Thursday, July 24, 2008

To what extent do protein patents cover posttranslationally modified proteins?

People often treat proteins as simply a string of amino acids as specified by a gene, and in particular this is often how they are represented in patents, i.e., essentially as a string of letters. For example, many patents claim proteins as defined by an amino acid sequence referenced by SEQ ID NO. However, while this simplistic view of proteins holds true for most bacterial proteins, and some very small proteins such as human growth hormone, most eukaryotic proteins (and in particular naturally occurring human proteins) are posttranslationaly modified. That is, the process of protein translation in a cell results in a string of amino acids as specified by the corresponding gene, but this polypeptide backbone is subsequently chemically modified to result in a final protein product having a markedly different structure than the originally translated polypeptide backbone. These posttranslational modifications involve the chemical addition of sugars and other molecules to certain amino acids in the polypeptide backbone. Common examples of posttranslational modifications include phosphorylation, sialation, glycosylation, and acetylation. Posttranslational modifications can dramatically affect the structure and function of the protein. Some modifications, particularly glycosylations, dramatically increase the size of the posttranslational modified protein relative to the protein as initially translated. Furthermore, these modifications entail the removal of one or more atoms from the modified amino acid, e.g., most of these modifications cause the removal of a hydrogen atom from the original amino acid and replacement by the modifying chemical group.

As a side note, posttranslational modification is one of the primary rationales offered by the biotechnology industry as to why an abbreviated approval process for generic biologics would raise safety and efficacy issues not presented by traditional small molecule generic drugs. Posttranslational modifications can be quite complex, and purified protein preparations are typically heterogeneous mixtures of a variety of different posttranslationally modified forms of the protein. The specific nature of posttranslational modifications for any given protein preparation can vary based on the particular cell line in which the gene is expressed, and the production conditions under which the cells are grown, the protein is expressed, and the protein is harvested and purified. The potential for substantial alteration in safety and/or efficacy based on minor changes to the production process, or use of a different cell line, is cited as necessitating a full scale assessment of safety and efficacy for any follow-on biologic, even if it has the same amino acid backbone sequence as a currently approved originator biologic.

Back to my main point, which is, to what extent do patent claims directed to proteins encompass posttranslationally modified proteins? The issue has been presented to the Federal Circuit in a brief filed by Roche on May 13, 2008 appealing the decision by the lower court in Amgen v. Roche (2008 WL 2231038). The allegedly infringing Roche product is MIRCERA, a pegylated version of erythropoietin (EPO) that has been on the market in Europe since 2007, and has been approved in the US by FDA. Pegylation is a form of non-natural posttranslational modification, which is accomplished outside of the cell in a chemical process that results in a covalent attachment of polyethylene glycol (PEG) to one or more amino acids on a protein. Pegylation can dramatically affect the biological and pharmacologic function of the protein, particularly by altering binding characteristics and increasing the half-life of the protein in the human body. Increased half-life translates into less frequent administration of the drug to the patient, with obvious clinical benefits.

Roche's challenge is directed particularly at claim 3 of U.S. Patent No. 5547933, which claims a “non-naturally occurring glycoprotein product of the expression in a mammalian host cell of an exogenous DNA sequence comprising a DNA sequence encoding human erythropoietin said product possessing the in vivo biological property of causing bone marrow cells to increase production of reticulocytes and red blood cells.” Roche argues that MIRCERA is not and cannot be produced by a mammalian host cell, as required by the claim, but can only produced by means of the cell free pegylation reaction. Roche also stresses the very different chemical and functional characteristics of MIRCERA in comparison to EPO produced in a cell. In particular, Roche argues that MIRCERA has twice the molecular weight, a lower molecular charge, different hydrodynamic size, different chromatographic profiles, different binding, distinct carbohydrate structures, and a much longer half-life. Roche also emphasizes the functional distinctions between MIRCERA and Amgen’s EPO products, arguing that MIRCERA provides substantially superior outcome for at least some subset of patients, and thus fulfills a medical need that is not currently being satisfied in the US.

It will be interesting to see how the Federal Circuit responds to Roche’s argument. In a previous decision involving a related Amgen EPO patent, Amgen v. HMR (314 F.3d 1313) the Federal Circuit strictly limited another claim directed towards the EPO protein to the amino acid sequence referenced in the claim. In that case, the claim defined EPO by reference to an amino acid sequence listing containing 166 amino acids. This amino acid sequence was derived from the DNA sequence of the corresponding EPO gene. However, subsequent to the filing date of the patent it was learned that the initially translated 166 amino acid EPO was posttranslational processed in the cell, resulting in the removal of a terminal amino acid, such that the final EPO product actually only contains 165 amino acids. The Federal Circuit held that this unanticipated posttranslational modification resulted in the claim not covering mature human EPO literally or under the doctrine of equivalents.

Looking beyond Amgen v. Roche, what are the ramifications of this issue for other protein patents? Many patents claim proteins solely in terms of amino acid sequence, with no explicit mention of posttranslational modifications. Commercially relevant products, such as biologic drugs, are often posttranslationally modified, and one might argue that many proteins claims are not literally infringed by posttranslationally modified versions of the claimed sequences. To find literal infringement, at the very least a court would have to find that the amino acids recited in the claim include derivatives of an amino acid lacking a hydrogen atom, and that the claim encompasses any of a host of chemical additions not defined in the specification. And if the court interprets the claim this broadly, potential 112 issues are raised. The Federal Circuit has repeatedly stated that biomolecules (like proteins and DNA) are chemical compounds, and that patent law should be applied to biomolecules in the same manner as it is to other chemicals. But in other contexts, an inventor is not permitted to claim a genus of chemical compounds sharing a common structural backbone and encompassing any chemical additions to that backbone. If the court were presented with this argument, and chose to actually treat a protein claim like any other chemical claim (as it did in Amgen v. HMR), then perhaps it would find that an interpretation of the claim that would encompass any posttranslationally modified version of the recited amino acid sequence violates the disclosure requirements of section 112.