PROLOGUE TO THE SERIES
This manuscript is the first in a series that will feature international patent disclosures that claim drug repurposing for a range of diseases with common characteristics. The common feature in the present case is the formal categorization of the new target condition as a rare disease. Before featuring these documents, we shall first explain why this series focuses on patent documents instead of peer-reviewed papers, for which there are numerous reviews available for every field we will discuss.
Landscaping a specific area of the intellectual property (IP) space for scientific purposes, rather than for patentability or freedom to operate, requires a different set of background knowledge and search techniques compared to reviewing the same scientific field through peer-reviewed publications.
The purpose of submitting a manuscript to a peer-reviewed journal is to communicate a team’s latest research results and showcase them in the context of other groups’ work. In contrast, filing a patent application marks the beginning of a multi-year process that incurs substantial costs. This process is undertaken only if the applicant, usually not the inventor(s) but their university’s technology transfer office or company, believes that the invention’s potential could be exploited before patent protection expires 20 years after the first filing, also known as the priority date. While getting a patent granted is necessary, it is not sufficient to exploit the invention; however, it does suffice to prevent third parties from exploiting it. Some patent applications are filed solely for the purpose of exclusion, as part of a “patent wall” intended to strategically protect a larger estate. IP can also be used as a bargaining chip in negotiations, even if no actual patent has been granted yet. Therefore, what is disclosed in patent applications is often different from what is presented in manuscripts intended for peer review.
Although patent documents are available online for free, they are not as easily searchable as scientific journal contributions. Patent codes are used to index them, but these are organized around IP legalities rather than scientific content. While free text searches are possible, the characteristics of patent texts mean that a Boolean search will return many hits that must then be examined by experts to identify the relevant ones. It is important to note that there is no patent code for documents with drug repurposing content.
What is a PCT Patent Disclosure?
This series of IP landscapes relies on drug repurposing patent applications published by the Patent Cooperation Treaty (PCT) and represented in RepoScope, a knowledge base currently under development as part of the Horizon Europe project REPO4EU. The project will ultimately launch the Drug Repurposing Platform, a comprehensive open-access online service.
A PCT document is not yet a patent, but rather an international publication of a patent application. This application is typically filed first at a national or regional patent office and can be “internationalized” within 12 months of its original filing (the priority date). The international application is made public as a document, identified by a code in the format WO/[year of publication]/[serial number], as soon as 18 months have passed since the priority date.
PCT applications are considered the center of global patenting since almost every life science patent application follows this route to ultimately become an enforceable national and regional patent. It is important to note that, while the descriptive part of the invention will not change during the patenting process, not all claims made on this basis will survive. What claims are ultimately granted is decided by the patent offices, and very often what is granted is considerably narrower in scope than the original attempt.
INTRODUCTION TO RARE DISEASES
The current version of the World Health Organization’s (WHO) International Classification of Diseases (ICD-11) includes some 5500 rare diseases and their synonyms, although the actual number is probably close to 8000, and new ones are described constantly. At least 80% of these diseases have a genetic basis, and the majority of these affect children, lack a cure, and are ultimately fatal.
The WHO defines a rare disease as “a medical condition with a specific pattern of clinical signs, symptoms, and findings that affects fewer than or equal to 1 in 2000 persons living in any World Health Organisation-defined region of the world.” The European Union (EU) definition keeps the 1 in 2000 prevalence but excludes diseases that are not also life-threatening, chronically debilitating, or inadequately treated. The United States employs a slightly different definition based on the 1983 Orphan Drug Act (amended by the 2002 Rare Diseases Act which established the Office of Rare Diseases at the National Institutes of Health), which requires less than 200,000 individuals in the United States to be affected; based on the 2020 census, this amounts to a prevalence of 1 in 1657.Our discussion will use the WHO definition of rare diseases.
Rare diseases would mostly not provide sufficient economic incentive for pharmaceutical companies to develop and market drug treatments. Unless premium prices can be charged (which is more difficult for repurposed agents than for new chemical entities), a prevalence of >10–30,000 patients in Europe or the United States is deemed viable from a business perspective by most companies. Governments in all major pharmaceutical markets have implemented initiatives to make such developments attractive by offering reduced regulatory fees, regulatory market exclusivity in addition to any exclusivity based on patents, and tax credits. 1 There are additional incentives with a broader scope, only two of which shall be mentioned here. The European Expert Group on Orphan Drug Incentives was formed in 2020 to develop policy proposals to facilitate EU policy makers to meet rare disease challenges. 2 The US Food and Drug Administration (FDA) has established and funded the Rare Disease Cures Accelerator-Data Analytics Platform to collect and share disease prevalence, patient selection, disease progression, and any data projecting likelihood of patient response to therapy including any genetic data. 3 Such efforts have been met with success, as shown by regulatory submissions, which can use abbreviated paths such as the §505(b)(2) path provided by the FDA, and also by patenting.
Landscaping the rare disease patent space presents some specific problems. Most rare diseases are known by synonyms, often by several ones. Moreover, several subtypes have been described for the majority of genetically defined rare diseases. This has caused development of specialized ontologies, such as the Orphanet Rare Disease Ontology. However, the much more general Medical Subject Headings (MeSH), according to which the PubMed peer review literature is indexed, and the Disease Ontology (which semantically integrates and extensively cross-maps its terms to the MeSH, ICD, NCI thesaurus, systematized nomenclature of human and veterinary medicine, and online mendelian inheritance in man ontologies) also serve well to give rare diseases unique identifiers. The present discussion is based on Disease Ontology identifiers.
METHODS
The RepoScope knowledge base is centered around PCT patent applications with drug repurposing content. It handles its entries in three main modules: conditions, compounds, and targets. Each condition, compound, or molecular target is a named entity that can be linked to other named entities in the same module, and also in any other module. Entries can be made in any module on which the patent document is centered (and thus seems to fit best), without compromising the linkage. Tags can be assigned to any named entity to create meaningful groupings. RepoScope does not differentiate between repurposing of an active pharmaceutical ingredient and drug repositioning (i.e., repurposing of clinical stage drug candidates or approved drugs to indications other than originally targeted), as both types of new uses will appear in PCT documents in the same way.
In our present work, we analyze the medical conditions with the #raredisease tag. This tag is applied only to documents addressing primary symptoms of at least one rare disease (e.g., chorea in Huntington’s disease); documents related to treatment of secondary symptoms (e.g., seizures in fragile X syndrome) are not included.
RESULTS
The RepoScope 2010–2023 data dump contains 190 unique repurposing-related PCT patent documents claiming utility in a total of 98 unique rare diseases (subtypes included under the umbrella term).
Time Course
The number of drug repurposing patent applications for rare diseases published through the international PCT system remained low between 2010 and 2016, with only about 5–10 such documents appearing per year. Activity started to take off in 2017 and has reached an average of 20 documents per year for 2020–2023. (Note that this reflects original priority filings made about 18 months earlier.) There was no drop in activity during the Covid-19 pandemic.
Statistics by Applicants
Looking at the size and type of applicants, 41% of applications were filed by small and medium corporate entities while 34% came from universities. Hospitals of any type contributed 5%. A remarkable 10% came directly from national authorities and institutions, such as the US Department of Health and Human Services or the French Institut National de la Santé et de la Recherche Médicale. These agencies have large budgets that put few if any limitations on their patenting activities. However, large pharmaceutical companies played a marginal role, filing no more than 3% of drug repurposing patent applications for rare diseases. The remaining 7% were filed by individual inventors whose affiliation at the time of filing could not be immediately determined.
By nationality, 33% of applicants were based in the United States. The EU (excluding the United Kingdom) contributed about the same share, 35%. Among the EU member states, France was the clear leader, with Spain a distant second. The United Kingdom had a relatively strong position on its own, to a good part because of the rare disease repurposing company, Healx. At 17%, Asian applicants (almost evenly distributed between China, Korea, and Japan) were comparatively underrepresented in terms of PCT disclosure numbers.
Snapshots of Patent Documents for Selected Rare Disease Groups
Tables 1 and 2 present the complete lists of drug repurposing patent applications for two important classes of rare diseases: lysosomal storage disease (14 documents) and muscular dystrophies (19 documents).
PCT Patent Disclosures Claiming Repurposing for Lysosomal Storage Diseases, 2010–2023.
| Patent Code | Compound(s) | Approved Use(s) | Claimed New Uses | Assignee |
|---|---|---|---|---|
| WO/2022/159086 | Gemfibrozil | Dyslipidemia | Krabbe disease | Rush University Medical Center (US) |
| WO/2021/116487 | Amrinone, nicainoprol, piboserod | Various | Niemann–Pick disease type C1 | SOM Biotech (ES) |
| WO/2020/168294 | Ambroxol | Mucus liquefaction | Mucopolysaccharidosis type III | Lysosomal and Rare Disorders Research and Treatment Center (US) |
| WO/2018/183940 | Sobetirome | Discontinued dyslipidemia and obesity candidate | Niemann–Pick disease | Neurovia (US) |
| WO/2016/038616 | Memantine, ifenprodil | Alzheimer disease, cerebral vasodilation | Neuropathic Gaucher disease | Yeda R&D (IL) |
| WO/2015/188037 | Ataluren | Duchenne muscular dystrophy | Mucopolysaccharidosis type I | PTC Therapeutics (US) |
| WO/2015/011284 | Repaglinide, pranlukast, zafirlukast, benzbromarone | Various | Fabry disease, Gaucher disease | Fondazione Telethon (IT) |
| WO/2015/097088 | Bicalutamide | Prostate cancer | Lysosomal storage diseases | BCN Peptides (ES) |
| WO/2015/049471 | Odiparcil | Discontinued antithrombotic candidate | Mucopolysaccharidosis type VI | Inventiva Pharma (FR) |
| WO/2014/143992 | Chlorotrianisene, clofoctol, tulobuterol | Various | Krabbe disease, Gaucher disease, metachromatic leukodystrophy | Rochester University (US) |
| WO/2014/022841 | Cyclodextrins | Inclusion agents in >30 drugs | Niemann–Pick disease type C1 | DHHS (US) |
| WO/2013/016315 | Avasimibe | Discontinued dyslipidemia candidate | Niemann–Pick disease | Dartmouth College (US) |
| WO/2012/094600 | Dihydropyridine Ca channel blockers | Hypertonia, heart disease | Gaucher disease, etc. | William Marsh Rice University (US) |
| WO/2011/109448 | Antiandrogens (flutamide, spironolactone, etc.) | Prostate cancer, hypertonia | Fabry disease | Baylor Research Institute (US) |
DHHS, US Department of Health and Human Services; PCT, Patent Cooperation Treaty.
PCT Patent Disclosures Claiming Repurposing for Muscular Dystrophies, 2010–2023.
| Patent Code | Compound(s) | Approved Use(s) | Claimed New Uses | Assignee |
|---|---|---|---|---|
| WO/2023/244738 | Pioglitazone | Type 2 diabetes | Duchenne muscular dystrophy | Johns Hopkins University (US) |
| WO/2023/175010 | Bazedoxifene | Osteoporosis | Limb girdle muscular dystrophy | Genethon, Inserm, etc. (FR) |
| WO/2023/073134 | Bosentan | Pulmonary arterial hypertension | Duchenne muscular dystrophy, facioscapulohumeral dystrophy | Association Institut de Myologie, Inserm |
| WO/2022/231257 | Oxiracetam | Nootropic | Duchenne muscular dystrophy | KSB Tugen (KR) |
| WO/2021/059270 | Mefenamic acid and related fenamate NSAIDs | Inflammatory pain | Various muscular dystrophies | Yissum R&D (IL) |
| WO/2019/084499 | Rebastinib, sorafenib, imatinib | Chronic myeloid leukemia | Facioscapulohumeral dystrophy | Genea Biocells (US) |
| WO/2018/177893 | Nintedanib | Idiopathic pulmonary fibrosis | Duchenne muscular dystrophy | Boehringer Ingelheim (DE) |
| WO/2017/013031 | Fluoxetine, vortioxetine | Depression, anxiety | Duchenne muscular dystrophy | Institut Pasteur, etc. (FR) |
| WO/2017/009644 | Sunitinib, vandetanib | Solid tumors | Facioscapulohumeral dystrophy | King’s College London (UK) |
| WO/2016/190697 | Exenatide | Type 2 diabetes | Duchenne muscular dystrophy | Immunoforge (KR) |
| WO/2015/189534 WO/2014/199171 | Benserazide | Parkinson’s disease | Duchenne muscular dystrophy | Proximagen (US) |
| WO/2015/050581 | Tadalafil | Erectile dysfunction, pulmonary arterial hypertension | Becker muscular dystrophy, Duchenne muscular dystrophy | Cedars-Sinai Medical Center (US) |
| WO/2015/022386 | Metformin, tetrahydrobiopterin with L-arginine or L-citrulline | Type 2 diabetes | Becker muscular dystrophy, Duchenne muscular dystrophy | Universitäts-Kinderspital beider Basel (CH) |
| WO/2014/190250 | Ataciguat | Discontinued candidate for peripheral artery disease and neuropathic pain | Duchenne muscular dystrophy | Johns Hopkins University, etc. (US) |
| WO/2014/180996 | 5-Azacytidine | Leukemias and myelodysplastic syndromes | Duchenne muscular dystrophy | Universität Heidelberg (DE) |
| WO/2012/067262 | G-CSF | Neutropenia, stem cell transplantation | Duchenne muscular dystrophy | Individuals (JP) |
| WO/2012/016930 | Amlexanox | Aphthous ulcers, inflammation | Duchenne muscular dystrophy | Université de Lille, etc. (FR) |
| WO/2010/010127 | Siponimod | Multiple sclerosis | Various muscular dystrophies and inclusion body myositis | Novartis (CH) |
NSAID, nonsteroidal anti-inflammatory drug; PCT, Patent Cooperation Treaty.
DISCUSSION
Tables 1 and 2 demonstrate the wide range of approved uses for drug repurposing patent applications in two representative rare disease categories: lysosomal storage diseases and muscular dystrophies. Lysosomal storage diseases are inherited metabolic disorders resulting from defects in lysosomal function or intracellular transport. Muscular dystrophies are caused by loss-of-function mutations in genes coding for essential muscle proteins, such as dystrophin. The original indication’s broadness reflects the diversity of well-established mechanisms and molecular targets. Only one case, ataluren, which is approved for the therapy of Duchenne muscular dystrophy and was claimed for mucopolysaccharidosis type I by its originator, has been approved for another rare disease.
The examples presented varying extents of data, and the evidence level also varied, as is typical with pharmaceutical patents. This is a natural consequence of the fact that patents are often filed in the early stages of development, especially in highly competitive settings. Applicants typically disclose only the required minimum and may have additional and/or more relevant data available at the priority date, which they could use during the examination process.
Seventy-five percent of all rare disease drug repurposing patents were filed by small and medium pharmaceutical companies or universities. Distinguishing between the two can be difficult, as small pharmaceutical companies often originate as university spin-offs founded to exploit inventions made by academic inventors at their universities. The limited interest of big pharmaceutical companies in drug repurposing, particularly in small markets, is reflected by their low representation. It is worth noting that national research institutions accounted for at least 10% of all applications. Additionally, it is possible that some of the 5% of applications filed by hospitals and their organizations were from public institutions, which were not distinguished from private hospitals and those attached to public universities in our count.
During the observation period from 2010 to 2023, approximately one-third of all rare disease drug repurposing patent applications published through the PCT system were contributed by both the United States and the EU. The dataset shows that the EU has a stronger position in patenting drug repurposing discoveries for rare diseases compared to general pharmaceutical patent applications. This observation is consistent with the period of 2011–2014. 4 In contrast, patentees from China, Korea, and Japan, who are respectable in the general pharmaceutical field, appear to have limited interest in patenting their drug repurposing discoveries for rare diseases. This is not in line with their much larger fraction of peer-reviewed manuscripts in this field. The question why Asian researchers translate a smaller fraction of their repurposing innovations to the international patent space would warrant closer investigation.
Our present study has limitations that are essentially those of the RepoScope database. Its entries are identified and validated through manual screening of the PCT database by a drug repurposing expert. As a result, its specificity for actual drug repurposing is close to 100%, but some documents with such content might have been missed if their title, abstract, and claim section are not suggestive of drug repurposing.
In summary, we find that most of the drug repurposing innovations in the rare disease field that result in international PCT patent disclosures are filed by small and medium corporations and universities, a significant part of which are situated in Europe or the United States. A highly diverse range of approved (or in some cases, discontinued) active pharmaceutical ingredients has been claimed for two representative rare disease classes: lysosomal storage disorders and muscular dystrophies.