T 1090/14 (Biocompatible matrix/LEUKOCARE) 25-09-2018

I. European patent No. 2 021 374, entitled "Biocompatible three dimensional matrix for the immobilization of biological substances" was opposed under

Articles 100(a) EPC in conjunction with Articles 54 and 56 EPC and under Articles 100(b) and (c) EPC.

II. Both the patent proprietor and the opponent (appellants I and II, respectively) filed an appeal against the interlocutory decision of the opposition division that, account being taken of the amendments in the form of auxiliary request 2, the patent and the invention to which it related met the requirements of the EPC (Article 101(3)(a) EPC).

III. In its decision, the opposition division inter alia held that the subject-matter of the main request and auxiliary request 1 lacked an inventive step

(Article 56 EPC).

IV. With the statement of grounds of appeal, appellant I re-filed sets of claims of the main and the first and second auxiliary requests considered by the opposition division and also sets of claims of auxiliary requests 3 to 10, filed before but not considered by the opposition division.

V. Claim 1 of the main request reads:

"1. A method of producing a solid coated carrier carrying biological material, comprising the steps of:

(a) incubating a solid carrier with a solution comprising 0.1 to 10 % (w/w) or (v/v) of at least one silane and subsequently removing the solution;

(b) attaching the biological material to the carrier by incubating the carrier with a preferably buffered aqueous solution containing the biological material and subsequently removing the aqueous solution, wherein the biological material is selected from the group consisting of polypeptides, peptides and proteins;

(c) incubating the carrier in an aqueous solution comprising one or more substances selected from (poly)peptides, amino acids, starch, sugars, polyalcohols, polyethyleneglycols (PEGs) or a mixture thereof, whereby the biological material is embedded in a coating layer; and

(d) sterilizing the produced solid coated carrier".

Claim 1 of auxiliary request 1 reads:

"1. A method of producing a solid coated carrier carrying biological material.

consisting of the steps of:

(a) incubating a solid carrier with a solution comprising 0.1 to 10 % (w/w) or (v/v) of at least one silane and subsequently removing the solution, and, optionally, further comprising a step (a') drying the carrier until the residual content of the solution is less than 10 % of the originally applied solution;

(b) attaching the biological material to the carrier by incubating the carrier with a preferably buffered aqueous solution containing the biological material and subsequently removing the aqueous solution, wherein the biological material is selected from the group consisting of (poly)peptides, peptides and proteins;

and, optionally further comprising a step (b') subsequent to the step (b) and previous to step (c):

(b') incubating the carrier in a buffered aqueous solution containing a blocking agent and removing the aqueous solution; or optionally further comprising a step (b") subsequent to the step (b) and previous to step (c):

(b") blocking unbound binding sites using an aqueous solution containing 0.5-10 % (w/w) substances selected from the group consisting of (poly)peptides, hydroxyethylstarch (HES), mannitol, sorbitol and polyethyleneglycol (PEG), milk, soya, wheat or egg derived protein and optionally performing one or more washing steps using an aqueous solution after blocking;

(c) incubating the carrier in an aqueous solution comprising one or more substances selected from (poly)peptides, amino acids, starch, sugars, polyalcohols, polyethyleneglycols (PEGs) or a mixture thereof, whereby the biological material is embedded in a coating layer; and, optionally, drying the carrier until the residual water content is < 20% (w/w); wherein steps (a), (b) and (c) are carried out in the above described order; and

(d) sterilizing the produced solid coated carrier".

*the differences between claim 1 of the main request and claim 1 of auxiliary request 1 are underlined.

Claim 1 of auxiliary request 2 reads:

"1. A method of producing a solid coated carrier carrying biological material,

consisting of the steps of:

(a) incubating a solid carrier with a solution comprising 0.1 to 10 % (w/w) or (v/v) of at least one silane and subsequently removing the solution, and, optionally, further comprising a step (a') drying the carrier until the residual content of the solution is less than 10 % of the originally applied solution;

(b) attaching the biological material to the carrier by incubating the carrier with a preferably buffered aqueous solution containing the biological material and subsequently removing the aqueous solution, wherein the biological material is selected from the group consisting of (poly)peptides, peptides and proteins;

and, optionally further comprising a step (b') subsequent to the step (b) and previous to step (c):

(b') incubating the carrier in a buffered aqueous solution containing a blocking agent and removing the aqueous solution; or optionally further comprising a step (b") subsequent to the step (b) and previous to step (c):

(b") blocking unbound binding sites using an aqueous solution containing 0.5-10 % (w/w) substances selected from the group consisting of (poly)peptides, hydroxyethylstarch (HES), mannitol, sorbitol and polyethyleneglycol (PEG), milk, soya, wheat or egg derived protein and optionally performing one or more washing steps using an aqueous solution after blocking;

(c) incubating the carrier in an aqueous solution comprising one or more substances selected from (poly)peptides, amino acids, starch, sugars, polyalcohols, polyethyleneglycols (PEGs) or a mixture thereof, whereby the biological material is embedded in a coating layer; and, optionally, air-drying the carrier until the residual water content is < 20%

(w/w); wherein steps (a), (b) and (c) are carried out in the above described order; and

(d) sterilizing the produced solid coated carrier".

*the differences between claim 1 of auxiliary request 1 and claim 1 of auxiliary request 2 are underlined.

VI. The following documents are mentioned in this decision:

D10: US 5 730 933, published 24 March 1998.

D16: WO 97/17436, published 15 May 1997.

VII. The board issued a communication pursuant to

Article 15(1) RPBA. In this it informed the parties, inter alia, of its preliminary opinion that auxiliary requests 3 to 10, filed with the statement of grounds of appeal of appellant I, had not been substantiated. The board further stated that, in keeping with established case law, it was inclined to regard these requests to become effective only at the date on which they were substantiated.

VIII. In a letter dated 22 August 2018, appellant I withdrew their request for oral proceedings.

IX. Oral proceedings before the board took place on 25 September 2018 in the absence of appellant I. At the end of these oral proceedings the chair announced the decision of the board.

X. The written arguments of appellant I, relevant to the decision, are summarised as follows:

Inventive step - Article 56 EPC

The patent related to the field of therapeutic or diagnostic molecules suitable for the transient or permanent application in a patient or for the treatment or diagnosis of diseases. Such treatments included the application of said molecules within the blood stream.

At the time of filing of the patent application, therapeutic molecules were often administered systemically, but to avoid problems with this, an alternative to systemic administration was the immobilisation of molecules of interest. For in vivo applications, the sterility of such immobilised devices was of utmost importance, however the direct sterilisation of biological molecules immobilised on devices was considered difficult, if not impossible. Thus, an alternative pursued in the art was the use of ex vivo methods, in particular the use of apheresis columns, such as e.g. TheraSorb®.

As described in paragraph [0006] of the introduction of the patent, such apheresis columns contained sepharose with coupled antibodies. Sepharose was the trade name for a cross-linked, beaded-form of agarose, a polysaccharide polymer material extracted from seaweed. Such ex vivo methods had major disadvantages in that they were not only expensive, but also required a large amount of work to be implemented (see paragraph [0006] of the patent).

The technical problem to be solved by the present patent was set out in paragraph [0007] as "to provide means and methods which enable the treatment of patients with biological material such as cells and proteins, which improve this [the above mentioned] situation." As a solution, the patent contributed a method of preparing terminally sterilised devices with immobilised, highly defined quantities of therapeutic molecules on a defined surface.

The opposition division erred in holding the subject-matter of claim 1 of the main request and of auxiliary request 1 to lack an inventive step. The opposition division had assessed inventive step starting from document D16 when in fact document D10 was the correct choice of closest prior art.

Document D10 described the protection of biomolecules and solid substrates carrying such biomolecules during sterilisation. The intended purpose of these immobilised molecules was as sterilised biological material for use in medical devices. Thus, document D10 had the same aim as the claimed invention.

Document D16 did not represent the closest prior art because its main emphasis was separation columns, corresponding in essence to the apheresis columns of the prior art described in paragraphs [0006] and [0007] of the patent. As it is a declared aim of the present patent to overcome the drawbacks associated with these columns, document D16 could not be regarded as being for the same purpose invention.

Document D10 disclosed two mixtures suitable for sterilisation: (1) a mixture comprising a biological material to be protected and an extraneous protein, such as e. g. gelatin, in which case the mixtures have to be cooled (to about -70 °C) in order to immobilise the mixture; (2) the mixture comprising the biologically active molecule, an extraneous protein and a free-radical scavenger.

The difference between the methods of the claimed invention and those disclosed in document D10 was that in the claimed method an unprotected biomolecule was attached to a carrier, fully or in part via a silane layer and subsequently protected, while in document D10 an already protected mixture was attached to a carrier.

The technical effect of this difference was that substantially all of the attached biomolecules remained attached to the solid carrier, even when put in contact with body fluids such as blood.

Accordingly, the technical problem was the provision of an improved method of preparing a solid carrier suitable for medical uses.

The claimed solution involved an inventive step because document D10 contained no suggestion to directly attach a biomolecule to a carrier. Even if the skilled person had contemplated such a direct attachment they would not have considered either omitting the step of freezing the mixture or omitting the use of a free-radical scavenger.

Even if document D16 were considered to represent the closest prior art, the claimed invention was not obvious. Document D16 did not disclose in one place a method similar to that now claimed. To arrive at the closest starting point, the skilled person would have had to make the deliberate choice of using a non-soluble support material instead of the preferred soluble one. They would have had to omit the step of lyophilisation which was described in document D16 as a pivotal step prior to sterilisation, and they would have had to select silanes from a choice of over 20 different activating agents instead of the preferred activator epichlorohydrin.

Based on the disclosure of D16 as a whole, it was only with hindsight that one could come to the conclusion that the skilled person might have considered combining all the different parts of the disclosure of document D16 in order to arrive at the present invention.

Furthermore, document D16 did not disclose any examples of a sterilised composition. Sterilisation was only disclosed in the context of a lyophilized powder, i. e. a composition that has been additionally protected by a step of freeze-drying, a step which was neither contemplated nor encompassed by the presently claimed methods. Thus, the skilled person, reading document D16 would not have contemplated sterilising a non-freeze dried carrier.

XI. The arguments of appellant II, relevant to the decision, are summarised as follows:

The opposition division's finding of lack of inventive step of the subject-matter of claim 1 of the main request and auxiliary request 1 was agreed with. However, it was inexplicable why the opposition division had considered the subject-matter of claim 1 of auxiliary request 2 to meet the requirements of Article 56 EPC, since this subject-matter was in fact identical to the subject-matter of the main request except for the change of "comprising" to "consisting of". This change however did not affect the outcome of assessment of inventive step. The subject-matter of claim 1 of auxiliary request 2 thus did not meet the requirements of Article 56 EPC for the reasons given in the decision under appeal for claim 1 the main request.

In more detail, document D16 disclosed a method for the production of a solid support material on which avidin was immobilised (see e.g. claim 7) and which included a protectant (bulking agent). This agent could be maltose (see page 5, final paragraph and Example 1). This material was also disclosed as suitable for sterilisation (see e. g. claims 33 and 34). Document D16 could be taken to represent the closest prior art for the claimed subject-matter since it was from the same technical field as the claimed invention and the method disclosed therein was similar to that claimed in terms of the steps to be carried out and their order. The opposition division was correct to hold that the only difference between the claimed subject-matter was the exact concentration of silane used, i. e. 0.1 to 10% (w/w or v/v). As also correctly identified by the opposition division this difference had no technical consequences as it represented the entire potentially useful range. Starting from document D16, the objective technical problem was merely to determine a useful range of silane concentrations. The claimed range was easily determined by the skilled person and could not impart an inventive step on the claimed subject-matter.

If instead of the disclosure of document D16 as a whole, only Example 1 of document D16 were chosen to represent the closest prior art, then the difference between it and the claimed method lay in the mode of chemical activation of the solid carrier (silane instead of epichlorohydrin) and in the subsequent sterilisation of the product. A potential problem derivable from this difference was the provision of an alternative sterile carrier coated with a biological material. The claimed solution was obvious because document D16 suggested the use of silane as a chemical activator of the carrier (see pages 9 and 11) and the sterilisation of such a product: "Thus, the affinity of the avidin for biotinylated biomolecules is maintained even after these rigorous processing steps, i.e., lyophilization and/or terminal sterilization" (see page 4, second paragraph). It was clear from this passage that sterilisation was contemplated both with and without the freeze drying step. It followed that the subject-matter of claim 1 of auxiliary request 2 and hence that of claim 1 of both the main and auxiliary request 1 lacked an inventive step.

XII. Appellant I requested in writing that the decision under appeal be set aside and that the patent be maintained on the basis of the claims of the main request, or, alternatively of auxiliary request 1, both filed with the statement of grounds of appeal.

Alternatively, it was requested that the appellant II's appeal be dismissed (auxiliary request 2).

Further alternatively, appellant I requested that the case be remitted to the opposition division for further prosecution on the basis of one of auxiliary requests 3 to 10, or that the patent be maintained on the basis of the claims of one of auxiliary requests 3 to 10, and a description to be adapted thereto.

XIII. Appellant II requested that appellant I's appeal be dismissed, the decision under appeal be set aside and the patent be revoked. It was further requested that auxiliary requests 3 to 10 not be admitted into the appeal proceedings.