Tuesday, 23 March 2010

T 458/07 – No Examples Needed

Claim 1 of the patent read:

A method for purifying a polypeptide from a composition comprising the polypeptide and a contaminant, which method comprises the following steps performed sequentially:
(a) binding the polypeptide to an ion exchange material using a loading buffer, wherein the loading buffer is at a first conductivity and pH;
(b) washing the ion exchange material with an intermediate buffer at a second conductivity and/or pH so as to elute the contaminant from the ion exchange material;
(c) washing the ion exchange material with a wash buffer which is at a third conductivity and/or pH, wherein the change in conductivity and/or pH from the intermediate buffer to the wash buffer is in an opposite direction to the change in conductivity and/or pH from the loading buffer to the intermediate buffer; and
(d) washing the ion exchange material with an elution buffer at a fourth conductivity and/or pH so as to elute the polypeptide from the ion exchange material.

[… The opponent] argues that the one example in the patent is not enough for that the disclosure in the patent could be regarded as sufficient. This was the more so, since the example apparently does not correctly represent the claimed subject-matter because the conductivity of the loading buffer is not stated, an additional wash step is carried out and not all contaminants are removed. [18]

R 27(1)(e) EPC 1973 [NB: and R 42(1)(e) EPC 2000] stipulates that the description shall “describe in detail at least one way of carrying out the invention claimed using examples where appropriate and referring to the drawings, if any” (emphasis added). Thus, it follows from this rule that there is no mandatory requirement for an example under the EPC. Hence, even the absence of an appropriate example would not be a reason for denying sufficiency of disclosure. [19]

The sufficiency of disclosure with regard to claimed subject-matter is judged on the basis of the whole disclosure in a patent and not only on that given by the examples. Furthermore, the skilled person’s knowledge at the time of priority of the patent must be taken into account. [20]

[…] At the priority date of the patent ion chromatography was a well-established technique for the purification of proteins. Ion chromatography separates proteins according to their charge. The separation is based on the reversible interaction of the protein to an oppositely charged chromatography material. An anion exchange resin has a positively charged surface. A cation exchange resin has negatively charged groups.

Initially, counter ions, i.e. ions of opposite charge present in the equilibration buffer are bound to the charged immobile functional groups of the chromatography resin. When a sample is added to the column, proteins with opposite charge to the resin displace the counter ions and are absorbed onto the column. Thus, negatively charged proteins bind to the anion exchange resin and positively charged proteins bind to the cation exchange resin.

Proteins bind to the resin when the conductivity of the buffer is low. The conductivity of the buffer is strongly dependent on the salt concentration in the buffer.

Differential elution of the bound proteins can be achieved by altering the conductivity (i.e. the salt concentration) of the buffer or by altering the pH. Elution can be stepwise or in a gradient. When elution is due to a change in the conductivity, the principle is that those proteins that due to their charge are less strongly associated with the resin are displaced from the column at lower conductivities (i.e. salt concentration), while the more strongly associated proteins are eluted at higher conductivities.

At the priority date the skilled person was also aware of a wide variety of combinations of constituents to be used for the chromatography buffers and that the type of resin and the buffers used depended on a given protein. Thus, the skilled person knew that fine-tuning of the chromatography process was necessary for each protein-contaminant-situation, but that this could be achieved on the basis of the well-known physicochemical principles on which ion-chromatography relies. [21]

Some of the above-mentioned knowledge about ion chromatography is summarized in paragraph [0005] of the patent in suit. The skilled person also learns from this paragraph that the claimed ion chromatography method is meant as an improvement of the “standard” way of conducting ion chromatography […], i.e. where separation of contaminant and protein are achieved by progressive increase of the salt concentration in the buffer. Moreover, the skilled person would recognize in view of the claims stating that the contaminant is eluted before the desired protein […], that the claimed method is an improvement of such ion chromatography situations where the contaminant elutes before the protein. [22]

Given all this knowledge, in the board’s view, the skilled person would not have any difficulty in performing the claimed method on the basis of the disclosure in the patent and this would even be so if the example would not reflect the claimed method. [23]

The board notes however in passing that it considers the example to describe a situation falling under the method of claim 1.

  • In particular, the conductivity of the loading buffer is indicated in Table 1.
  • As regards the additional wash step included in the example the board considers that its presence in the example and absence in the claim could only give rise to an objection pursuant to A 83, if this step was an essential feature of the invention. If this was so, the issue would rather have to be dealt with under A 84 than under A 83.
  • Finally, the failure to demonstrate in the example the removal of all contaminants is in the board’s view also no reason for considering that the example does not reflect the invention as claimed.

Firstly, the claims expressly relate to “purifying a polypeptide from a composition comprising the polypeptide and a contaminant and to the elution of “the contaminant” ([…] emphasis added). Thus, removal of all impurities is not required by the claim.

Secondly, in view of the general principles on which ion chromatography is based […] and given the differing charges of the variants it would not even be expected by the skilled person that it would be possible to remove all impurities by a single round of chromatography. [24]

I shall come back on this decision tomorrow.

To read the whole decision, click here.