Does the ITC’s Staff recommendation bode well for Biomarin’s attempt to exclude Ascendis’ Yuviwel from the U.S. market?
Zachary Silbersher
Biomarin’s effort to block Yuviwel, Ascendis’ TransCon CNP drug, has reached a lull. Last year, Biomarin brought a proceeding before the International Trade Commission (ITC) to block Ascendis from importing its drug. The ITC held an evidentiary hearing in late April of this year, and the ALJ is scheduled to issue its “final initial” determination by the end of August. In the meantime, the Commission Investigative Staff (Staff) filed its brief following the evidentiary hearing. Does the Staff’s findings bode well or ill for Ascendis’ hopes of keeping its Yuviwel drug on the market?
The Staff’s findings and arguments are not technically binding on the ALJ. Nevertheless, they are presumably persuasive and afforded weight by the ALJ. Moreover, from the perspective of investors, the Staff’s findings represent an arguably objective assessment of the parties’ competing arguments that can be predictive of the overall outcome.
There are a host of disputes at issue in the ITC dispute between Biomarin and Ascendis. This post will focus only on a few select issues where the Staff’s analysis may be subject to disagreement by the ALJ or Commission, and thus, possibly impact the dispute’s outcome.
Does Ascendis’s TransCon CNP infringe Biomarin’s RE267 patent?
Biomarin has asserted that Ascendis infringes four claims of the RE267 patent, including claims 32, 34, 41 and 43. The Staff Attorney finds that Ascendis infringes only two of those claims, namely claims 41 and 43, but not claims 32 and 34. While that may sound partially positive for Ascendis, the realities are grimmer given that Biomarin technically needs to show infringement of only a single patent claim to be entitled to an ITC ban against Yuviwel.
TransCon CNP includes three components: (i) a CNP variant; (ii) PEG; and (iii) a linker/linkage. Claims 32 and 34 each depend upon claim 15, which requires, “wherein hydrolysis of the hydrolysable linkage releases the CNP variant.” The Staff found that the CNP variant in TransCon CNP, namely, CNP-38, is released by direct cyclization of the linker, and not by hydrolysis of the peptide-linker bond. In other words, TransCon CNP’s release of its CNP variant does not depend upon a reaction with water. Given this, the Staff found that claim 15 cannot be infringed, and as a result, neither claim 32 nor 34 can be infringed.
By contrast, the Staff found that claims 41 and 43 are infringed by TransCon CNP. Claims 41 and 43 depend from claim 18, which is directed to a “macromolecule capable of releasing a CNP variant” where a “synthetic polymeric group [is] coupled to the CNP variant through a hydrolysable linkage.” Thus, although claim 18 requires a “hydrolysable linkage,” the Staff found the claim does not require that hydrolysis is what releases the CNP variant, as required by claim 15.
The Staff interpreted claim 18’s requirement for a “hydrolysable linkage” broadly. In other words, the Staff agreed with Biomarin’s experts that a “hydrolysable linkage” only means that the linkage is capable of undergoing hydrolysis, regardless of when that happens. Ascendis argues that its CNP variant is not released through hydrolysis. Rather, even if hydrolysis occurs, it only occurs after the CNP variant has been released. That does not appear to be in dispute. Nevertheless, Biomarin’s experts argue, and the Staff agrees, that claim 18 only requires that a hydrolysable linkage exists, not that hydrolysis is what releases the CNP variant. Indeed, the Staff contrasts claim 15, which specifically requires that hydrolysis releases the CNP variant, from claim 18, which does not include this requirement.
The Staff’s analysis has traction, and from a patent law perspective, it is likely technically correct. Nevertheless, it is a rather thin reed on which to find infringement and ban an entire drug from the United States market that may be preferred by an entire population of pediatric patients. TransCon CNP is a sustained release drug that, unlike Biomarin’s Voxzogo, allows patients to receive injections on a weekly rather than daily basis. Claim 18 of Biomarin’s patent is directed to a sustained release version CNP variant formulation. The claim does not, however, specify how the “sustained release” is accomplished. Instead, the claim only says that a “hydrolysable linkage” is included.
There does not appear to be any dispute that TransCon CNP does not release its CNP variant through hydrolysis—i.e., it does not use hydrolysis to achieved sustained release. But because its linkage is nevertheless capable of hydrolysis, only after the CNP variant is released, then the Staff has found that claim 18 is infringed. And based on that, children with achondroplasia may be compelled to continue to endure daily injections even though a drug with weekly injections are available. There is arguably risk there that the Staff’s finding is not challenged by one of the tribunals to weigh in on this issue.
Does Biomarin’s RE267 patent lack written description?
Ascendis’ primary defense to Biomarin’s allegations is that the RE267 lacks written description. Very generally, a patent must satisfy what is known as a “written description” requirement in order to avoid being invalidated. The requirement is intended to ensure that a patentee does not patent an invention that he or she did not actually possess at the time of filing the application. In other words, an inventor cannot “claim” an invention over something not previously disclosed in the patent’s specification (the disclosure statement that accompanies a patent application.
Biomarin’s RE267 patent is directed to a combination of three components: (i) CNP-38 coupled to (ii) a PEG or other synthetic polymer group through (iii) a hydrolysable linkage. Ascendis argues that this specific combination of components is not disclosed anywhere within the specification for the RE267 patent. While each individual component may disclosed, they are each disclosed in respective laundry liss. In other words, they are nowhere linked together to describe the combination actually claimed in the patent.
Going a step further, Ascendis argues it is not mystery why the RE267 patent does not explicitly describe the claimed combination CNP-38, PEG and a hydrolysable linkage. Ascendis claims the initial goal of the patent was contrary to the goal of Ascendis’ TransCon CNP drug. The RE267 patent’s specification indicates that it was directed to producing active CNP variants with improved neutral endopeptidase resistance. By contrast, the TransCon CNP drug is an inactive prodrug designed for sustained release of a particular CNP variant.
Ascendis’ story goes further, (and it is one that is not necessarily uncommon within the world of pharmaceutical patents.) Biomarin has a portfolio of patents that cover its Voxzogo drug. Yet, according to Ascendis, when Biomarin allegedly learned that Ascendis was developing a sustained release CNP version, it knew none of its patents could be used to stop Ascendis’ drug. Because of this, Biomarin purportedly brought back to life an earlier patent application directed to something else entirely, i.e., active CNP variants with improved neutral endopeptidase resistance, and tried to shoehorn claims directed to a sustained release version into that patent. In short, Ascendis claims that the specification for the RE267 patent was never intended to cover a inactive prodrug designed for sustained release of a particular CNP variant, which is precisely why the patent lacks any disclosure of the claimed combination recited in the patent’s claims.
The Staff brief disagrees with all of Ascendis’ arguments. It finds that the patent’s specification contains sufficient written description to avoid invalidation of the claims. The Staff, however, focuses primarily on the discrete disclosure of each individual component of the claimed combination.
The Staff essentially sidesteps the Ascendis’ arguments that fault the patent’s written description for failing to disclose an embodiment including the components combined together. The Staff argues that Ascendis relies upon law holding that if you claim a genus in your patent, you must disclose a sufficient number of species to satisfy the written description requirement. The Staff Ascendis’ discounts argument because it finds that Biomarin’s patent is not claiming a broad genus. That, however, is a question on which the ALJ or Commission may disagree. Biomarin’s patent arguably does claim a genus given that multiple different embodiments are encompassed within what is claimed, and yet, the patent’s specification purportedly fails to disclose a single working example of what is claimed.
Does the public interest compel allowing patients a choice between Voxzogo and Yuviwel?
The most compelling section of the Staff’s brief relates to public disclosure, which I discussed in an earlier post. This might be one issue where the ALJ, the Commission or even the Federal Circuit (the appellate body that would hear any appeal of the ITC's decision) might deviate from the Staff's recommendation.
As discussed in my prior blog post, Ascendis argues that, even if TransCon CNP drug is found to infringe Biomarin’s patent, the ITC should nevertheless refrain from issuing a remedial order because doing so would be contrary to the public interest. Ascendis argues that Yuviwel’s weekly dosage regime, compared to Voxzogo’s daily regime, is “transformational” because children with achondroplasia will face 85% fewer shots per year. Ascendis emphasizes that this leads to increased likelihood of injection site reactions, and the FDA’s grant of accelerated approval and priority review is proof the agency recognized the benefits of Ascendis’ drug over the only other alternative on the market.
Despite this, the Staff did not find the public interest warrants a denial of relief to Biomarin. The Staff reasons that actual comparisons of the benefits of daily versus weekly injections was clouded by the fact that comparisons between different clinical studies is always problematic. While that may be true, the ALJ or Commission may disagree. Indeed, under that logic, public interest arguments for pharmaceutical drugs would presumably always fail given that they would inevitably depend upon a comparison across different clinical trials. Rather, the public interest question focuses on whether the public will be adversely affected by being deprived a diversity of medical options. Adequately answering that question would appear to afford latitude in any comparisons across clinical trials that may be required to assess what is best for a given patient population.
The Staff acknowledged that Yuviwel has additional benefits over Voxzogo, such as not requiring toddler patients are fed and hydrated before administration, which can lead to increased adherence. The Staff, however, discounted this evidence because Yuviwel has the additional risk of neutralizing antibodies. But even if Yuviwel has its own disadvantages, the ALJ may find that is arguably irrelevant to the question for the public interest, i.e., whether the public will be best served by allowing patients to have two medical options rather than just one. In other words, the public interest does not necessarily demand that Yuviwel is a better drug across the board, but only that, given the different preferences, immunities, allergies and sensitivities of certain pediatric patient populations, they have access to a diversity of medical options that can best blanket every child patient in that population.
It bears emphasis that the ITC rarely relies upon public interest considerations to preclude an import ban when one is otherwise warranted. Indeed, as I’ve discussed in a prior post, the ITC has heard very few cases related to pharmaceutical drugs that raise health-related public interest concerns. This fact may discourage any Staff attorney from going out on a limb and arguing that the public interest alone warrants denial of an import ban. Indeed, the Staff did acknowledge that public interest concerns exist, namely, the adverse effects of Voxzogo's daily injections versus Yuviwel's weekly injections, but did not conclude they warranted a complete denial of relief to Biomarin.
In sum, the Staff’s brief undoubtedly provides some transparency into how the ALJ or Commission may come out on a host of disputes at issue in this proceeding. Nevertheless, the public interest issue in particular may still have sufficient traction to allow Ascendis to continue to distribute Yuviwel to patients unimpeded by an import ban.