In April of 2021, we provided a three-part series relating to the IP and Competitive Landscape for the mRNA market. In this post we provide a 2021 year in review update on mRNA pioneers and key players and offer additional conclusions and outlook for 2022 and beyond.

Key mRNA Pioneers and Market Players

Moderna

Figure 1: Overview of certain attributes of Moderna as of December 13, 2021.

Since April, Moderna’s pipeline has increased from 26 total mRNA-based drug candidates to 34, 19 of which are in clinical trials (up from 12). The company’s COVID-19 vaccine (now marketed as Spikevax) remains its only commercial product, the sales of which are expected to reach $20 billion this year. That success and Moderna’s overall market and tech position drove its growth as indicated by its market cap, which has soared from about $53 billion since our first post in April 2021 to about $181 billion in September 2021, and was approximately $110 billion on December 13, 2021. There has been no change in the number of mRNA-based IPRs and oppositions that Moderna has filed (remaining at four total U.S. inter partes review proceedings (IPRs), two total European oppositions, as we previously discussed) or major changes to its already sizable patent portfolio.

As we’ve discussed, in a Q2 call in August, Moderna stated that it plans to “expand [its] horizons” into gene editing and gene therapy through internal development, licensing, or “if it makes sense, M&A.”  Moderna also indicated that it was seeking to develop new capabilities in the area of lipid nanoparticle (LNP) delivery technology for its current platform and in the gene editing space, while it is not interested in developing small or large molecule therapies because they “love information molecules too much.” In November, it was reported that Moderna entered into a collaboration with AI-driven CRISPR gene editing company Metagenomi (Emeryville, CA) to include new gene editing systems for in vivo human therapies.

As reported in November, Moderna indicated in a job posting that it plans to build an independent research and business unit for genomic medicines called Moderna Genomics (mGx) in Technology Square, Cambridge, which will be “an innovation engine for the company focused on discovering and delivering the next generation of in vivo gene editing and nonviral gene therapies. Moderna Genomics strives to be an industry leader in genomic medicines.”

Moderna is facing a number of potentially significant legal hurdles surrounding its COVID-19 vaccine and possibly future products. For example, as we’ve posted, Moderna sought to invalidate three Arbutus-owned U.S. patents directed toward lipid nanoparticle delivery technology through inter partes review (IPR) proceedings before the USPTO. Moderna was successful in invalidating U.S. Patent No. 9,404,127, but was unsuccessful in invalidating all claims of U.S. Patent No. 9,364,435 and any claims of U.S. Patent No. 8,058,069. Moderna appealed the latter two rulings to the Federal Circuit. On December 1, the Federal Circuit dismissed Moderna’s appeal on the ‘435 patent for lack of standing at the time the appeal was initially filed, and while finding that Moderna had standing to appeal the ‘069 patent, it upheld the PTAB’s decision that the claims of the ‘069 patent were not invalid. Moderna has subsequently commented that, while it disagrees that the upheld claims of the ‘069 patent are not invalid, it is “confident that [its] COVID-19 vaccine is not covered by those claims.”  The possibility of a patent infringement lawsuit (or settlement) between Moderna and Arbutus remains open.

Moderna is also currently in a dispute with the National Institutes of Health (NIH) relating to ownership of the patent application directed to its COVID-19 vaccine’s core sequence (mRNA-1273). The parties collaborated on its development but, in a filing with the USPTO, Moderna claims it “reached a good-faith determination” that none of the individuals from NIH involved in the collaboration are inventors. This is significant, because if any NIH personnel were inventors, NIH may co-own patents issuing from or related to the pending application and be allowed to utilize the claimed inventions as it sees fit without accounting to Moderna. NIH has indicated its willingness to engage in a lawsuit to resolve the matter, and recent reports show that the parties are currently in “good faith discussions” surrounding the issue. Most recently, Moderna has reportedly decided not to pay the issue fee for the allowed claims of the subject patent application to facilitate “an amicable resolution” with NIH, although Moderna could seek the same or similar patent claims at a later time.

Other notable developments include the collaboration between Moderna and AstraZeneca on a series of mRNA-based projects ranging from oncology to cardiometabolic diseases. Recently, the parties announced that a therapy where “naked” mRNA is injected directly into the heart of patients undergoing elective coronary artery bypass surgery met its phase II.a primary endpoint test of hitting safety and tolerability in patients with heart failure, allowing the candidate AZD8601 to move on with further trials. Moderna also recently reported initial clinical trial data indicating its mRNA-based seasonal flu vaccine candidate had efficacy on par with traditional seasonal flu vaccines (40 to 60% efficacy) but not as effective as its COVID-19 vaccine (95% efficacy). Also, it was recently reported that preclinical data relating to its mRNA HIV vaccine, developed along with the National Institute of Allergy and Infectious Diseases (NIAID), indicated that the vaccine is “safe and promoted desired antibody and cellular immune responses against an HIV-like virus” in mice and non-human primates.

BioNTech

Figure 2: Overview of certain attributes of BioNTech as of December 13, 2021.

BioNTech currently has a total of 18 mRNA-based candidates in its pipeline, up from 15 since April 2021. Of those candidates, 11 are in the clinic (up from 8). Sales of BioNTech’s COVID-19 vaccine, being sold in collaboration with Pfizer, is expected to reach $36 billion in 2021 and another $29 billion in 2022. Like Moderna, these sales numbers and the prospect of future therapies have driven BioNTech’s growth in 2021. When we first profiled the company in April 2021, BioNTech had a $27 billion market cap, which skyrocketed to nearly $94 billion in August 2021, and was approximately $67 billion on December 13, 2021. There has been no change in the number of mRNA-based IPRs and oppositions that BioNTech has filed (still at 6 total oppositions as we previously discussed), nor have there been any major changes to its large patent portfolio.

BioNTech has stated that it plans to focus its efforts on infectious disease and immuno-oncology and, unlike Moderna, to look at modalities independent of mRNA to achieve its objectives, whether through small molecule immunomodulators, TCR cell therapies, antibodies, or biologics. BioNTech has pushed forward with phase II clinical trials for candidates based on 2 of its platforms: its homegrown FixVac platform (cancer immunotherapies targeting shared antigens frequently expressed across patients in certain cancers) and its Individualized Neoantigen Specific Immunotherapy (iNeST) platform (individualized cancer immunotherapy targeting individual patient’s cancer mutation) co-developed with Roche’s Genentech. BioNTech founders Ugur Sahin and Ozlem Tureci recently stated in the Economist that: “We believe that in 15 years, one-third of all newly approved drugs will be based on mRNA.”

In August 2021, BioNTech purchased a cell therapy R&D platform and clinical manufacturing plant in Gaithersburg, MD from Kite (a Gilead company). The purchase apparently supports BioNTech’s pipeline of cell therapies, including its CAR-T therapies, and compliments its T-cell and neoantigen TCP therapies that were enhanced by its acquisition of Neon Therapeutics in 2020. More interesting details of BioNTech’s recent development and commercialization efforts can be found in their Q3 2021 update.

While Pfizer has stated that it doesn’t “need to work with BioNTech” on mRNA-based therapies, it is unclear how it plans to do so independently from BioNTech or any other company without engaging in any merger and acquisition (M&A) activity. In any case, the relationship between the companies appears to remain strong, with Pfizer CEO Albert Bourla recently stating that deciding to pursue an mRNA-based vaccine with BioNTech was “love at first sight and it was the beginning of a tremendous relationship, collaboration, between the two companies ….”

CureVac

Figure 3: Overview of certain attributes of CureVac as of December 13, 2021.

Since April, CureVac’s pipeline has increased from 13 total mRNA-based candidates to 14, 3 of which are in the clinic (down from 4). CureVac’s flagship COVID-19 vaccine (CVnCoV), which entered phase III clinical trials earlier this year, turned out disappointing results in June, yielding a mere 48% efficacy against the virus, compared to a 95% efficacy for the Moderna and BioNTech mRNA vaccines. In contrast with those companies, CureVac’s market cap, which was $17 billion when we first profiled the company in April 2021, and which at one point this year reached $22 billion, was approximately $7.2 billion on December 13, 2021, an approximately three-fold reduction from its high point. There has been no change in the number of mRNA-based IPRs and oppositions that CureVac has filed (still at one opposition as we previously discussed), nor have there been any significant changes to its patent portfolio.

The downturn in CureVac’s stock value was doubtless driven by the failure of CVnCoV, and perhaps also the termination of its lung cancer program with Boehringer Ingelheim for reasons unstated. It is interesting to note that CureVac utilizes a native form of mRNA, whereas Moderna and BioNTech utilize a modified form based on the innovations of Drs. Kariko and Weissman (innovations addressing adverse immune responses to injected synthetic mRNA by replacing the nucleosides uridine and cytidine in the mRNA with pseudouridine and 5-methylcytidineone) as we previously discussed. We will deliberately avoid speculating about whether the difference in mRNA “backbone” relates to efficacy on our part, but several respected publications, such as Nature, have opined on this matter, which should be of great interest to the mRNA ecosystem.

Despite the poor initial results of their flagship vaccine, CureVac still initially attempted to venture forward, relying on slightly better results in people 18 to 60 years old, yielding 53 % efficacy, with stronger protection against moderate to severe cases (77%) and complete protection against hospitalization and death. However, the company ultimately scrapped the program, and is instead focusing on a second-generation candidate it is developing with GlaxoSmithKline, which is slated to begin clinical trials in the coming months. The decision to abandon the first-generation product project may have negatively affected Swiss pharma titan Novartis, which had planned to manufacture the mRNA and bulk drug product for CureVac’s CVnCoV vaccine on its site in Austria.

Sanofi

 

Sanofi (NASDAQ: SNY), headquartered in Paris, FR, acquired mRNA pioneer Translate Bio in September 2021 for approximately $3.2 billion and mRNA startup Tidal Therapeutics in April 2021 for approximately $470 million. With its acquisition of Translate alone, Sanofi obtained an mRNA pipeline of nine candidates (two in the clinic), hundreds of patents, and undoubtedly valuable mRNA-based technical and regulatory know-how.

It is unclear whether and to what extent Sanofi plans to pursue development of the Translate pipeline, announcing in September that despite positive results in clinical trials, it doesn’t plan to pursue the development of a messenger RNA vaccine against Covid-19 that it had co-developed with Translate, because the therapy will come too late to market. Also, on its website, Sanofi only lists 2 mRNA candidates in its pipeline, one previously developed with Translate for the A/H3N2 strain of the influenza virus and the other a solid tumor therapy developed with BioNTech, presumably under a 2015 Collaboration and License Agreement. Sanofi is also collaborating with BioNTech to support BioNTech’s manufacture of its COVID-19 vaccine.

On June 29, 2021, Sanofi announced that it will invest over €400 million annually in an mRNA-based vaccine Center of Excellence. The Center will reportedly work to accelerate the development and delivery of next-generation vaccines by integrating end-to-end mRNA vaccine capabilities with dedicated R&D, Digital, and Chemistry, Manufacturing and Controls (CMC) teams.

Also, in November 2021, Sanofi signed a deal with Baidu, a Chinese tech giant, to utilize its AI algorithm for mRNA-based therapies.

Arcturus, eTheRNA, Abogen, and other Companies

Since April 2021, Arcturus’s pipeline has increased from 4 total mRNA-based candidates to 5, 3 of which are in the clinic (up from 2). Arcturus still has not filed any IPRs or oppositions, at least as the public-facing challenger. eTheRNA’s pipeline has similarly increased from 3 total mRNA-based candidates to seven, one of which is in preclinical studies. eTheRNA is still listed as filing eight oppositions (against CureVac’s patents) and no IPRs.

Abogen Biosciences, an mRNA startup based in Suzhou, China, has been making fundraising news all year, including recently announcing that it has crossed the $1 billion threshold in series financing. The company, which has reportedly been very secretive since its founding in 2019, apparently has a COVID-19 vaccine candidate (ABO-028M) set to go into phase III clinical trials in Mexico, Indonesia and Nepal. The drug reportedly has greater stability at warm temperatures than the Moderna and BioNTech vaccines.

The startup space has continued to evolve this year. The following is a non-exhaustive list of mRNA-based companies to keep an eye on (in no particular order): In-Cell-Art (Nantes, FR) (20 vaccine candidates using proprietary Nanotaxi® nanocarrier delivery, including four mRNA projects); Ethris (Planegg, Germany) (proprietary Stabilized Non-Immunogenic mRNA (SNIM® RNA) platform and delivery systems, with four preclinical stage candidates); Sequris (Maidenhead, UK) (recently announced agreement with BARDA to develop two influenza virus vaccine candidates using cell-based combination platform technology AUDENZ™ and Sequiris’s own self-amplifying mRNA platform); RNAimmune (Gaithersburg, MD) (AI-aided mRNA design platform and proprietary PLNP based carrier); Strand Therapeutics (Cambridge, MA) (first platform for creation of programmable, long-acting mRNA therapeutics capable for delivery of multi-functional treatments and using self-replicating mRNAs); GreenLight Biosciences (Medford, MA) (proprietary platform for fast, clean, and cost-efficient mRNA manufacturing for vaccines and antibody therapies); Kernal Biologics, Inc. (Cambridge, MA) (hyperselective designer mRNA that targets specific cells using proprietary LNP technology); Tiba Biotechnology (Cambridge, MA) (fully biodegradable nanoparticle delivery platform and computational RNA design in collaboration with partners including USAMRIID, BMGF, and NIH); ReCode Therapeutics (Menlo Park, CA) (customizable SORT LNP delivery platform that can be customized, with 2 preclinical stage candidates); Stemirna Therapeutics (Shanghai, China) (a Chinese company with several independently-developed mRNA drug products in the preclinical stage focusing primarily on infectious diseases and immune-oncology); a group of researchers (including CRISPR pioneer Feng Zhang) from MIT’s McGovern, Howard Hughes Medical, and Broad Institutes who developed the SEND system; and others.

Conclusions and Outlook

A number of significant changes have taken place over the past nine months of 2021 relating to the competitive landscape. The two lead—and only—mRNA products on the market have already generated tens of billions of dollars in revenues for Moderna and BioNTech, with such revenue levels certain to continue into 2022 and potentially rise as the companies distribute booster shots and develop vaccines for the Omicron variant that each company says could be ready in months. The two companies’ efforts resemble a modern day “space race” to determine who can develop and distribute vaccines faster and more widely. The combination of global need, market competition, and advanced technological tools for drug discovery and development (including artificial intelligence (AI), CRISPR, and other technologies) is spurring innovation in the mRNA space at an exponential rate. This could all lead to major growth for these and other well-positioned mRNA market players especially if the predictions of BioNTech founders Ugur Sahin and Ozlem Tureci that “in 15 years, one-third of all newly approved drugs will be based on mRNA” holds true.

Figure 4: Overview of mRNA IP and Competitive Landscape as of December 13, 2021. N.B. the above overview and other information provided is in a constant state of flux and subject to significant ongoing change (e.g., market capitalization, opposition and IPR filings, litigations, pipelines, alliances, etc. are all constantly changing and will continue to do so on an ongoing basis).

While Moderna and BioNTech have established themselves as the clear market leaders, CureVac has been forced to downshift based on its disappointing results in the clinic, leaving it without a commercial product to date. Perhaps its collaboration with GSK, including for a second generation COVID-19 vaccine candidate, will change the company’s fortunes in 2022. This seems likely if the new vaccine is able to show higher efficacy on par with the Moderna and BioNTech vaccines, demonstrating proof of concept of CureVac’s distinct technology and paving the way for new indications based on that platform. CureVac could also be viewed as an attractive acquisition target since the company is currently valued at one third of what it once was while still boasting a huge patent portfolio and undoubtedly deep expertise and know-how relating to mRNA.

Sanofi made major strides in mRNA this year as the first big pharma company to gain access to the space through significant acquisitions (versus collaboration agreements) of Translate Bio and Tidal Therapeutics. The Translate deal alone has given Sanofi turnkey mRNA pipelines, development programs, patent portfolios, and know-how. How Sanofi exactly plans to utilize those assets is presently unclear, but we will undoubtedly learn more in 2022. As demonstrated by its acquisitions and formation of its mRNA-based vaccine Center of Excellence, Sanofi appears to be committed to mRNA and here to stay.

As for big pharma giant Pfizer, it certainly sees mRNA as a key part of its future, but without an apparent homegrown mRNA program (six of the seven mRNA products in its pipeline are in collaboration with BioNTech), it is unclear how it plans to level up beyond its collaboration with BioNTech. A merger or acquisition involving BioNTech would solidify Pfizer’s firm position in the vaccine space while allowing the opportunity for diversification into new indication areas unique to mRNA. While that would be a blockbuster deal, it would not necessarily change much for Moderna in the near term, since Moderna is already holding its own competing against a BioNTech-Pfizer collaboration in the COVID-19 vaccine space.

Additionally, Moderna is pivoting into gene editing and diving deeper into its mRNA “information molecules” niche without focusing on small or large molecules, distinct from BioNTech’s approach of remaining open to utilizing modalities outside of mRNA to achieve its therapeutics goals. This distinction could be the key that puts Moderna on track to developing an even newer class of therapies (e.g., mRNA utilized in combination with CRISPR for genetic disease therapies), even while BioNTech continues on a more traditional pharma path, potentially alongside or as part of Pfizer. Keep an eye on Moderna’s acquisition activity this year involving companies that utilize CRISPR and AI-driven technologies.

As these pioneers position themselves for market dominance, numerous startups are pouring into the space with potentially promising therapies. Importantly, as these companies innovate novel mRNA sequences for such therapies, they face a major hurdle in deciding which delivery technology to utilize. Delivery technology, like the lipid nanoparticle (LNP) delivery technology utilized in the Moderna and BioNTech vaccines, is difficult to develop in effective formulations, and several of the pioneers have secured broad patents covering such formulations. This requires startups to confront the issue of whether to in-license LNP technology, design around existing LNP patents (which can be difficult because of their breadth), or innovate new technologies and file for patent protection of their own. Of course, the LNP patent landscape is not only an issue for startups, but also for the larger players like Moderna, which failed to invalidate key LNP patents owned by Arbutus and now potentially faces a patent infringement lawsuit or a large payout under a licensing agreement or settlement.

The mRNA market landscape is sure to evolve significantly in 2022 as the aforementioned and other companies continue to innovate, compete, merge, acquire, and develop critical therapies based on a new technological platform. It will be interesting to see if the FDA and other regulators further accelerate their approval programs to keep up with the current global healthcare crisis, and whether such institutions will be disrupted to the point of more permanent institutional change, such as accelerating approvals for other breakthrough therapies for other diseases that affect smaller populations in the mRNA space and elsewhere. Such a shift would indicate that the COVID-19 pandemic may be viewed historically as a tragedy that ultimately advanced global healthcare and the ecosystem that supports it.

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Photo of Dan Shores Dan Shores

Dan Shores is Partner at Rothwell Figg.  Dan Shores is a dedicated patent lawyer and strategist who believes in his clients and the power of their ideas. He focuses on serving biotech, medical device, energy, software, cybersecurity, and other technology-based companies and understands

Dan Shores is Partner at Rothwell Figg.  Dan Shores is a dedicated patent lawyer and strategist who believes in his clients and the power of their ideas. He focuses on serving biotech, medical device, energy, software, cybersecurity, and other technology-based companies and understands the myriad of challenges that such companies face when breaking through and establishing themselves in their respective markets. Dan works with clients to build robust patent portfolios, protect trade secrets, negotiate strategic collaborations, conduct due diligence and landscape investigations, and prepare for success in funding rounds and exits. An engineer by education, and having extensive experience in transactional, litigation, procurement, and strategic counseling matters for technology-based companies, Dan is a problem-solver who excels at deciphering key translational aspects of a broad array of technologies to maximize leverage in the context of clients’ desired implementation of such technologies whether as participants in dynamic markets or as first movers.

Dan has served companies utilizing the following technologies (without limitation): mRNA therapies; lipid nanoparticle delivery technologies; genetically engineered swine and organs for xenotransplantation; artificial intelligence for drug discovery; CAR-T therapies; oligonucleotide development; pharmaceutical treatment of rhinitis with levocetirizine; pharmaceutical treatment of hepatitis B with telbivudine; genetically-modified cotton seed; fiber-optic probes for tissue investigation; implantable glucose-sensing devices; high throughput genetic seed-chipping technology; cybersecurity threat assessment platforms; interactive media systems for healthcare institutions; artificial intelligence (various applications); identification systems for cable-based medical devices; identification of digital positions of interest on media items; heat-treated glass with multilayer low-emissivity coatings; automotive and agricultural equipment; pressure-sensitive adhesives; three dimensional printing of buildings and other structures; and integrated electronic securities marketplace systems.

Dan is a registered patent attorney licensed to practice before the United States Patent and Trademark Office, and is admitted to practice law in Massachusetts and in the District of Columbia. He is a member of the bars of the Supreme Court of the United States, United States Court of Appeals for the Federal Circuit, and United States District Court for the District of Massachusetts. Dan lives in Boston with his wife Lindsay and their two English Bulldogs Jarves and Rosie.

Photo of Sheena Wang Sheena Wang

With a master’s degree in biotechnology by Johns Hopkins, and a bachelor of science from the University of Western Ontario with an honors double major in genetics and cell biology, Sheena Wang brings a background in both law and science to her role…

With a master’s degree in biotechnology by Johns Hopkins, and a bachelor of science from the University of Western Ontario with an honors double major in genetics and cell biology, Sheena Wang brings a background in both law and science to her role, integrating both in support of the firm’s IP practice and clients.