Spotlight on mRNA – IP landscape

mRNA: a new era in genetic medicine?

08.10.2021

This article is the third in our five part series “Spotlight on mRNA: a new era of genetic medicine?”. You can find our first two articles here: ‘A brief history of mRNA research’ and ‘What is mRNA and what can it be used for?’.

Following the use of mRNA based vaccines against COVID-19, mRNA has been catapulted into the public eye and mRNA companies are enjoying staggering levels of growth and investment. The reason? mRNA has the potential to transform the future of medicine. Although we are still in relatively early days, exciting new developments in the field of mRNA research mean that applications researchers were dreaming of 30 years ago may soon become a reality. As we discussed previously, synthetic mRNA has the potential to be used not only as a vaccine for many infectious diseases, but also for use as a transformative therapy in cancer immunotherapy and in regenerative medicine. If the hype is to be believed, the possibilities are vast.

In our previous articles we took a closer look at what mRNA is and what it could potentially be used for, and also took a brief look at the history of mRNA research. Here we will look at the IP landscape around this promising technology. In future articles, we will review recent partnerships and deals in the mRNA space and examine how mRNA products are regulated.

A growing and complex IP landscape

The number of patents filed relating to use of mRNA as a vaccine for both infectious diseases and cancer has increased dramatically over the five years to 2020[1]. As we highlighted in our previous article, numerous companies and institutions are actively working in this field. It is not surprising then that the patent landscape is highly fragmented. Patent owners range from large multinational companies (such as GSK, Bayer and Boehringer Ingelheim), smaller biotech companies (such as Translate Bio) to universities and research institutions (such as University of Pennsylvania, where mRNA pioneers Katalin Karikó and Drew Weissman conducted their early research)[2].

The web of intellectual property that protects the mRNA candidates currently in development is complex and overlaid by a large network of partnerships and licensing arrangements. For the purpose of this article, we will briefly examine some of the IP that protects key aspects of the technology and look at some of the key players in the space. This article is based on publically available information only and is non-exhaustive; we do not propose here to dig deep into the extensive web of patent filings, partnerships and litigation.

There are a few companies leading the way in the mRNA field, each with market capitalisations in the multiple billion dollars. Moderna, BioNTech and CureVac are the largest of these and each have numerous mRNA products in their pipelines as well as large mRNA patent portfolios, valuable know how and key patent licences and partnerships in place. Companies such as Arcturus and Translate Bio also have significant presences in the market, along with market capitalisations over a billion dollars and multiple products in their pipelines. For the purpose of this article we will focus on these companies. However, this is by no means an exhaustive review and we expect more companies and research institutions focussed on mRNA to emerge in the future. We will be watching this space closely.

Platform technology

As outlined in part one of this article, one of the main advantages of synthetic mRNA is that it can operate as a platform technology such that, in simplistic terms, only the coding region of mRNA needs to be switched out in order to target a different indication. At a very basic level, the key elements of the mRNA platforms under development are (i) the genetic code which instructs ribosomes in cells to make the encoded protein (i.e. the coding region of the mRNA), and (ii) a delivery system (commonly, though not exclusively, lipid nanoparticles) which delivers the engineered mRNA into cells in the body.

There are a few key challenges that need to be overcome to develop a successful mRNA product. Firstly, it is crucial that the mRNA does not trigger an overactive response from a patient’s immune system. Second, the mRNA needs to be delivered into the host cells without first being broken down. Once that has been achieved, it is important to ensure the ribosomes inside a patient’s cells can read the mRNA correctly. Finally, it is important to ensure that a patient’s cells express enough of the protein encoded for by the mRNA to have a therapeutic effect. Companies active in the mRNA space are investing heavily into building and optimising their mRNA platforms to overcome each of these challenges. This has translated into significant focus on and patenting of mRNA sequence engineering and chemistry, delivery systems (including composition and chemistry of lipid nanoparticle delivery systems) and manufacturing processes.

Foundational mRNA

As we highlighted in our previous article, one of the key breakthroughs in the field of mRNA came in 2005, when discoveries made by Katalin Karikó and Drew Weissman at the University of Pennsylvania solved the issue of synthetic mRNA triggering an uncontrolled immune response in patients by modifying mRNA nucleosides[3]. The University of Pennsylvania owns a number of patents relating to nucleoside-modified mRNAs and their uses. Both Moderna and BioNTech’s COVID vaccines use a modified nucleoside approach and both companies have taken non-exclusive sub-licences of mRNA patents owned by The University of Pennsylvania (via a cascade of sub-licences from mRNA RiboTherapeutics and Cellscript)[4] [5]. Whilst these licences are non-exclusive, we understand that mRNA RiboTherapeutics and Cellscript are subject to certain time restrictions on granting additional sublicenses for in vivo uses in humans[6] and it is not clear whether any other companies operating in this space have been able to take licences to the University of Pennsylvania patents. In this regard, it is worth noting however that not all mRNA products under development use this nucleoside-modified approach. For example, CureVac’s COVID vaccine uses unmodified, natural mRNA[7].

The delivery system

The second key mRNA breakthrough has been development of delivery systems, which enable mRNA to be delivered into host cells before it is broken down by the body’s own defences. The most commonly used delivery system is lipid nanoparticles (LNPs). LNPs are used not only for mRNA therapies but also in gene editing technologies and this dual utility has led to significant investment and development time focussed on optimising the chemistry and safety of LNPs over the past few years.

Early work on LNPs was carried out by Canadian biotech Arbutus Biopharma Corporation in collaboration with the University of British Columbia[8]. Several companies have since taken licences of LNP patents owned by Arbutus. In 2018, Arbutus spun out rights to its LNP technology (excluding rights to hepatitis B) into a company called Genevant Sciences GmBH as part of a joint venture with Roivant Sciences Ltd[9]. The Arbutus patents have also been the subject of some litigation (see below).

Moderna has been focussed on the potential of mRNA since it was founded in 2010 and has invested heavily in delivery science. Reflecting its work in this area, Moderna has indicated that it has an extensive portfolio of patents relating to its mRNA platform, including novel lipid components designed for optimal expression of both therapeutic and vaccine mRNAs[10].

BioNTech uses a number of delivery formulations for its products, including lipid nanoparticles and its own proprietary lipoplex (lipid carriers) formulations for which it has several patent filings in its sole name. Again reflecting the importance of delivery systems to the success of an mRNA product, BioNTech also has several active third party partnerships focussed on this area, including a partnership with Genevant giving access to Genevant’s LNP technology in oncology and protein replacement therapies for rare diseases; a non-exclusive licence from Acuitas Therapeutics, Inc for LNP formulations used in the Pfizer / BioNTech COVID vaccine; and a collaboration with the Translational Oncology group at the University Medical Center of the Johannes Gutenberg University Mainz, with which it co-owns several delivery system formulation patents, including for lipid nanoparticles[11].

CureVac is in the process of developing its own proprietary LNP system, however it currently relies on third party LNP delivery systems for its clinical assets. CureVac is also party to a Development and Option Agreement with Acuitas that provides CureVac with access to Acuitas’ LNP technology and has entered into a Development and Option Agreement with Arcturus Therapeutics to access Arcturus’ lipid-mediated delivery IP [12].

As we mentioned above, the patent landscape is fragmented and there are many companies who are active in this space in addition to Moderna, BioNTech and CureVac (such as Arcturus Therapeutics, Translate BIO and Acuitas Therapeutics). In addition, the broader utility of lipid nanoparticles as delivery systems for other biotech products, such as gene editing technology, means that there is significant research being directed towards LNPs outside the field of mRNA. This broader utility will inevitably result in patents relating to LNPs having broader claims than just delivery of mRNA based vaccines and therapies. It will be interesting to see if this translates to more cross licensing between companies active in the mRNA field and those developing LNPs for other purposes.

mRNA patent portfolios

According to its annual report, Moderna’s patent portfolio relating to its platform includes approximately 100 issued or allowed U.S. patents or patent applications and approximately 220 granted foreign patents and pending foreign patent applications. In addition to delivery systems, Moderna indicates that it has a broad patent portfolio, which provides protection for its multiple programs and development candidates (including both product and method of use claims). For example, Moderna has a broad prophylactic vaccine patent family. This patent family includes claims to lipid nanoparticle encapsulated mRNAs that encode infectious disease antigens for different indications (including COVID-19) and also includes methods using those compositions for vaccination. Moderna’s other programs for which it has various issued and pending patents include cancer vaccines, intratumoral immune-oncology and regenerative therapeutics [13].

BioNTech has also indicated it has a broad patent estate comprising over 100 patent families which are owned by BioNTech (exclusively or jointly), all of which include at least one filing in the EU or US with several pending or granted in multiple jurisdictions. BioNTech’s patent estate includes patent filings directed to features of therapeutic mRNA structures, mRNA formulations (including its lipoplex formulations and lipid nanoparticles), mRNA manufacturing and uses of mRNA therapeutics. Aside from the Pfizer/BioNTech COVID-19 vaccine, BioNTech’s most advanced mRNA product development programs are in oncology, but its pipeline also includes mRNA products for treatment of certain infectious diseases and mRNA products for protein replacement therapy in certain rare diseases[14].

CureVac similarly has a large patent portfolio relating to mRNA products. According to its SEC filings, as of January this year it owned over 800 issued patents worldwide, including 63 issued U.S. patents and 57 issued European patents. These include claims relating to CureVac’s mRNA technology platform, its delivery system and its product candidates (which include oncology candidates and rabies vaccines)[15].

There are many other companies active in this field, including Arcturus and Translate Bio in particular, each of which are also building patent portfolios relating to mRNA.

Litigation and patent challenges

Given the number of companies active in this space and the complicated web of patent filings and partnerships that have developed alongside the technology, litigation seems inevitable. By way of example, the Arbutus LNP formulation patents mentioned above have already been the subject of some litigation, first between Arbutus and its sub-licensee Acuitas and also between Arbutus and Moderna. Arbutus previously challenged the validity of a sub-licence of its LNP patents granted by Acuitas to Moderna although that litigation settled, resulting in Moderna being granted limited rights to the relevant Arbutus patents[16]. Moderna has also sought to invalidate Arbutus’ patents by filing a series of inter partes reviews with the U.S. Patent and Trademark Office (Moderna succeeded, or partially succeeded in two of three actions but failed to revoke one of Arbutus’ U.S. patents) and via Opposition Proceedings at the EPO[17] [18]. We understand that these patent actions are all currently under appeal and will keep an eye out for further developments.

At the time of writing, we are not aware of any infringement litigation having been instigated relating to mRNA patents. However, at this stage, this is probably unsurprising as the Pfizer/BioNTech and Moderna COVID-19 vaccines are the only mRNA products currently on the market and companies may be reluctant to take any steps that would be seen to be hindering the global fight against the COVID-19 pandemic. Moderna, for its part, has made a public pledge not enforce its COVID-19 related patents against third party vaccines intended to combat the pandemic and has stated that it is willing to license its intellectual property for COVID-19 vaccines to third parties in the post pandemic period[19]. However, we will be keeping a close eye on how patentees in this arena react as and when other mRNA products receive regulatory approval (whether for COVID-19 or other therapeutic indications).

Outlook for the future

The synthetic mRNA field is still relatively young, but innovation is continuing at a rapid pace. The COVID-19 vaccines have demonstrated both the extraordinary utility of the technology and the potentially phenomenal value of mRNA products. It seems likely that there will be more patent challenges and potential infringement litigation in the near future as companies jostle for position in the market.

With regard to the COVID-19 vaccines in particular, it will be interesting to see how the unique circumstances in which the vaccines were developed plays into future patent disputes. For example, the first half of 2020 saw significant developments being made on an almost daily basis, with critical information (such as the genetic sequences for the SARS-CoV-2 coronavirus responsible for COVID-19) being published much more rapidly than would typically be the case. For patents with priority or filing dates during this period, one can envisage interesting arguments about the state of the art and the common general knowledge being raised in future validity challenges. We will keep our eyes on this as the technology continues to develop.

In our next instalment of this five part series, we will review some of the recent key partnerships and deals in the mRNA space.

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[1] Nature Reviews Drug Discovery 19, 578 (2020), doi: https://doi.org/10.1038/d41573-020-00119-8
[2] Ibid.
[3] , L. M. Stuart, M.D., Ph.D., 24 September 2021, In Gratitude for mRNA Vaccines, The New England Journal of Medicine, (https://www.nejm.org/doi/full/10.1056/NEJMcibr2111445)
[4] Moderna, Inc. Annual Report for the year ending 31 December 2020 (https://investors.modernatx.com/static-files/6c67452f-6a27-47a2-8ee7-48d18c54ea4c)
[5] BioNTech SE Annual Report for the year ending 31 December 2020 (https://investors.biontech.de/static-files/e862a8ea-5d90-4672-acfb-34de57b58806)
[6] Moderna, Inc. Annual Report for the year ending 31 December 2020 (https://investors.modernatx.com/static-files/6c67452f-6a27-47a2-8ee7-48d18c54ea4c)
[7] CureVac COVID vaccine let-down spotlights mRNA design challenges, Nature 594, 483 (2021), doi: https://doi.org/10.1038/d41586-021-01661-0
[8] Gaviria, M., Kilic, B. A network analysis of COVID-19 mRNA vaccine patents. Nat Biotechnol 39, 546–548 (2021). https://doi.org/10.1038/s41587-021-00912-9
[9] Arbutus Annual Report for the year ending 31 December 2020 (https://investor.arbutusbio.com/node/16081/html)
[10] Moderna, Inc. Annual Report for the year ending 31 December 2020 (https://investors.modernatx.com/static-files/6c67452f-6a27-47a2-8ee7-48d18c54ea4c)
[11] BioNTech SE Annual Report for the year ending 31 December 2020 (https://investors.biontech.de/static-files/e862a8ea-5d90-4672-acfb-34de57b58806)
[12] CureVac Annual Report for the year ending 31 December 2020 https://www.sec.gov/Archives/edgar/data/1809122/000110465921055619/tm215958-1_20f.htm
[13] Moderna, Inc. Annual Report for the year ending 31 December 2020 (https://investors.modernatx.com/static-files/6c67452f-6a27-47a2-8ee7-48d18c54ea4c)
[14] BioNTech SE Annual Report for the year ending 31 December 2020 (https://investors.biontech.de/static-files/e862a8ea-5d90-4672-acfb-34de57b58806)
[15] CureVac N.V. Annual Report for the year ending 31 December 2020 https://www.sec.gov/Archives/edgar/data/1809122/000110465921055619/tm215958-1_20f.htm
[16] Gaviria, M., Kilic, B. A network analysis of COVID-19 mRNA vaccine patents. Nat Biotechnol 39, 546–548 (2021). https://doi.org/10.1038/s41587-021-00912-9
[17] Moderna loses key patent challenge. Nat Biotechnol 38, 1009 (2020). https://doi.org/10.1038/s41587-020-0674-1
[18] Arbutus Biopharma Corporation Quarterly Report for the quarterly period ended September 30 2020 (https://investor.arbutusbio.com/node/15781/html)
[19] Statement by Moderna on Intellectual Property Matters during the COVID-19 Pandemic: https://investors.modernatx.com/news-releases/news-release-details/statement-moderna-intellectual-property-matters-during-COVID-19