“Patent value of basic bioscience research in the settlement money between BMS and MSD"

26 Dec 2022
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BMS filed an application with data which have identified the correlation between PD-L1 and PD-1.

BMS concluded the lawsuit after receiving advance payment, etc. from MSD which has commercialized Keytruda.

Patents for blockbuster-class antibody drugs like Herceptin, Avastin, and Humira, etc. have recently expired. In preparation for this, original companies are releasing bio-better products which have improved existing antibodies, while spurring the development of new antibody drugs which will lead the new market.

In Korea, Companies including bioventures are steadily developing new antibody drugs including monoclonal antibodies, double antibodies, and antibody-drug conjugates (ADC), and some of them have attracted attention with successful clinical trials and technology export.

According to an investigation, it was identified that there are more than 2,000 antibody-related patents which exist in effect at the Korean Intellectual Property Office. In this editorial, the problems commonly encountered in the practical business of patent on the invention of antibodies are summarized.

◆ Instructions for description of an antibody patent specification

Compared to other fields, the bioscience fields often have problems with reproducibility. Therefore, the contents described in a patent specification should be such that the antibody can be reproduced without excessive experimentation.

In the case of a typical monoclonal antibody patent, method of acquiring antigens (or manufacturing method), method for manufacturing antibody-producing cells by using antigens, selection process of antibody, results of sequence analysis of selected antibodies, and specific experimental results on binding affinity (Kd) for antigen should be described. To further support the reproducibility, antibody-producing cell lines such as hybridomas may be deposited with a designated institution prior to filing an application.

In the case of biobetters, the antigen-binding site of an existing antibody with the same antigen is often improved. For these patents, the examiners of the Korean Intellectual Property Office tend not to acknowledge the inventive step only with sequence being different the existing antibodies because improved antibodies can be easily obtained through affinity maturation, etc. Therefore, it is desirable to describe in the specification data including technical characteristics (novel cross-reactivity, etc.) or superior effects (improvement in antibody binding capacity, decrease in immunogenicity, etc.) compared to existing antibodies.

◆ In principle, the CDR sequence in a variable region should be specified in the claims of antibody patent.

In principle, in the claims of antibody patent, the actually-manufactured antibody and the CDR sequence in a variable region (a total of six exists in heavy and light chains of variable region) should be described up to the same extent. It is not allowed to limit only to partial CDR region of actually-manufactured antibody, or expand the claimed CDR region by introducing the concept of sequence homology, etc. This is because it is difficult to acknowledge activities similar to original antibody unless a technical basis is presented (2001 Heo 1006; 2007 Heo 289; 2007 Heo 5116; 2007 Heo 10224 judgment, etc.).

In the meantime, in the practical business of patent, a constant region of antibody is required to be specified. Therefore, infringement can be questioned when antibodies with different isotypes or Fc regions or antibody fragments (Fab, F(ab)', scFv, etc.) as long as the CDR sequence in a variable region is identical.

◆ Antibodies characterized by antigens or epitopes may be granted broad rights

According to the principle of claim description as mentioned above, a patent evasion is possible if a competitor appropriately alters the sequence in a variable region of patented antibody. However, if the antigen to which the antibody binds or epitope itself is newly discovered, claims are legitimate only by claiming an antibody which binds to the antibody with the antigen or epitope.

For example, if a disease-specific mutant antigen is discovered or a novel epitope region of existing antigen is discovered, a question of infringement can be raised on all antibodies which bind to the antigen or epitope without specifying the sequence in a variable region of antibody individually.

The patent right registered in this way is very strong as it can often block even the sale of subsequent products in the field of target therapeutic antibody as well as its own product. AMGN's original antibody patent is a good example of this type of patent with Sanofi-Regeneron's hyperlipidemia medicine, Praluent (ingredient name: alirocumab) being recently litigated by AMGN in the United States, Europe, and Japan, etc.

AMGN claimed and obtained the registration of PCSK9 antibody, which limited only the specific epitope sequence of PCSK9 and did not have any sequence limitation on the antibody. Meanwhile, the case of alirocumab, which is the successor PCSK9 antibody of Sanofi-Regeneron is an infringement on AMGN’s patent as although the sequence information is not implied in AMGN's patent specification, it binds to the same epitope.

However, because the above patent allows monopoly on all future antibodies which bind to a specific antigen or epitope, the description requirements may always be controversial. Therefore, even when current practical business are followed, the description requirements are likely to be denied if it is unclear whether the actually-manufactured antibody represents the effects of all antibodies falling under the above definition.

Because the legal claim form of antibody patents and the standards on experimental data required therefor are flexible, it is necessary to closely monitor the changes in the interpretation of patent requirements established in each country's patent disputes.

◆ Patent value of basic research in the bioscience field

In the field of basic research, there are many cases where the correlation between biomarkers corresponding to antigens and diseases was identified for the first time. In this case, an antibody which binds to the antigen may be patented for pharmaceutical use.

Due to characteristics of bioscience, patent with enormous commercial value can emerge once it is confirmed that the biomarker is useful as a target for an actual drug. A representative example is the PD-1 antibody use patent applied by Professor Honjo and Ono Pharm.

This patent was filed based on basic data which identified the correlation between the inhibition of binding of PD-L1 expressed in cancer cells to PD-1 in immune cells and the anticancer effect. PD-1 antibody actually manufactured in the above patent specification was merely an antibody using the prior art. However, based on the fact that the patentability in the correlation between PD-1 inhibition and cancer treatment was acknowledged, and that it is a common art to manufacture an antibody for a target and inhibit the binding to a ligand even based on the art at the time, the registration was granted to the PD-1 antibody patent for anticancer use for the entire PD-1 antibodies which have not been limited to specific sequences.

BMS held the license in the United States and Europe for the above patent, and immediately filed a patent litigation as soon as its competitor, MSD, launched Keytruda (ingredient name: pembrolizumab), a PD-1 antibody cancer immunotherapy. In 2017, MSD agreed to pay an advance payment of USD 625 million and maximum 6.5% of Keytruda's global sales to BMS and Ono Pharm, and the lawsuit was concluded.

In Korea, most antibody patents are filed by universities or research institutes. The case of Keytruda lawsuit shows that the researches in bioscience field can be protected by original patents with enormous added value in the future.

In other words, it is necessary to carefully examine whether or not a patent owned or filed by a third party is not the original patent that covers the developed product. My product being protected by a patent is quite different from infringement on other companies' products.

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