- Email: [email protected]
Function prediction in BioPatents
UPDATE
BIOSILICO Vol. 1, No. 1 March 2003
POLICY DEBATE
Function prediction in BioPatents Robert Harrison, Huber & Schüssler Intellectual Property Attorneys,Truderinger Strasse 246, 81825 Munich, Germany; tel: +49 89 4377 880, fax: +49 89 4377 8899, e-mail: [email protected], web: www.huber-schuessler.com
Patent laws throughout the world insist that the function of a newly discovered biological material must be given in the specification. However, a recent decision by the European Patent Office (EPO) suggests that determination of the function by homology studies may, at least in Europe, not be adequate. The debate about whether patent protection should be granted for biological matter such as DNA sequences or proteins continues to rage. Despite these continuing discussions, all of the major patent offices of the world are now granting patent protection to biological material based either on their own interpretation of the existing law, court decisions or new laws. In the European Union (EU), for example, Directive 98/44 on the Legal Protection of Biotechnology Inventions [1] was passed in 1998 and obliged the member states of the EU to provide for protection under their national laws by 30 July 2000.At the time of writing (October 2002) only the UK, Denmark, Finland, Ireland and Greece had indeed implemented the Directive into their national laws.Although not bound by the Directive, the European Patent Office (EPO) implemented the provisions of the Directive concerning patents in 1999. Rule 23e of the European Patent Convention (EPC) states that ‘an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element’. However, the industrial application – or function – of a sequence or a partial sequence of a gene must be disclosed in the patent application [2]. If a function is not disclosed, then the application will be rejected. The EU Directive was clear on this matter. It stated,‘a mere DNA sequence
12
www.drugdiscoverytoday.com
without indication of a function does not contain any technical information and is therefore not a patentable invention’ [3]. Similarly, in the United States a patent can be granted on biological material as a composition of matter that is new and useful [4].The patent specification must also include details of a specific and substantial utility of the biological material.This specific and substantial utility must be credible [5]. Given the large number of new proteins and DNA sequences being discovered, determination of their function is no trivial matter.The growth in databases that contain details of the biological material together with their known functions for a wide variety of organisms has, however, enabled homology analysis to be performed to see whether similar material with a known function is found in other organisms.The results of such analysis might be used to illustrate the function of a newly discovered biological material and thus obtain patent protection. In the discussion concerning the drafting of the US Patent and Trademark Office’s new Guidelines for the Examination of (Biotechnology) Applications for Compliance with the Utility Requirement [6], one proposal put forward was to adopt a per se rule rejecting the use of homology studies to assert the utility of biological material. This proposal was, however, rejected. Instead, the US Patent Examiner was instructed to consider all of the evidence available to determine whether the utility given is credible [7]. In Europe, however, a recent decision by the EPO may have restricted this approach [8].
European Patent Opposition: GSK and Dophar versus ICOS European Patent No. 0 630 405 (assigned to the ICOS Corporation) claimed a purified
and isolated polynucleotide encoding the amino acid sequence of V28 seven transmembrane (7TM) receptor set given in a particular sequence or a fragment thereof and possessing at least one ligand-binding activity or immunological property specific to the V28 7TM receptor.The grant of the patent was opposed by two opponents, SmithKlineBeecham (now GSK) and Dophar International Research. One of the opponents argued that the patent specification was insufficient because the function of the V28 7TM was not disclosed. The patent specification disclosed both the nucleotide and the amino acid sequence of the V28 gene. However, it did not disclose a ligand that bound to the protein.The patent also claimed an antibody specific to the V28 7TM protein. However, the specification did not disclose any details of the antibody substance claimed. The receptor function was merely predicted based on the structural characteristics of the protein.At the time of the filing of the patent, a review of 74 proteins that belong to the superfamily of 7TM receptors had been published.The review disclosed the structural features of the proteins that included regions of high homology shared among all members of the family.The review also illustrated ligandbinding domains and the signal transduction coupling of said proteins. It was on the basis of this information, that the newly discovered protein was predicted by the Applicant to be a receptor. The patent specification also disclosed several methods by which a skilled person could verify that the protein is indeed a receptor. For example, methods for the identification of ligands were described.The Applicant argued that it is not necessary for the predicted function to have actually been demonstrated because – given the
1478-5282/03/$ – see front matter ©2003 Elsevier Science Ltd. All rights reserved. PII: S1478-5282(02)02220-1
UPDATE
BIOSILICO Vol. 1, No. 1 March 2003
POLICY DEBATE information available – the identification of the function falls within the routine procedure of persons skilled in the art. Finally, an article published three years after the filing date of the patent application demonstrated that the claimed protein was indeed a co-receptor for the HIV-2 virus. The EPO’s Opposition Division decided that the mere disclosure of the amino acid sequence of the V28 protein and the predicted function of the protein as a receptor in combination with the method disclosed for the identification of the ligand did not suffice to disclose a receptor protein.The Opposition Division therefore decided that the appropriate claims were invalid because at the date of filing of the application, the function had not been established, even though the predicted function was later shown to be correct. The Opposition Division also rejected the claims relating to an antibody to the V28 protein.The Opposition Division did not agree with the Applicant’s assertion that the generation of antibodies was routine in the art. It continued that the identification of such an antibody would require extensive laboratory work to determine that the protein had no cross-reactivity with further proteins. Furthermore, the Opposition Division concluded the identification of such antibodies necessitates the prior identification of the ligand or antiligand molecules or the binding site of said
molecules. None of these was disclosed in the application. The Applicant further argued that the patent was valid as the specification showed that the V28 protein could be made and that it could be used. Potential uses of the invention are, in the opinion of the Applicant, disclosed in the specification. However, the Opposition Division rejected this argument because all of the potential uses relied on the identification of the proposed function of the V28 7TM protein as a receptor.
Conclusions The decision in the European Patent Opposition was obviously a blow to the patent holder, who may have lost a potentially valuable patent. However, the implications are broader because the investment into the identification of potentially new proteins and sequences using in silico techniques is considerable [9]. Investors will clearly be looking for adequate protection for the intellectual property that their financial support creates.They will be hoping that the EPO uses a similar case in the future to reconsider its decision and follow US practice. Indeed, in a presentation at the Fifth Conference on Patent Law in the Field of Biotechnology, held on 12 November 2001, in Munich, an Examiner at the EPO – expressing his personal opinion – stated that structural similarity could be used to predict the function of proteins [10].
Acknowledgements The author would like to thank Andrea Schüßler (Huber & Schüssler Patent Attorneys, Munich, Germany) and Steve Yoder (Heller Ehrman White & McAuliffe, Washington, DC, United States) for their comments.
References 1 Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998, Official Journal 1998, L 213, p. 13 2 Art 5(3) of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998, Official Journal 1998, L 213, p. 13 and Rule 23e, Para. 3, European Patent Convention 3 Recital 23 of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998, Official Journal 1998, L 213, p. 13 4 35 U.S.C. 101 (US Patent Code) 5 US PTO Guidelines for Examination of Application for Compliance with the Utility Requirement, Sec. B, No. 2, Federal Register, Vol. 66, No. 4, 5 January 2001, pg. 1098 6 Federal Register, Vol. 66, No. 4, 5 January 2001, pg. 1092–1099 7 Comment 19 of the US PTO Guidelines for Examination of Application for Compliance with the Utility Requirement, Federal Register, Vol. 66, No. 4, 5 January 2001, pg. 1096 8 Official Journal Europen Patent Office, June 2002, 293–308 9 Dorey, E. (1999) Lion shares in informatics bonanza. Nat. Biotechnol. 17, 742–743 10 Claes, B. (2001) Examination of subject matter related to biological sequence information: function and speculation. In Proc. Fifth Conf. Patent Law in the Field of Biotechnol., Forum Institut für Management, Heidelberg, Germany
Do you want to reproduce material from BIOSILICO? This publication and the individual contributions contained in it are protected by the copyright of Elsevier Science. Except as outlined in the terms and conditions (see p. X), no part of BIOSILICO can be reproduced, either in print or in electronic form, without written permission from Elsevier Ltd. Please send any permission requests to: Elsevier Science Ltd PO Box 800, Oxford UK OX5 1DX
www.drugdiscoverytoday.com
13
BIOSILICO Vol. 1, No. 1 March 2003
POLICY DEBATE
Function prediction in BioPatents Robert Harrison, Huber & Schüssler Intellectual Property Attorneys,Truderinger Strasse 246, 81825 Munich, Germany; tel: +49 89 4377 880, fax: +49 89 4377 8899, e-mail: [email protected], web: www.huber-schuessler.com
Patent laws throughout the world insist that the function of a newly discovered biological material must be given in the specification. However, a recent decision by the European Patent Office (EPO) suggests that determination of the function by homology studies may, at least in Europe, not be adequate. The debate about whether patent protection should be granted for biological matter such as DNA sequences or proteins continues to rage. Despite these continuing discussions, all of the major patent offices of the world are now granting patent protection to biological material based either on their own interpretation of the existing law, court decisions or new laws. In the European Union (EU), for example, Directive 98/44 on the Legal Protection of Biotechnology Inventions [1] was passed in 1998 and obliged the member states of the EU to provide for protection under their national laws by 30 July 2000.At the time of writing (October 2002) only the UK, Denmark, Finland, Ireland and Greece had indeed implemented the Directive into their national laws.Although not bound by the Directive, the European Patent Office (EPO) implemented the provisions of the Directive concerning patents in 1999. Rule 23e of the European Patent Convention (EPC) states that ‘an element isolated from the human body or otherwise produced by means of a technical process, including the sequence or partial sequence of a gene, may constitute a patentable invention, even if the structure of that element is identical to that of a natural element’. However, the industrial application – or function – of a sequence or a partial sequence of a gene must be disclosed in the patent application [2]. If a function is not disclosed, then the application will be rejected. The EU Directive was clear on this matter. It stated,‘a mere DNA sequence
12
www.drugdiscoverytoday.com
without indication of a function does not contain any technical information and is therefore not a patentable invention’ [3]. Similarly, in the United States a patent can be granted on biological material as a composition of matter that is new and useful [4].The patent specification must also include details of a specific and substantial utility of the biological material.This specific and substantial utility must be credible [5]. Given the large number of new proteins and DNA sequences being discovered, determination of their function is no trivial matter.The growth in databases that contain details of the biological material together with their known functions for a wide variety of organisms has, however, enabled homology analysis to be performed to see whether similar material with a known function is found in other organisms.The results of such analysis might be used to illustrate the function of a newly discovered biological material and thus obtain patent protection. In the discussion concerning the drafting of the US Patent and Trademark Office’s new Guidelines for the Examination of (Biotechnology) Applications for Compliance with the Utility Requirement [6], one proposal put forward was to adopt a per se rule rejecting the use of homology studies to assert the utility of biological material. This proposal was, however, rejected. Instead, the US Patent Examiner was instructed to consider all of the evidence available to determine whether the utility given is credible [7]. In Europe, however, a recent decision by the EPO may have restricted this approach [8].
European Patent Opposition: GSK and Dophar versus ICOS European Patent No. 0 630 405 (assigned to the ICOS Corporation) claimed a purified
and isolated polynucleotide encoding the amino acid sequence of V28 seven transmembrane (7TM) receptor set given in a particular sequence or a fragment thereof and possessing at least one ligand-binding activity or immunological property specific to the V28 7TM receptor.The grant of the patent was opposed by two opponents, SmithKlineBeecham (now GSK) and Dophar International Research. One of the opponents argued that the patent specification was insufficient because the function of the V28 7TM was not disclosed. The patent specification disclosed both the nucleotide and the amino acid sequence of the V28 gene. However, it did not disclose a ligand that bound to the protein.The patent also claimed an antibody specific to the V28 7TM protein. However, the specification did not disclose any details of the antibody substance claimed. The receptor function was merely predicted based on the structural characteristics of the protein.At the time of the filing of the patent, a review of 74 proteins that belong to the superfamily of 7TM receptors had been published.The review disclosed the structural features of the proteins that included regions of high homology shared among all members of the family.The review also illustrated ligandbinding domains and the signal transduction coupling of said proteins. It was on the basis of this information, that the newly discovered protein was predicted by the Applicant to be a receptor. The patent specification also disclosed several methods by which a skilled person could verify that the protein is indeed a receptor. For example, methods for the identification of ligands were described.The Applicant argued that it is not necessary for the predicted function to have actually been demonstrated because – given the
1478-5282/03/$ – see front matter ©2003 Elsevier Science Ltd. All rights reserved. PII: S1478-5282(02)02220-1
UPDATE
BIOSILICO Vol. 1, No. 1 March 2003
POLICY DEBATE information available – the identification of the function falls within the routine procedure of persons skilled in the art. Finally, an article published three years after the filing date of the patent application demonstrated that the claimed protein was indeed a co-receptor for the HIV-2 virus. The EPO’s Opposition Division decided that the mere disclosure of the amino acid sequence of the V28 protein and the predicted function of the protein as a receptor in combination with the method disclosed for the identification of the ligand did not suffice to disclose a receptor protein.The Opposition Division therefore decided that the appropriate claims were invalid because at the date of filing of the application, the function had not been established, even though the predicted function was later shown to be correct. The Opposition Division also rejected the claims relating to an antibody to the V28 protein.The Opposition Division did not agree with the Applicant’s assertion that the generation of antibodies was routine in the art. It continued that the identification of such an antibody would require extensive laboratory work to determine that the protein had no cross-reactivity with further proteins. Furthermore, the Opposition Division concluded the identification of such antibodies necessitates the prior identification of the ligand or antiligand molecules or the binding site of said
molecules. None of these was disclosed in the application. The Applicant further argued that the patent was valid as the specification showed that the V28 protein could be made and that it could be used. Potential uses of the invention are, in the opinion of the Applicant, disclosed in the specification. However, the Opposition Division rejected this argument because all of the potential uses relied on the identification of the proposed function of the V28 7TM protein as a receptor.
Conclusions The decision in the European Patent Opposition was obviously a blow to the patent holder, who may have lost a potentially valuable patent. However, the implications are broader because the investment into the identification of potentially new proteins and sequences using in silico techniques is considerable [9]. Investors will clearly be looking for adequate protection for the intellectual property that their financial support creates.They will be hoping that the EPO uses a similar case in the future to reconsider its decision and follow US practice. Indeed, in a presentation at the Fifth Conference on Patent Law in the Field of Biotechnology, held on 12 November 2001, in Munich, an Examiner at the EPO – expressing his personal opinion – stated that structural similarity could be used to predict the function of proteins [10].
Acknowledgements The author would like to thank Andrea Schüßler (Huber & Schüssler Patent Attorneys, Munich, Germany) and Steve Yoder (Heller Ehrman White & McAuliffe, Washington, DC, United States) for their comments.
References 1 Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998, Official Journal 1998, L 213, p. 13 2 Art 5(3) of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998, Official Journal 1998, L 213, p. 13 and Rule 23e, Para. 3, European Patent Convention 3 Recital 23 of Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998, Official Journal 1998, L 213, p. 13 4 35 U.S.C. 101 (US Patent Code) 5 US PTO Guidelines for Examination of Application for Compliance with the Utility Requirement, Sec. B, No. 2, Federal Register, Vol. 66, No. 4, 5 January 2001, pg. 1098 6 Federal Register, Vol. 66, No. 4, 5 January 2001, pg. 1092–1099 7 Comment 19 of the US PTO Guidelines for Examination of Application for Compliance with the Utility Requirement, Federal Register, Vol. 66, No. 4, 5 January 2001, pg. 1096 8 Official Journal Europen Patent Office, June 2002, 293–308 9 Dorey, E. (1999) Lion shares in informatics bonanza. Nat. Biotechnol. 17, 742–743 10 Claes, B. (2001) Examination of subject matter related to biological sequence information: function and speculation. In Proc. Fifth Conf. Patent Law in the Field of Biotechnol., Forum Institut für Management, Heidelberg, Germany
Do you want to reproduce material from BIOSILICO? This publication and the individual contributions contained in it are protected by the copyright of Elsevier Science. Except as outlined in the terms and conditions (see p. X), no part of BIOSILICO can be reproduced, either in print or in electronic form, without written permission from Elsevier Ltd. Please send any permission requests to: Elsevier Science Ltd PO Box 800, Oxford UK OX5 1DX
www.drugdiscoverytoday.com
13