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“A vague patent registration of new platform, PROTAC, may meet with failure.”

26 Dec 2022
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The Korea Research Institute of Chemical Technology (KRICT), etc. started its researches... Acquisition of rights to platform-level differs from country to country


I participated as a patent consulting agency at Interbiz held in Jeju Island in early July, this year. The management staff who worked hard on quarantine in the midst of COVID-19 are still vivid in my memory even after about 4 months. In addition, I would like to share a story based on anecdotes which occurred at that time. At a drinking party on the last night of 2 night/3 day schedule, a close patent attorney said that he was hearing about PROTAC everywhere and asked a question, “Do you know what PROTAC is?” Getting intoxicated, I remember giving ridiculous answers. “Isn’t it something like grabs the collar and beats the other" In fact, I had studied PROTAC before, and I thought it was a very attractive technology in the world of low molecular weight compound.


It is undeniable that the mainstream of drug development in the past was low molecular weight compound, but the center of gravity has already shifted to biomedicine including antibodies. By the way, when monitoring recent technology trends, it seems that ADC (Antibody-Drug Conjugate) and the aforementioned PROTAC (Proteolysis-targeting Chimera) are emerging as breakthroughs in low molecular weight compounds.


Let's look at ADC for a moment. When I wrote an editorial in September 2019 (Hit News, “GSK-Roche could not develop independently, either... What is the patent strategy for ADC medicine?”), there were only a handful of ADC medicines approved at that time. However, ADC has recently regained a lot of attention. For just two years from 2019 to 2020, five drugs were approved by the FDA as follows: ① Polivy (Genentech), ② Padcev (Seattle Genetics/Astellas), ③ Enhertu (AstraZeneca/Daiichi Sankyo), ④ Trodelvy (Gilead/Immunomedics), ⑤ Blenrep (GSK). Considering the development status of global big pharmaceuticals, new ADC medicine is expected to appear steadily in the future. Since we have already dealt with ADC once, we will only comment on updating the current status, and discuss PROTAC emerging in the field of low molecular weight compounds.


Do you know what PROTAC is?


PROTAC (Proteolysis-targeting chimera) is not a name representing related technologies, but is the platform name of Arvinas, a leader in the TPD (Targeted Protein Degrader) field (however, since PROTAC is commonly used as a proper noun in the industry, hereafter expressed as “PROTAC”). PROTAC compound refers to a “bifunctional” compound composed of 3 functional moieties (① E3 ligase binder, ② Target protein binder, and ③ a linker connecting the two) as shown in the figure below:

Mechanism of PTOTAC


Specifically, PROTAC compound has E3 ligase-binding ligand (purple) and target protein ligand (pink) bound to E3 ligase and target protein, respectively, and induces ubiquitination of target protein by collecting E3 ligase and target protein to a close location artificially, and plays a role to decompose them. Therefore, it can remove the undruggable target which the existing low molecular weight compound could not access, emerging as a strategy which can overcome the tolerance of drug already developed.


Because PROTAC compounds can theoretically target any disease protein in the human body, it is very important appropriately select target protein ligand moiety to design PROTAC.


Development of PROTAC


The first concept of PROTAC was presented in a 2001 PNAS paper by team of Professor Crews, etc. at Yale University in the United States. However, early PROTAC had a peptide structure, not a low-molecular weight compound, so there was a limitation in penetration into the cell. Thereafter, in 2012, team of Professor Crews succeeded in synthesizing a novel low molecular weight compound (VHL binder) which binds to E3 ubiquitin ligase called VHL (von Hippel-Lindau) and applied for a patent (International Application No. PCT/US2013/021136).


After that, Arvinas, founded by the team of Professor Crews, was listed on the US NASDAQ for the first time (in 2018) as a PROTAC-specialized company, and in 2019, started phase 1 clinical trials of PROTAC for metastatic prostate cancer (ARV-11) and breast cancer (ARV-471). The clinical results of the above pipeline are expected to be accepted as the yardstick for success chance in the PROTAC field.


In the meantime, after the fact that a thalidomide-based compound binds to VHL and another E3 ubiquitin ligase, cereblon, was known in 2010, the development of PROTAC compounds by use of thalidomide-based drugs began on a full scale centering on James Bradner Research Team (later C4 Therapeutics) of Dana-Farber Cancer Institute (DFCI), USA, in 2015. In addition, cIAP, MDM, etc. have been developed as E3 ligases which can be used as a binding target of PROTAC, but there are not many types yet.


After the development of low molecular PROTAC began on a full scale in 2015, PROTAC attracted attention as having the potential to become a mainstream drug group comparable to protein kinase inhibitors and monoclonal antibodies (Scudelari, Nature 2019). Currently, U.S. biotech companies including Arvinas, C4 Therapeutics, Kymera, and Nurix are spurring the development of PROTAC, and global big pharmaceuticals are also showing great interest (if commercialization comes into view, like at phase 2 or phase 3 clinical trials, pipeline acquisitions through M&A are likely to occur as in the case of CAR-T). In Korea, it is investigated that the Korea Research Institute of Chemical Technology (KRIC) and some companies are researching and developing PROTAC.


How should PROTAC invention be registered?


The original technology for PROTAC invention was applied provisionally in 2011 by the team of Professor Crews at Yale University, who newly discovered the VHL binder. With the international application (International Application No. PCT/US2013/021136) based thereon, Yale University applied for a patent in major countries in the pharmaceutical industry, including the United States, Europe, China, Japan, and Korea.


Yale University's above patent described only the novel VHL E3 binder in examples, and the specific target protein ligands and linkers of PROTAC manufactured through this were described in a very limited manner. Nevertheless, Yale University described in claims all PROTAC compounds using these through the novel VHL E3 binder. Because this covers unknown target compounds which may be developed in the future as well as drugs known for all conceivable disease targets, whether such a platform patent should be granted was an issue discussed during the examination process.


The issue of deciding how far a platform patent should be acknowledged is intricately intertwined with problems as to what extent the reproducible range of a person skilled in the art should be acknowledged from the experimental contents and how far the exclusive rights should be allowed compared to the contribution of the inventor, and each country's political perspectives on development (whether it is an advanced country in new drugs) is also relevant in a certain part.


As a result, the above-mentioned platform patent registration was successful in the United States (considering the fact that Avinas is a U.S. company and the examination trend in the United States which broadly protects platform technology, Avinas' patents were likely to be registered in a wide range). However, unlike the United States, in Europe, the acquisition of rights on platform-level have not been granted, and it has not yet been registered. In the meantime, in Korea, its registration was granted only after the scope is narrowed to PROTAC format specifically described in the specification, not the platform-type PROTAC.


As mentioned above, it is quite difficult to predict how far the acquisition of rights to inventions of PROTAC may be acknowledged in the current situation where the practical business of major countries has not yet been clearly established. In the end, it seems safe to work out an application strategy after understanding PROTAC technology and investigating the examination trends in major countries scrupulously. It is safer to do so not to meet with failure by pushing ahead an application without abundant examples with a vague expectation that it can be registered in a wide range.

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