Is Moderna’s COVID-19 vaccine using Arbutus Biopharma’s patents?
Zachary Silbersher
We previously blogged about Moderna Therapeutics’ ($MRNA) ongoing patent dispute with Arbutus Biopharma ($ABUS). On July 23, 2020, Arbutus prevailed in Moderna’s third IPR challenge to one of its patents, the ‘069 patent. Given that Moderna’s COVID-19 vaccine candidate is currently one of the most promising, the question is, will Moderna’s vaccine infringe Arbutus’ patents?
The market reacted to the Patent Office decision refusing to invalidate the ‘069 patent by sending Moderna down 9% and Arbutus up over 100%. The market reaction suggests a number of lingering questions: Will Moderna’s IPR loss for the ‘069 patent hinder or delay its commercialization of its mRNA-1273 vaccine? Can Arbutus demand an injunction against Moderna’s vaccine? Can Arbutus collect a sizeable royalty?
Some of these questions can be dispensed with at the outset. Even if Moderna is technically infringing upon one or more of Arbutus’ patents, that is unlikely to hinder or delay Moderna’s launch of its vaccine. Arbutus will likely, at best, have a claim to a royalty. For Arbutus to seek an injunction against Moderna’s vaccine, it would likely have to demonstrate it is also practicing the patent. Even then, seeking an injunction from a court requires consideration of the public interest. It is far from certain that a court, in the midst of a pandemic, will hold up distribution of a potentially life-saving vaccine on the basis of patent claim.
Yet, underlying all of these question is the more immediate one: is Moderna actually using Arbutus’ patents in its proposed mRNA-1273 vaccine, which is now in Phase 3 testing? At least three years ago, Arbutus stated, “We have seen no evidence of a Moderna delivery system that is free of our intellectual property.” By contrast, Moderna has repeatedly insisted that its technology does not use Arbutus’ patents. In 2017, Moderna’s CEO stated that Arbutus’ technology was apparently “not very good.” More recently, on July 24, 2020, Moderna issued a press release in response to its loss in the IPR for the ‘069 patent that stated: “Our improved proprietary LNP formula, used to manufacture mRNA-1273, is not covered by the Arbutus patents,” and “Moderna is not aware of any significant intellectual property impediments for any products we intend to commercialize, including mRNA-1273.”
To assess whether Moderna’s vaccine is potentially infringing Arbutus’ patents requires comparison of public information on Moderna’s vaccine to the claims of Arbutus’ patents. On February 14, 2020, Moderna filed its Phase 1 clinical trial protocol for COVID-19 vaccine candidate. The protocol contains the following information related to its vaccine:
https://www.nejm.org/doi/suppl/10.1056/NEJMoa2022483/suppl_file/nejmoa2022483_protocol.pdf
Thus, Moderna has disclosed that its vaccine is “manufactured into LNPs composed of proprietary ionizable lipid, [redacted] and 3 commercially available lipids, cholesterol, DSPC, and PEG2000 DMG.”
Turning to the ‘069 Arbutus patent, the patent has 22 claims. There is only one independent claim, and it is set forth below. Thus, to infringe any of the 22 claims in the patent requires showing that, at the very least, the independent claim is infringed.
1. A nucleic acid-lipid particle comprising:
(a) a nucleic acid;
(b) a cationic lipid comprising from 50 mol % to 65 mol % of the total lipid present in the particle;
(c) a non-cationic lipid comprising a mixture of a phospholipid and cholesterol or a derivative thereof, wherein the phospholipid comprises from 4 mol % to 10 mol % of the total lipid present in the particle and the cholesterol or derivative thereof comprises from 30 mol % to 40 mol % of the total lipid present in the particle; and
(d) a conjugated lipid that inhibits aggregation of particles comprising from 0.5 mol % to 2 mol % of the total lipid present in the particle.
The patent therefore requires five components: (i) nucleic acid; (ii) cationic lipid; (iii) phospholipid; (iv) cholesterol; and (v) conjugated lipid. Based on the disclosure from Moderna’s Phase 1 protocol, Moderna’s vaccine appears to use many components of Arbutus’ ‘069 patent. First, the nucleic acid encompasses the mRNA payload. Second, the cationic lipid will be addressed below. Third, the non-cationic lipid (mixture of phospholipid and cholesterol,) according to claim 1 of the ‘069 patent, includes a mixture of a phospholipid and a cholesterol. The patent discloses that the phospholipid can include a number of different embodiments, including distearoylphosphatidylcholine, otherwise known as DSPC. (‘069 patent col. 19, line 25). Moderna’s Phase 1 protocol indicates that its vaccine includes a mixture of DSPC and cholesterol.
Finally, for the conjugated lipid, the patent discloses that this mixture can include a number of different embodiments, including a polyethyleneglycol (PEG)-lipid conjugate. (‘069 patent col. 21, lines 43-48). More specifically, the patent further discloses that “[a]dditional PEG-lipid conjugates suitable for use in the invention include, but are not limited to, mPEG2000-1,2-di-O-alkyl-sn3-carbomoylglyceride (PEG-C-DOMG).” (col. 21, lines 61-63). While the ‘069 patent does not specifically disclose PEG2000 DMG as an embodiment for the conjugated lipid, that in itself does not mean that Moderna’s vaccine is not infringing. Very generally, patents are not required to disclose all potential or possible examples of each claimed features.
But to infringe the ‘069 patent requires more. Specifically, the ‘069 patent recites relative mol percentages of the cationic lipid, non-cationic lipid and conjugated lipid. Even if Moderna’s vaccine includes all the recited lipids, it may nevertheless avoid infringing Arbutus’ patent if the relative mol percentages of its mRNA vaccine differ from the recited mol percentages in Arbutus’ patent. Here, however, information on the relative mol percentages does not appear to be publicly-available. As shown above in the excerpt from Moderna’s Phase 1 protocol, the relative concentrations and amounts of the different lipids are redacted. That information is could therefore be critical to determining whether or not Moderna’s vaccine may be infringing Arbutus’ patents.
As discussed in our earlier blog posts, Moderna also suffered a partial loss with its second IPR, which challenged Arbutus’ ‘435 patent. The ‘435 patent is very similar to the ‘069 patent to the extent it also claims a nucleic acid-lipid particle comprising a nucleic acid, a cationic lipid, a noncationic lipid and a conjugate lipid. Moderna successfully invalidated the broadest independent claim of the ‘435 patent, but failed to invalidate more narrow dependent claims. For some of those non-invalidated claims, determining whether Moderna infringes them also hinges on assessment of respective mol percentages.
The relative mol percentages for Moderna’s vaccine, however, is not the only cloud hanging over the question of whether the mRNA-1273 vaccine will infringe Arbutus’ patents. What is also far from clear is whether Moderna’s vaccine is using a “cationic lipid” as described in the ‘069 patent and the ‘435 patent. (The two patents are related, and therefore, we will refer only to the ‘069 patent for brevity.)
Moderna’s IPR for the ‘069 patent argues that long before Arbutus’ patents, it was well known to use cationic lipids in LNP delivery of mRNA because their positive charges interact with the negative charge on the cell membrane and facilitate transfection—i.e., the fusion event necessary to deliver the mRNA payload. (See IPR2019-00554, Paper 1 at 7-8). Moderna also claimed, however, that the chemical structure of the cationic lipid can have a “major impact” on delivery for certain mRNA payloads (otherwise known as “transfection efficiency”). (Id. at 9). Recent literature from 2019 suggests that “[e]arly work focused on the use of cationic lipids, but more recent work has focused on pH-dependent ionizable materials.”
The ‘069 patent discloses numerous potential embodiments of what could constitute the cationic lipid. These could include DODAC, DODMA, DSDMA, DOTMA, DDAB, among numerous others. (See ‘069 patent, col. 45, line 30 to col. 49, line 65). By contrast, Moderna’s Phase 1 clinical protocol indicates that the vaccine includes a “proprietary ionizable lipid.” Yet, it is not exactly clear what Moderna’s proprietary ionizable lipid is. This information is redacted throughout its Phase 1 protocol.
Going back to Moderna’s press release from July 24, 2020, the company stated that it does not see any “significant intellectual property impediments” to its vaccine. That statement may hinge on its use of its proprietary ionizable lipid. The word “significant” may be key. On the one hand, Moderna may be able to claim that Arbutus’ patents do not disclose the specific embodiments of the cationic lipid or ionizable lipid that are actually employed in its vaccine. If that is the case, then Moderna will not infringe the patents. On the other hand, generally-speaking, patents are not required to disclose all possible embodiments. A product can infringe a patent even if the claims can be interpreted to include non-disclosed embodiments that were otherwise known to a person of ordinary skill. Furthermore, there are certain doctrines, such as the doctrine of equivalents, that can deem a product infringing where certain features are literally different from what is claimed, but functionally the same.
Another wrinkle here is that Moderna has now claimed to have moved past Arbutus’ patents and developed its own LNP delivery technology. Supporting this, Moderna’s clinical trial protocol discussed above describes its ionizable lipid as “proprietary.” Moderna has also its own patents covering an ionizable lipid: U.S. Patent No. 9,868,691. (Interestingly, during prosecution of this patent, none of Arbutus’ patents appear to have been cited by either Moderna or by the Patent Office.) Moderna has at least five other issued patents and one pending patent application within the same family of patents. These include U.S. Patent Nos. 9,867,888; 9,868,693; 10,442,756; 10,266,485; 10,392,341; and U.S. Patent Application No. 2020/0123100. These patents claim priority to provisional applications filed in late 2015 and in 2016. Whether the ionizable lipid covered by these patents is the same one used in Moderna’s vaccine is not certain.
All of this may explain why Moderna does not see any “significant” intellectual property impediments to its vaccine. It is undoubtedly aware of Arbutus’ patents. Yet, it may feel confident that it is not infringing those patents because its proprietary ionizable lipid used in its vaccine is distinct enough from the scope of cationic lipid embodiments disclosed in Arbutus’ patents. Whether or not Moderna is correct about that may boil down to how a court interprets the scope of the “cationic lipid” claimed in the patents. This is an issue on which Arbutus may believe it has a strong enough argument to convince a court. Given that, Arbutus may still have plans to file suit and pursue a claim construction that is broad enough to cover Moderna’s ionizable lipid. There is a lot more evidence that a court would have to consider before resolving this question. It would include, for instance, examination of the file histories for each patent, existing literature on the scope of cationic lipids, as well as expert testimony.
To date, however, Arbutus has not filed suit accusing Moderna of infringing any of its patents. While patent lawsuits are typically filed after a product is commercially launched, the statute permits suit to be filed upon use alone. Moderna’s existing clinical trials should therefore technically give standing to Arbutus to file suit. That said, there are no doubt PR considerations that would have to be considered before saddling one of the most promising COVID-19 vaccine candidates with a patent lawsuit. Another issue to consider is that the three IPR decisions are now either on appeal or heading there, and even if Arbutus were to file suit tomorrow, the suit would likely be stayed by a court pending the outcome of those appeals.
Moderna and Arbutus have history going back a few years over whether Moderna’s commercial potential is leveraging Arbutus’ LNP technology. That dispute has been pushed to the fore because Moderna suddenly has a promising COVID-19 vaccine. Whether this dispute will come to a head publicly or quietly goes away remains to be seen.