites they produce through fermentation. Alternatively, organisms may be genetically modified to provide new utility, such as pest resistance or nutritional quality in agriculture. Where these utilities are observed in one organism, the question arises of which closely related organisms provide similar utility, or which related organisms may be engineered to achieve similar benefits, respectively. Addressing these questions of conserved properties between organisms is critical for patentees' compliance with the written description and enablement requirements for patents on inventions involving organisms.

Complicating the issue is the difficulty in defining and reproducing organisms as physical entities, in contrast to small molecules or proteins such as antibodies. Patents are written documents, ending in claims defining what the inventor regards as the invention. In the small molecule context, a patent's claims may use graphic formulae and chemical nomenclature to identify the compound(s) invented. The Papesch court recognized, however, that the things patented are the compounds so identified, not the formulae and nomenclature themselves. While such representations may suffice for small molecules, organisms (and their cells) are characterized by their ability to replicate, with changes accumulating over successive generations. The influenza A/H3N2 virus subtype, for example, encompasses influenza A viruses that may have been isolated nearly sixty years apart but are nonetheless related by descent and genetically closer to each other than to viruses of the influenza A/H1N1 virus subtype. Cell lines, as another example, are often referred to by a shorthand name such as MDCK or HEK two thousand nine hundred three, reflecting their original isolation-Madin and Darby's isolation of cells from a canine kidney (MDCK), or a human embryonic kidney cell line designated two thousand nine hundred three (HEK two thousand nine hundred three). But through over fifty years of passaging since their original isolations, substantial diversity has accumulated among lineages that authors may still call 'MDCK' or 'HEK two thousand nine hundred three'. Biological nomenclature, then, may encompass diverse categories of related organisms or biological entities, more broadly than chemical nomenclature or formulae identify a specific compound.

The difficulty in defining an organism by name alone may be addressed by depositing the organism itself, making it available to the public to satisfy the requirements of thirty-five U.S.C. section one hundred twelve. But making such deposits poses at least three issues for patentees. First, patents directed to bacteria and their products often recite deposited strains in the claims. Macleod identifies several judgments from foreign courts that suggest these claims are broader in practice than they might appear, but also recognizes the other potential interpretation of these claims as extremely narrow, extending only to the deposited strain's descendants. Second, making a deposit during prosecution, such as to address an enablement rejection, may unintentionally limit claim scope to require the deposited material even if the deposited material is not recited. Third, where multiple deposits are made, they may be perceived as collectively representing a claim term, with the commonalities among them being construed as claim limitations even if a broader scope would still be distinct from the prior art. Sections three point A and three point B discuss these second and third issues in more detail, respectively.

The potential limitations or uncertainty posed by deposits are especially undesirable where the specific organisms used to exemplify an invention are not truly necessary to implement it, or even commercially relevant over the twenty years of a patent's term. Efforts to stabilize influenza virus antigens, for example, often target residues that are conserved across a diversity of subtypes, let alone between more closely related viruses within a subtype. Public health authorities regularly update the candidate viruses for inclusion in seasonal influenza vaccines to account for viral evolution, making it foreseeable that these modifications may be applied to proteins of later-arising viruses while the exemplified viruses become outdated. Regulatory considerations, too, may warrant replacing an exemplified organism with another in a commercial product, such as genetic stability in the context of a live biotherapeutic product. Claims limited to specific organisms, then, are not likely to fully serve the needs of patentees.

Genus claims, encompassing whole categories of organisms, pose their own challenges with respect to thirty-five U.S.C. section one hundred twelve (a). The species concept is controversial in bacteriology and virology, introducing uncertainty into the meaning of claims referring to bacteria and viruses by a categorical name such as that of a species. Nomenclature for these organisms also changes frequently as knowledge of biodiversity, and the organisms themselves, evolve, but the prohibition against added matter can cause a mismatch between terminology and knowledge reflected in a specification filed today and that in use fifteen years later when infringement is accused. And as others have articulated, genus claims have received increasingly negative treatment with respect to the written description and enablement requirements. The Federal Circuit's shift toward disfavor of genus claims is reviewed by Karshtedt et al. in The Death of the Genus Claim. Lemley and Sherkow review the implications of this 'war on genus claims' in the specific context of antibodies in The Antibody Patent Paradox, noting an apparent primacy of structure for compliance with both doctrines. The structural features defining a general category of organisms are less immediately apparent, however, than for chemical compounds or antibodies. And, in contrast to small molecules or proteins that can be produced by repeatable methods, the tendency of organisms to change over successive generations complicates attempts to define them by a specific sequence, as may be done for antibodies.

The problems evolution poses for organism-centered claims may be addressed by systematics, the branch of evolutionary biology concerned with classification of organisms, accounting for the evolutionary processes that produce observed diversity. Within systematics, taxonomy is the study of classification and nomenclature, while phylogenetics is the study of evolutionary history using genetics. Here, I review issues raised by the evolution of bacteria and influenza viruses, the Federal Circuit's treatment of similar issues and potential solutions grounded in the systematics of these organisms. Bacteria are particularly illustrative of issues arising from changes to classification schemes and nomenclature, while influenza viruses highlight issues arising from rapid evolution during a twenty-year patent term. The issues are not mutually exclusive, though, as viral taxonomy has recently undergone a substantial albeit controversial shift, and bacterial populations change over time in response to vaccine-related selection.

I focus the discussion on bacteria and influenza viruses as examples from my scientific research experience, but eukaryotes are not immune to these issues. Advances in phylogenetic understanding have also warranted reclassifications in medically relevant fungi and mosquitoes and agriculturally relevant plants. Human activity can also drive animal, plant, and fungal evolution over short time scales, such as through urbanization, agriculture, and climate change. And while reclassifications are perhaps not as frequent as in bacteria or evolution not quite as rapid as in seasonal influenza viruses, multiple written description and enablement cases discussed below concerned diversity and conservation of features within eukaryotic taxa.

This is not to say that the issues are precisely analogous to eukaryotes-the 'species problem' for bacteria and viruses stems partly from difficulty applying workable eukaryotic species concepts to other domains of life. These concepts, then, may instead be more applicable at taxonomic scales below the species level, such as plant cultivars or animal genetic backgrounds or breeds. Beyond whole organisms, the HEK two nine three and MDCK cell examples above illustrate that a cell population's name may encompass more diversity than initially apparent and that non-trivial changes can arise in cultured eukaryotic cell populations over time. Systematic concepts have also been applied to better understand and classify somatic cell types, given their ability to change and diverge with replication. The cluster differentiation system, for example, seeks to provide a uniform nomenclature for cell surface markers based on binding by specific antibodies, allowing cells to be classified by the presence or absence of certain markers. Phylogenetics, too, has been used to analyze evolution of cell populations within organisms, such as evaluating B-cell lineages to identify mutations important for antigen binding and stratifying cancers into subtypes by inferring their evolutionary trajectories. The details will depend on the context of an invention, but applicants working with replicating entities should find some benefit in proactively addressing questions of diversity within a category, how that diversity or understanding of it might change over time, and biologically relevant features conserved within the category.