Patenting Antibodies in Canada

Antibodies represent a significant slice of the biotechnology market. Global sales of monoclonal antibodies – for use as therapeutics, diagnostics or as reagents in research – totaled approximately $35 billion in 2008 and grew to $55 billion in 2010, wherein the top 5 brands had sales of over $5 billion each.

This remarkable growth is likely to continue given the increasing number of antibodies receiving market authorization by the various regulatory agencies. For example, the U.S. Food and Drug Administration approved4 new therapeutic monoclonal antibodies in 2009, while the European Medicines Agency approved a record-setting7. Even more telling is that over 200 antibodies were working their way through the various stages of a clinical trial in the United States in 2008. This upcoming flood of antibody products is likely to push global revenues to new heights.

Manufacturers of innovative antibody products, like other segments of the pharmaceutical industry, must constantly guard against infringing products. Given the financial stakes involved, it is imperative that innovators protect their intellectual property as much as possible, for as long as possible, in order to realize the maximum return on their investment. Weakened patent portfolios from a lack of timely and sustained capital has been cited as one of the barriers to successful commercialization of biotechnology in Canada. A poignant reminder of the value of a properly drafted patent comes from a recent case in the U.S. In Centocor Ortho Biotech, Inc. v. Abbott Labs a jury award of $1.67 billion for patent infringement was overturned by a panel of the Federal Circuit when it found the antibody claims to be invalid.

A patent fences off the invention so that others know where they may not trespass. The invention is defined by the claims which essentially gives the inventor or patent owner the right to exclude others from making, using or selling the invention for a limited period of time – which for most countries is 20 years from the filing date. The claims must be considered novel, inventive and useful over what has been disclosed in the prior art. The claims must also be sufficiently supported by the disclosure provided in the patent application upon filing. The disclosure must also fully and correctly describe the invention such that it would enable one of skill in the art to make and use the invention as claimed.

In the recent decision of Re Immunex Corporation Patent Application No. 583,988 (hereinafter, “Immunex”), the Patent Appeal Board (PAB), in seeking consistency with other common-law jurisdictions, adopted the principles established in U.S. and U.K. courts that an applicant may claim monoclonal antibodies immunoreactive with a specific antigen without an antibody having actually been prepared, provided that the antigen is a novel polypeptide that has been well-defined, for example, by its structure, formula, chemical name, or physical properties, or by depositing the protein in a public depository. Immunex’s patent application was filed on November 24, 1988, with claims directed to monoclonal antibodies immunoreactive with IL-1R polypeptides, as well as antibodies claimed in a product-by-process format. The antibody claims were originally rejected by the patent examiner because such an antibody had not been produced by the filing date. The main issue was whether these claims were sufficiently supported by the description. In addressing this issue, the PAB considered whether the claims were enabled, adequately described and had utility.

Enablement

Methods for producing polyclonal antibodies have long been recognized by the Canadian Intellectual Property Office (CIPO) as sufficiently well-established such that they do not

need to be described in detail to be enabling. Where an applicant had not prepared polyclonal antibodies at the time of filing, the description may still be enabling, provided that there is nothing peculiar about the antigen or any indications that would affect the likelihood of producing the claimed polyclonal antibodies by one skilled in the art.

However, prior to Immunex, claims to monoclonal antibodies were rejected unless the applicant had prepared an antibody at the time of filing. Unfortunately, this practice was based on an old decision by the PAB in Re Institut Pasteur Application (hereinafter, “Pasteur”), which held that the basic hybridoma techniques for producing monoclonal antibodies were not sufficiently well-established in the mid-1980’s such that a mere reference to it would not be enabling. CIPO continued to apply this decision until January 2009 when the Manual of Patent Office Practice (MOPOP) was amended and CIPO acknowledged that monoclonal antibody production technology had become so routine that the protocol need not be described in detail to be enabling. Nevertheless, CIPO maintained that in certain circumstances, possession of a working example was still pertinent to enablement, for example, where there were indications that suggest undue experimentation or undue adaptation of known procedures to overcome some difficulty in making a monoclonal antibody.9

In Immunex, the PAB found that there were two types of IL-1 receptors, Type I and Type II, which were antigenically different. However, the description in the application was only directed to a Type I receptor. Accordingly, the monoclonal antibody claims to any IL-1R polypeptide was not enabled across its scope since the task of isolating a Type II receptor for use as an immunogen would have been an undue burden. Fortunately for Immunex, the PAB was also of the opinion that the antibody claims would be enabled if they were appropriately limited to Type I IL-1R polypeptides and invited Immunex to make the necessary amendments to limit the claims to an antibody that binds to a Type I receptor.

CIPO typically rejects the submission of post-filing data to support that the description was enabling at the time of filing. However, the PAB in Immunex was willing to accept that post-filing data may provide an indication that the description was enabling since the claimed monoclonal antibody was produced without requiring undue burden by following a protocol very similar to the one described in the application.6

Enablement can still be an issue in Canada when the claims are directed to humanized antibodies. Claims to humanized antibodies were rejected in a recent case with the PAB citing the lack of a working example. In addition, it found that merely providing access to a mouse antibody would not have enabled the skilled person to make a humanized antibody from it given the nascent state of antibody humanization technology as of that application’s 1990 filing date. However, an argument can be made that producing humanized antibodies from a given mouse antibody would not be an undue burden today given the wide-spread use of this particular antibody technology.

Written Description

Subsequent to the Pasteur decision,10 CIPO would reject claims to a monoclonal antibody as lacking a sufficient description unless an

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antibody had been prepared at the time of filing. In the 2009 amendment to MOPOP, CIPO did state that where a monoclonal antibody was not prepared, the applicant was required to provide an explicit description of the epitope to which the monoclonal antibody binds, for example, in terms of a binding pocket defined by specific noncontiguous amino acids.9 In Immunex, the PAB held that the novel Type I IL-1 receptor was adequately described by the provision of a DNA sequence encoding such a receptor.6 In these circumstances, an applicant need not possess a monoclonal antibody immunoreactive with the novel polypeptide at the time of filing in order to fulfill the written description requirements.

A working example may still factor into whether the written description is sufficient in cases where the antigen is complex or where the antigen, although novel, may be cross-reactive because it possesses an epitope common to a known antigen. In addition, claims reciting therapeutic or diagnostic antibodies, or claims reciting antibodies with special attributes, would require correspondingly detailed support.6 The position of the PAB on these issues was arrived at with guidance from seminal decisions in the U.S. For example, in Centocor, the Federal Circuit held that “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-a with A2 specificity, can result in a claim that does not meet written description even if the human TNF-a protein is disclosed because antibodies with those properties have not been adequately described”.5 In Noelle v. Lederman,7 the same court held that an applicant may not claim an antibody that binds to a genus of polypeptides if only one species of the genus has been described. In that case, claims to a genus of CD40CR antibodies were not supported sufficiently by simply describing mouse CD40CR antigen. In another U.S. case, it was held that an applicant may not claim a broad family of antibodies if the antigen is complex or poorly-defined and where the specification “teaches nothing about the structure, epitope characterization, binding affinity, specificity, or pharmacological properties common to the large family of antibodies”.

utility

In Immunex, the issue of whether the claimed monoclonal antibodies had utility was also addressed. The PAB held that it would have been apparent that an anti-Type I IL-1 receptor monoclonal antibody would at least be useful in assays for immunopurification of IL-1 receptor polypeptides.6 However, if the patent promises a specific result, such as monoclonal antibodies with therapeutic benefits against a particular disease, then the invention must accomplish that result in order to demonstrate utility. Evidence as to demonstrated utility can be provided during court proceedings as opposed to in the patent itself. However, the disclosure must at minimum make reference to a study demonstrating utility.

Synopsis

Patent protection for novel antibodies should be sought as soon as possible in order to preserve their full commercial potential. However, applicants must take care to ensure that claims to antibodies are well-supported in the application. While it is preferable to have a working example in hand before filing, applicants may now be able to claim antibodies directed to a novel polypeptide in Canada without having produced one, provided that the target polypeptide is welldefined, for example, by its full amino acid sequence. Where a working example is produced without undue experimentation after the filing date, it may be used to argue that the specification was enabling. Sufficiency of support for antibody claims would benefit from prophetic examples and detailed protocols, especially where the technique used is not well-established, for example, antibody humanization, or where routine procedures were modified. For the purpose of providing support, monoclonal antibodies should be characterized as much as possible (i.e. epitope mapping, functional properties) before filing, especially if they bind to complex antigens. If you wish to claim a therapeutic use for the antibody then some evidence of therapeutic utility should be provided.

The Immunex decision certainly is helpful to innovators of novel antibodies and finally puts Canada in line with other countries.

references:

1. Antibodies represented over 30% of the biotechnology market in 2008; see https://www.leaddiscovery.co.uk/ reports/1494/Monoclonal_Antibody_

Therapeutics_20092024. 2. http://knol.google.com/k/krishan-maggon/top-ten-monoclonal-antibodies2010/3fy5eowy8suq3/143#. 2. J.M. Reichert, “Monoclonal Antibodies as

Innovative Therapeutics”, Current Pharmaceutical Biotechnology, 2008, 9:423-430. 4. http://www.ic.gc.ca/eic/site/trm-crt. nsf/eng/rm00395.html. 5. Centocor Ortho Biotech, Inc. v. Abbott

Labs, 2010-1144 (Fed. Cir. Feb. 23, 2011). 6. Re Immunex Corporation Patent Application No. 583,988 (2011) 89 C.P.R. (4th) 34. 7. Noelle v. Lederman, 69 U.S.P.Q. 2d 1508 (Fed. Cir. 2004). 8. Eli Lilly & Co. v. Human Genome Sciences

Inc, [2008] EWHC 1903 (Pat), aff’d [2010]

EWCA Civ 33. 9. Manual of Patent Office Practice [MOPOP], ch. 17, available at http://www.ic.gc.ca/ eic/site/cipointernet-internetopic.nsf/ eng/h_wr00720.html. 10. Re Institut Pasteur Application (1995), 76

C.P.R. (3d) 206. 11. Re Sloan-Kettering Institute for Cancer

Research Patent Appn. No. 2,072,017 (2009) 82 C.P.R. (4th). 12. In re Alonso, 88 U.S.P.Q. 2d 1849 (Fed. Cir. 2008). 13. Novopharm Ltd. v. Pfizer Canada Inc. et al., 2010 FCA 242.

Micheline Gravelle, M.Sc. (Immunology), is a partner with Bereskin & Parr LLP and head of the firm’s Biotechnology & Pharmaceutical practice group. She is also a registered Canadian and U.S. patent agent. Micheline can be reached in Toronto at 416-957-1682 or mgravelle@ bereskinparr.com.

Sie Lung Tjew, M.Sc. (Microbiology & Immunology), J.D., is a Student-at-Law at Bereskin & Parr LLP. He can be reached in Toronto at slungtjew@bereskinparr.com.

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