1 May 2010BiotechnologyCaroline Pallard

The risk of narrow protection

A peptide can be used, for example, as a vaccine, while an oligonucleotide can be used to silence a given gene whose expression product is involved in the development of a disease. Normally, biotechnology patent applications disclose a high number of peptides or oligonucleotides. The applicant usually follows this strategy in order to reduce the filing costs by gathering several peptides/oligonucleotides in a single application.

However, this is not without risk, since at the time of filing the application, the applicant may not yet know which peptides or oligonucleotides will prove to be the most promising. This article gives an overview of some of the problems encountered in Europe by this type of patent application.

Lack of unity

A lack of unity of invention decision is often formulated during the international phase of this kind of application, which means that each peptide/oligonucleotide needs to be seen as a single invention. As a consequence, each peptide/oligonucleotide can only be protected in one distinct divisional European patent application, which results in a dramatic increase in the patent cost for the applicant.

Filing a European application fulfilling the requirements of unity of invention is becoming ever more important in view of a change in European law that came into force on April 1, 2010. Before the change, an applicant was allowed to file a divisional application as long as a parent application was still pending.

From April 1, the time limit for filing a European divisional application will be drastically reduced to two years after the issuance of the first European office action. It is expected that this time limit may not be long enough to provide the applicant the opportunity to determine which peptides/oligonucleotides are the most attractive.

It is therefore crucial to try to file European patent applications fulfilling the unity requirements.

The Patent Cooperation Treaty (PCT) rules defining unity of invention are as follows:

Rule 13.1 PCT states that:

“The international application shall relate to one invention only or to a group of inventions so linked as to form a single general inventive concept.”

Rule 13.2 PCT further defines the circumstances in which the requirements of unity of invention are considered to be met: there should be a technical relationship among those inventions involving one or more of the same or corresponding special technical features. In cases of peptides/oligonucleotides, the so-called Markush practice, which allows a group of alternative chemical compounds, applies, i.e. peptides/oligonucleotides are regarded as being unified where the following criteria are fulfilled:

  • Each of the peptides/oligonucleotides has a common property or activity, and
     
  • A common structure is present, i.e. a significant structural element is shared by all of the peptides/oligonucleotides.

It is therefore crucial to try to formulate a technical relationship between a group of peptides or oligonucleotides based on their structures/sequences. Does each peptide or oligonucleotide share a common motif? Is each of the peptides able to bind a given human leukocyte antigen (HLA) molecule? Is each of the oligonucleotides able to bind or hybridise a given stretch of ribonucleic acid (RNA)? Applicants should be aware that even if such a structural unifying feature can be found, if one member of the defined family is already known in the prior art, it will probably jeopardise the unity of the invention (i.e. a posteriori lack of unity).

The following paragraphs concern the disclosure in European patent application EP 97916104.9 (decision T1396/06) of HIV peptides that could be used as a vaccine. Several issues were discussed during the examination proceeding: inventive step, allowability of post-submitted evidence and sufficiency of disclosure.

Inventive step

Claim 1 of the main request reads:

“An immunogenic peptide of less than 15 amino acids residues, wherein the peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1, 2, 57-60, 71-74, 88-104, 108 and 109.”

It was known that each of the peptides of claim 1 were able to bind HLA-A3.2. The application discloses the identification of several HIV peptides comprising a specific motif for binding HLA-3.2. Subsequently, the application shows that the peptides able to bind HLA-A3.2 with a minimum binding affinity are also able to induce a cytotoxic T-lymphocyte (CTL) response in vitro. No in vivo data are present in the application.

The main request was held to be non-inventive. The board reasoned that:

  • Document 1 is the closest prior art: it discloses a method for identifying immunogenic peptides binding HLA-A2.1 and further discloses that HLA-A3.2 is the most frequently expressed HLA allele subtype of the Caucasoid population.
     
  • The differences between Document 1 and claim 1 are the identities of peptides and the identities of the HLA alleles bound by the peptides.

The board held that the problem solved by claim 1 is to provide immunogenic peptides binding HLAA3.2. The solution to this problem is provided by the peptides of claim 1.

The board used Document 4, which discloses an allele-specific motif for several human HLA molecules. The motif identified for HLA-A3.2 is the same as the one identified in the present application. Document 4 further suggests the use of these motifs to identify immunogenic peptides. The board held that the skilled person would be motivated to combine Documents 1 and 4 and would arrive at the invention of claim 1 with a “reasonable expectation of success”.

The appellant held that a high expenditure of work and time would be needed, and there was no absolute “certainty to succeed” and certainly no reasonable expectation of success.

The board stated that certainty of success is not required according to the jurisprudence of the boards of appeal, which makes a clear distinction between reasonable expectation of success and certainty of success.

“Even if such a structural unifying feature can be found, if one member of the defined family is already known in the prior art, it will probably jeopardise the unity of the invention”

The board referred to case T918/01, wherein it was held that if certainty of success were required in this type of application, then clinical trial results would be needed in the patent application, which would be unreasonable. In T918/01, the board held that reasonable expectation of success should be assessed on a case-by-case basis. A reasonable expectation of success is present when the prior art has rendered the invention “plausible”.

In T1396/06, the board held that a peptide as defined in claim 1 had been rendered plausible by the prior art cited. The only thing that needed to be done was to check that this peptide exists.

In T1396/06, the board therefore decided that the skilled person would have a reasonable expectation of success of finding immunogenic peptides as defined in claim 1 based on the teaching of Documents 1 and 4. Although the skilled person would have to carry out a “high expenditure of work” in trying to identify immunogenic peptides able to bind HLAA3.2, this work was no more than routine. Therefore, the main request was held to be non-inventive.

The fact that some of the peptides of the invention are able to bind HLA-A3.2 with a higher affinity did not modify the board’s conclusions.

Allowability of post-submitted evidence

The appellant submitted a further auxiliary request wherein claim 1 was limited to “an immunogenic peptide of less than 15 amino acids comprising SEQ ID NO:1”.

Post-published evidence was submitted showing that SEQ ID NO:1 was immunogenic in an animal model and in peripheral blood mononuclear cells (PBMCs) of HIV-infected patients expressing HLA-A3.

The post-published evidence was acceptable since it could be seen as supplementary evidence of the fact that a given peptide is immunogenic and not as the sole basis to establish that the application as filed solved the technical problem.

The board still held that this auxiliary request lacked an inventive step, since there was no evidence that peptides other than the one consisting of SEQ ID NO:1 would have such immunogenic effect and since other peptides falling within this request had already been found to be non-inventive.

Finally, a further auxiliary request limited to the immunogenic peptide consisting of SEQ ID NO:1 had been submitted. The board held that even if the skilled person was motivated to look for additional peptides comprising a given motif as identified in Document 4, it would not permit a conclusion on the reasonable expectation of success of providing the specific immunogenic peptide consisting of SEQ ID NO:1. Therefore, the auxiliary request protecting this specific peptide was considered inventive.

Sufficiency of disclosure

The board further held that although the present application did not contain any clinical trial of the peptide consisting of SEQ ID NO:1, a sufficient disclosure of a therapeutic application was provided in the patent application, since it was established that the peptide consisting of SEQ ID NO:1 had a direct effect on the metabolic mechanism specifically involved in the disease. This disclosure was further completedby post-published evidence that backs up the experimental data shown in the application. Therefore, the board concluded that this last request was sufficiently disclosed.

The applicant indeed provided experimental data concerning a single specific peptide. However, the cost of R&D is such that it is almost impossible for an applicant to finance experimental data in an animal model, let alone conduct a clinical trial for more than one specific peptide/oligonucleotide. The outcome of T1396/06 may be considered as quite disappointing for the applicant since only one single peptide was protected.

It cannot be excluded that third parties might design around the patent by using a peptide comprising SEQ ID NO:1. The future will show whether this decision will be further confirmed in Europe. However, it is already common practice in European patent applications protecting immunogenic peptides to request experimental data for each claimed peptide.

Conclusions

When drafting patent applications concerning peptides or oligonucleotides, we advise applicants to look for a structural unifying motif shared by each of the peptides or oligonucleotides to be protected. If such a motif cannot be found, it might be best to file an application for each peptide/oligonucleotide, depending on the number of peptides or oligonucleotides.

We further advise applicants to file a patent application comprising at least in vitro data in cell lines showing a first indication of a therapeutic effect of at least one given peptide/oligonucleotide, and preferably of several variants, in order to support broader claims that will be more difficult to design around.

It is however preferable to provide experimental evidence showing a therapeutic effect in an animal model or in patient-derived cell lines or tissues of at least one peptide or oligonucleotide as disclosed in the application. Post-published evidence may be submitted later to further support the presence of an inventive step of sufficient disclosure.

Caroline Pallard is a European patent attorney at N.V. Nederlandsch Octrooibureau. She can be contacted at: pallard@octrooibureau.nl