Shortly after we posted about Moderna, Inc.’s October 2020 pledge not to enforce its COVID-19-related patents during the pandemic, the United States Food & Drug Administration (FDA) granted emergency regulatory approval for two COVID-19 vaccines produced by Moderna and BioNTech (with Pfizer), making these groups the first to ever enter the commercial market with mRNA-based therapies. This little-known and never-before-approved mRNA technology has since been widely administered and represents a primary weapon being used to defeat the pandemic.
While this effort carries on, market players are confident that COVID-19 is but one of many indications that the mRNA technology platform might be utilized for, and that approval of the mRNA vaccines could open the door for the approval of other mRNA-based medicines, creating a wide range of new markets.
With the anticipated increase in market activity and competition, we will provide an overview of the mRNA IP and competitive landscape in a series of three posts in the context of certain key players’ patent positions, drug pipelines, strategic relationships, and other attributes. These posts are based on publicly available information, are non-exhaustive, and do not identify all market players or potential market players in this space.
In Part I, we will focus on three mRNA companies: Moderna, BioNTech, and CureVac. In Part II, we will focus on Translate BIO, Arcturus, and eTheRNA and discuss issues surrounding certain lipid nanoparticle (LNP) delivery technologies. In Part III, we will provide a summary of the competitive and IP landscape as covered in the previous posts and offer conclusions.
mRNA Market Players
Moderna, Inc. (NASDAQ: MRNA) is headquartered in Cambridge, MA, and as of April 2021, has a market capitalization of over $53 billion.
Along with BioNTech/Pfizer, Moderna was one of the first developers to enter the market in December 2020 with an mRNA product, its COVID-19 vaccine mRNA-1273. Moderna’s mRNA product pipeline includes 26 drug candidates directed to an array of indications, including therapeutics and vaccines for infectious diseases, oncology, rare disease, autoimmune disease, and cardiovascular disease.
According to Moderna’s website, it has four mRNA candidates in Phase 2 clinical trials, including a cytomegalovirus vaccine, personalized cancer vaccine, and myocardial ischemia therapy; eight mRNA candidates in Phase 1 clinical trials including for cancer and infectious diseases; and 14 mRNA candidates in preclinical phase for various oncology, infectious disease and other indications.
Figure 1: Overview of certain attributes of Moderna as of April 2021.
Moderna has indicated it has over 270 issued or allowed U.S. and foreign patents protecting mRNA-based technology, with over 600 worldwide pending patent applications. The company has identified at least seven granted U.S. patents that it alleges protect its COVID-19 mRNA-1273 vaccine.
Moderna appears to have sub-licensed foundational mRNA patents from Cellscript, LLC based on advancements made by Drs. Katalin Karikó and Drew Weissman at the University of Pennsylvania (UPenn) in the 2000s. The Karikó-Weissman team addressed adverse immune responses to injected synthetic mRNA by replacing the nucleosides uridine and cytidine in the mRNA with pseudouridine and 5-methylcytidineone. Cellscript itself has a sub-license from its affiliate mRNA RiboTherapeutics, Inc., which holds an exclusive license from UPenn.
An exemplary patent resulting from this work is U.S. Patent No. 8,278,036, which has broad claims (e.g., Claim 1: A method for inducing a mammalian cell to produce a protein of interest comprising: contacting said mammalian cell with in vitro-synthesized modified RNA encoding a protein of interest, wherein said in vitro-synthesized modified RNA comprises the modified nucleoside pseudouridine) and reportedly may be included in the non-exclusive sublicense granted to Moderna.
With respect to invalidity proceedings, Moderna has filed several inter partes reviews (IPRs), including against CureVac’s U.S. Patent No. 8,383,340 (IPR2017-02194 filed September 29, 2017: all claims found unpatentable); Arbutus Biopharma Corporation’s (Arbutus) U.S. Patent No. 9,404,127 (IPR2018-00680 filed February 21, 2018: all claims found unpatentable); Arbutus’ U.S. Patent No. 9,364,435 (IPR2018-00739 filed March 5, 2018: claims 1-6, 9, 12, 14, and 15 found unpatentable); and Arbutus’ U.S Patent No. 8,058,069 (IPR2019-00554 filed January 9, 2019: no challenged claims found unpatentable).
Moderna has also filed oppositions in the European Patent Office (EPO), including against Arbutus’ EP2279254 (Opposition filed April 2018: amended claims corresponding to Auxiliary Request 1 accepted and revocation denied, pending appeal by Moderna) and CureVac’s EP2101823 (Opposition filed August 2017: patent revoked, pending appeal).
In August 2018, an anonymous third party sought ex parte reexamination for Moderna’s U.S. Patent No. 9,872,900, with claims directed to an RNA vaccine. Moderna was successful in the reexam (App No. 90/014,167) and the U.S. Patent and Trademark Office (USPTO) issued a reexamination certificate indicating “The patentability of claims 1-26 is confirmed.”
There is no record of Moderna being a party to a patent infringement lawsuit before the federal district courts and it has pledged not to enforce its “COVID-19 related patents against those making vaccines intended to combat the pandemic” during the pandemic.
Moderna has entered into several strategic agreements, including with Vertex (September 2020 Moderna strategic research collaboration and licensing agreement for the discovery and development of LNPs and mRNAs for the delivery of gene-editing therapies for the treatment of cystic fibrosis); Merck (January 2015 Master Collaboration and License Agreement for the discovery and development of vaccines and passive immunity treatments against viral diseases using modified mRNA; N.B. in October 2020, Merck ceded back rights to the adult respiratory syncytial virus vaccine the pair had been co-developing); AstraZeneca (a series of strategic agreements relating to the discovery, development and commercialization of certain mRNA therapeutic candidates including for a range of cancers); and Lonza, Ltd. (May 2020 Global Long Term Agreement “10-year strategic collaboration” to enable larger scale manufacture of Moderna’s COVID-19 vaccine and future products).
Notably, Dr. Karikó, who has been mentioned as a potential recipient of the Nobel Prize for her groundbreaking work mentioned above, is reportedly a Vice President with BioNTech.
BioNTech SE (NASDAQ: BNTX) is headquartered in Mainz, Germany, and as of April 2021, has a market capitalization of over $27 billion.
Through its collaboration with Pfizer, BioNTech was one of the first developers to enter the market in December 2020 with an mRNA product, its COVID-19 vaccine BNT162. According to BioNTech’s website, its product pipeline includes approximately 15 mRNA candidates directed to oncology, influenza, COVID-19, HIV, tuberculosis, rare disease, and other indications.
BioNTech’s website also indicates it has one mRNA drug candidate (BNT122) in Phase 2 clinical trials for metastatic melanoma and other solid tumors (in collaboration with Genentech), seven mRNA candidates in Phase 1 clinical trials for various cancers (itself and in separate collaborations with, e.g., Genentech and Sanofi), seven mRNA candidates in preclinical phase for various oncology, infectious disease and rare disease indications (itself and in separate collaborations with, e.g., Pfizer and Genevant).
Figure 2: Overview of certain attributes of BioNTech as of April 2021.
BioNTech has stated that its overall worldwide owned and in-licensed patent portfolio includes more than 200 patent families, at least 100 of which are solely or jointly owned by BioNTech. The company has described its mRNA patent portfolio as including patents and applications directed to mRNA structures (e.g., for increased immunogenicity), mRNA formulations (e.g., lipolex formulations, lipid nanoparticles), mRNA manufacturing (e.g., mRNA purification and production), and mRNA product candidates (directed to various indications including oncology, infectious disease, rare disease).
Like Moderna, BioNTech has reportedly in-licensed foundational mRNA patents based on advancements made by Drs. Karikó and Weissman. An exemplary patent resulting from this work is U.S. Patent No. 8,278,036 which has broad claims and may be included in the non-exclusive sublicense Cellscript granted to BioNTech.
With respect to invalidity proceedings, BioNTech has filed EPO oppositions against Moderna’s EP3492109 (Opposition filed December 2020: proceedings pending); CureVac’s EP3292873 (Opposition filed January 2020: proceedings pending); CureVac’s EP3319622 (Opposition filed November 2020: proceedings pending); CureVac’s EP3173092 (Opposition filed March 2020: proceedings pending); CureVac’s EP3153179 (Opposition filed March 2020: proceedings pending); and CureVac’s EP3116535 (Opposition filed May 2020: proceedings pending). There is no record of BioNTech filing an IPR before the USPTO to date.
Regarding litigation before the U.S. federal courts, Allele Biotechnology & Pharmaceuticals (Allele) reportedly sued Pfizer and BioNTech (in one suit) and Regeneron (in a separate suit) claiming that the COVID-19 vaccines BNT162 (by BioNTech/Pfizer) and REGN-COV2 (by Regeneron) were each developed using Allele’s “mNeonGreen fluorescent protein” covered under U.S. Patent No. 10,221,221 without the company’s permission. These cases are pending in the Southern District of California (BioNTech/Pfizer) and the Southern District of New York (Regeneron). Pfizer and BioNTech recently moved to dismiss the complaint against them.
BioNTech has reportedly entered into a number of collaborations including with Pfizer (July 2018 Research Collaboration License Agreement to develop mRNA-based immunotherapies and a March 2020 Collaboration Agreement to develop and manufacture COVID-19 mRNA vaccines); Genentech (September 2016 Collaboration Agreement relating to BioNTech’s iNeST platform in mRNA drug class), Sanofi (November 2015 Collaboration and License Agreement relating to BioNTech’s intratumoral therapy platform in its mRNA drug class), Bayer (May 2016 Agreement relating to mRNA-based vaccines and therapeutics for animal health indications); Regeneron (July 2020 strategic collaboration relating to BioNTech’s BNT111 FixVac mRNA oncology product); The Bill and Melinda Gates Foundation (September 2019 collaboration to develop HIV and tuberculosis programs that includes an initial equity investment of $55 million) and Genevant Sciences GmbH (July 2018 License and Co-Development Agreement under which Genevant licenses Arbutus Biopharma Corporation LNP technology to BioNTech—more on this in Part II).
CureVac NV (NASDAQ: CVAC) is headquartered in Tübingen, Germany, and as of April 2021, has a market capitalization of over $17 billion.
According to its website, CureVac’s pipeline includes four mRNA-based prophylactic vaccines, four RNA-based cancer immunotherapies, and four protein-based therapies (including for ocular and lung). As of the date of this article, CureVac does not have any mRNA products on the market. However, its mRNA-based COVID-19 vaccine candidate (in collaboration with Bayer) is reportedly in Phase 3 clinical trials.
Per CureVac’s website, it has 3 candidates in Phase 1 clinical trials for rabies, melanoma, and lung cancer (in collaboration with Ludwig Cancer Center and Boehringer Ingelheim), and approximately 10 mRNA candidates in preclinical development or discovery for an array of indications in the areas of oncology, infectious diseases, and other indications (in collaboration with entities such as GSK, Bill and Melinda Gates Foundation, Coalition for Epidemic Preparedness Innovations (CEPI), CRISPR Therapeutics, Genmab, Harvard Medical School, and Yale University School of Medicine).
Figure 3: Overview of certain attributes of CureVac as of April 2021.
CureVac has stated that it is a pioneer in the mRNA space and has built a U.S. and worldwide patent portfolio totaling approximately 700 issued patents including over 60 issued U.S. patents, over 50 issued European patents, and over 150 issued patents in other countries, with hundreds of worldwide patent applications pending. CureVac has also indicated these patents include claims relating to its mRNA technology platform, including its “RNAoptimizer technology platform, CV8102, BI 1361849 (former CV9202), CV7202, CV-SSIV, our SARS-CoV-2 vaccine and our CVCM delivery system.” The company also claims that its patents and applications are “the most cited among mRNA companies’ intellectual property.”
With respect to invalidity proceedings, CureVac has filed EPO oppositions against UPenn’s EP2528626 (Opposition filed June 2017: patent revoked). There is no record of CureVac filing an IPR before the USPTO. Defensively, CureVac’s patents have been the subject of numerous attacks before the EPO, including by BioNTech, Moderna, and eTheRNA as stated herein and in the forthcoming posts, as well as others including: EP1797886 (April 9, 2020 Opposition filed by Gerhard Weinzierl; April 14, 2020 Opposition filed by Koenig Szynka Tilmann Von Renesse); EP2680881 (December 18, 2017 Opposition filed by Strawman Ltd.); EP2680880 (December 18, 2017 Opposition filed by Strawman Ltd.); EP3326641 (Four Oppositions filed in Finland on April 28, 2020 by Dr. Martin Grund, Rainer Friedrich, Pfizer, Inc., and Merck Sharp & Dohme, Corp.; Four Oppositions filed in EP by Dr. Martin Grund on March 26, 2020, Rainer Friedrich on April 17, 2020, Pfizer, Inc. on March 26, 2020, and Merck Sharp & Dohme, Corp. on March 24, 2020). Europe does not require the actual opponent party in interest to be disclosed, therefore any of the market players could be behind these oppositions while using “Strawman Ltd.,” for example.
CureVac has reportedly partnered with third parties in connection with mRNA technology, including Novartis (March 2021 initial agreement for manufacturing of CureVac’s COVID-19 vaccine candidate CVnCoV); Bayer (January 2021 collaboration and services agreement for the development and supply of CureVac’s CVnCoV candidate); GlaxoSmithKline (July 2020 Collaboration and License Agreement to research, develop, and commercialize CureVac’s prophylactic and therapeutic non-replicating mRNA-based vaccines targeting infectious diseases); Genmab (December 2019 Collaboration and License Agreement for the development of mRNA-based antibody therapeutics); CRISPR Therapeutics (November 2017 Development and License Agreement for developing CRISPR-based therapeutics in select disease areas and novel Cas9 mRNA constructs with improved properties for gene editing applications); Bill and Melinda Gates Foundation (February 2015 Global Access Commitments Agreement to develop prophylactic vaccines based on CureVac’s mRNA platform and $52+ million in funding from the foundation) and Boehringer Ingelheim (August 2014 Exclusive Collaboration and License Agreement to develop next generation lung cancer immunotherapy with CureVac’s CV9202).
With respect to LNP delivery technology, CureVac has reportedly entered into agreements with Arcturus Therapeutics (January 2018 Development and Option Agreement that provides CureVac with access to Arcturus’s LNP formulation technology for use in CureVac’s mRNA technology); and Acuitas (April 2016 Development and Option Agreement that provides CureVac access to Acuitas’s LNP formulation technology that is used in combination with CureVac’s mRNA technology). More on these entities and LNP technology will be provided in Part II.
In Part II, we will discuss Translate BIO, Arcturus, eTheRNA and certain issues relating to Arbutus’ LNP delivery technology.
Disclaimer: The information contained in this posting does not, and is not intended to, constitute legal advice or express any opinion to be relied up legally, for investment purposes or otherwise. If you would like to obtain legal advice relating to the subject matter addressed in this posting, please consult with us or your attorney. The information in this post is also based upon publicly available information, presents opinions, and does not represent in any way whatsoever the opinions or official positions of the entities or individuals referenced herein.