How should policymakers incentivize and regulate convalescent serum therapy for COVID-19?

By Jacob S. Sherkow, Lisa Larrimore Ouellette, Nicholson Price, and Rachel Sachs

Over 120 years ago, a milk wagon horse named Jim was the United States’ most potent weapon against a raging diphtheria epidemic. During his lifetime, Jim—inoculated against the bacterial toxin that causes the disease—produced gallons of anti-diphtheria serum that, once extracted, could then be administered directly to patients. But tragic difficulties in making a safe and standard therapy from a single horse led Congress to pass the 1902 Biologics Control Act—the predecessor to the FDA’s current oversight over biologic products.

While convalescent sera have largely fallen out of favor since the development of modern vaccines, there is renewed hope in the space: the development of therapeutic sera from recovered COVID-19 patients. Encouraging the development of safe, pure, and potent COVID-19 convalescent serum has recently tasked policymakers with numerous challenges—some old, and some new. In this post, we explain the “manufacture” of COVID-19 convalescent sera and explore the regulatory and innovation policy difficulties in maintaining it.

How will the FDA’s new COVID-19 vaccine guidance affect development efforts?

By Rachel Sachs, Jacob S. Sherkow, Lisa Larrimore Ouellette, and Nicholson Price

Policymakers are expectantly awaiting the development of a COVID-19 vaccine, which they view as critical to future management of the pandemic. A number of pharmaceutical companies have jumped into the vaccine race, moving at record speed, with several vaccines already about to enter Phase III trials. Last week, the Food and Drug Administration (FDA) released a guidance document on the development of new vaccines for COVID-19. In this post, we review the FDA’s new guidance, consider the ways in which the FDA must attempt to balance risk and access in this context, and address the critical question of patient access to future approved vaccines.

How Does Patent Eligibility Affect Investment?

David Taylor (SMU) was interested in how patent eligibility decisions at the Supreme Court affected venture investment decisions, so he thought he would ask. He put together an ambitious survey of 14,000 investors at 3000 firms, and obtained some grant money to provide incentives. As a result, he got responses from 475 people at 422 firms. The response rate by individual is really low, but by firm it's 12% - not too bad. He performs some analysis of non-responders, and while there's a bit of an oversample on IT and on early funding, it appears to be somewhat representative.

The result is a draft on SSRN and forthcoming in Cardozo L. Rev. called Patent Eligibility and Investment. Here is the abstract:

Have the Supreme Court’s recent patent eligibility cases changed the behavior of venture capital and private equity investment firms, and if so how? This Article provides empirical data about investors’ answers to those important questions. Analyzing responses to a survey of 475 investors at firms investing in various industries and at various stages of funding, this Article explores how the Court’s recent cases have influenced these firms’ decisions to invest in companies developing technology. The survey results reveal investors’ overwhelming belief that patent eligibility is an important consideration in investment decisionmaking, and that reduced patent eligibility makes it less likely their firms will invest in companies developing technology. According to investors, however, the impact differs between industries. For example, investors predominantly indicated no impact or only slightly decreased investments in the software and Internet industry, but somewhat or strongly decreased investments in the biotechnology, medical device, and pharmaceutical industries. The data and these findings (as well as others described in the Article) provide critical insight, enabling evidence-based evaluation of competing arguments in the ongoing debate about the need for congressional intervention in the law of patent eligibility. And, in particular, they indicate reform is most crucial to ensure continued robust investment in the development of life science technologies.

The survey has some interesting results. Most interesting to me was that fewer than 40% of respondents were aware of any of the key eligibility decisions, though they may have been vaguely aware of reduced ability to patent. More on this in a minute.

There are several findings on the importance of patents, and these are consistent with the rest of the literature - that patents are important for investment decisions, but not first on the list (or second or third). Further, the survey finds that firms would invest less in areas where there are fewer patents - but this is much more pronounced for biotech and pharma than it is for IT. This, too, seems to comport with anecdotal evidence.

But I've always been skeptical of surveys that ask what people would do - stated preferences are different than revealed preferences. The best way to measure revealed preferences would be through some sort of empirical look at the numbers, for example a differences-in-differences approach before and after these cases (though having 60% of the people say they haven't heard of them would certainly affect whether the case constitutes a "shock" - a requirement of such a study).

Another way, which this survey attempts, is to ask not what investors would do but rather ask what they have done. This amounts to the most interesting part of the survey - investors who know about the key court opinions say they have moved out of biotech and pharma, and into IT. So much for Alice destroying IT investment, as some claim (though we might still see a shift in the type of projects and/or the type of protection - such as trade secrets). But more interesting to me was that there was also a similar shift among those folks who claimed not to know much about patent eligibility or think it had anything to do with their investment. In other words, even for that group who didn't actively blame the Supreme Court, they were shifting investments out of biotech and pharma and into IT.

You can, of course, come up with other explanations - perhaps biotech is just less valuable now for other reasons. But this survey is an important first step in teasing out those issues.

There are a lot more questions on the survey and some interesting answers. It's a relatively quick and useful read.

Recent Advances in Biologics Manufacturing Diminish the Importance of Trade Secrets: A Response to Price and Rai

Guest post by Rebecca Weires, a 2L in the J.D./M.S. Bioengineering program at Stanford

In their 2016 paper, Manufacturing Barriers to Biologics Competition and Innovation, Price and Rai argue the use of trade secrets to protect biologics manufacturing processes is a social detriment. They go on to argue policymakers should demand more enabling disclosure of biologics manufacturing processes, either in patents or biologics license applications (BLAs). The authors premise their arguments on an assessment that (1) variations in the synthesis process can unpredictably affect the structure of a biological product; (2) variations in the structure of a biological product can unpredictably affect the physiological effects of the product, including immunogenicity; and (3) analytical techniques are inadequate to characterize the structure of a biological product. I am more optimistic than Price and Rai that researchers will soon overcome all three challenges. Where private-sector funding may fall short, grant-funded research has already led to tremendous advances in biologics development technology. Rather than requiring more specific disclosure of synthesis processes, as Price and Rai recommend, FDA could and should require more specific disclosure of structure, harmonizing biologics regulation with small molecule regulation. FDA should also incentivize development of industrial scale cell-free protein synthesis processes.

Burk: Is Dolly patentable subject matter in light of Alice?

Dan Burk's work should already be familiar to those who follow patentable subject matter debates (see, e.g., here, here, and here). In a new essay, Dolly and Alice, he questions whether the Federal Circuit's May 2014 In re Roslin decision—holding clones such as Dolly to not be patentable subject matter—should have come out differently under the Supreme Court's June 2014 decision in Alice v. CLS Bank. Short answer: yes.

Burk does not have kind words for either the Federal Circuit or the Supreme Court, and he reiterates his prior criticism of developments like the gDNA/cDNA distinction in Myriad. His analysis of how Roslin should be analyzed under Alice begins on p. 11 of the current draft:

[E]ven assuming that the cloned sheep failed the first prong of the Alice test, the analysis would then move to the second prong to look for an "inventive concept" that takes the claimed invention beyond an attempt to merely capture the prohibited category of subject matter identified in the first step. . . . The Roslin patent claims surely entail such an inventive concept in the method of creating the sheep. The claims recite "clones," which the specification discloses were produced by a novel method that is universally acknowledged to have been a highly significant and difficult advance in reproductive technology—an "inventive concept" if there ever was one . . . [which] was not achieved via conventional, routine, or readily available techniques . . . .

But while Burk thinks Roslin might have benefited from the Alice framework, he also contends that this exercise demonstrates the confusion Alice creates across a range of doctrines, and particularly for product by process claims. He concludes by drawing an interesting parallel to the old Durden problem of how the novelty of a starting material affects the patentability of a process, and he expresses skepticism that there is any coherent way out; rather, he thinks Alice "leaves unsettled questions that will haunt us for years to come."

Sampat & Williams on the Effect of Gene Patents on Follow-on Innovation

Bhaven Sampat (Columbia Public Health) and Heidi Williams (MIT Econ) are two economists whose work on innovation is always worth reading. I've discussed a number of their papers before (here, here, here, here, and here), and Williams is now a certified genius. They've posted a new paper, How Do Patents Affect Follow-On Innovation? Evidence from the Human Genome, which is an important follow-up to Williams's prior work on gene patents. Here is the abstract:

We investigate whether patents on human genes have affected follow-on scientific research and product development. Using administrative data on successful and unsuccessful patent applications submitted to the US Patent and Trademark Office, we link the exact gene sequences claimed in each application with data measuring follow-on scientific research and commercial investments. Using this data, we document novel evidence of selection into patenting: patented genes appear more valuable — prior to being patented — than non-patented genes. This evidence of selection motivates two quasi-experimental approaches, both of which suggest that on average gene patents have had no effect on follow-on innovation.

Their second empirical design is particularly clever: they use the leniency of the assigned patent examiner as an instrumental variable for which patent applications are granted patents. Highly recommended.

The Latest on Biosimilars: The Federal Circuit Holds that the "Patent Dance" Is Optional

In a previous post, I discussed a district court decision holding that the process for resolving patent disputes under the Biologics Price Competition and Innovation Act (BPCIA) is optional. That post contains extensive background on the BPCIA and its purpose of providing an abbreviated pathway for “biosimilar” drugs to get to market and compete with their branded analogs, resulting in lower prices for consumers. The bottom line is that, under the BPCIA, makers of biosimilar products can rely on the clinical trial data developed for the branded (or “reference”) product in order to accelerate FDA approval. Nevertheless, the BPCIA provides 12 years of data exclusivity to the manufacturer of the reference product. And beyond that period, even if the biosimilar garners FDA approval, the brand owner can try to continue to keep it out of the market by asserting claims of patent infringement. The BPCIA provides for a procedure involving pre-suit information exchange between the brand and biosimilar makers—the so-called “patent dance”—that is intended to apprise the brand of the biosimilar’s manufacturing process and narrow down the number of patents to be be asserted. But the district court, and now the Federal Circuit on appeal, have held that the biosimilar can lawfully refuse to participate in the patent dance.

Price and Rai on Biologic Secrecy

Nicholson Price and Arti Rai just posted Manufacturing Barriers to Biologics Competition and Innovation, which is forthcoming in the Iowa Law Review. Here is the abstract:

As finding breakthrough small-molecule drugs gets harder, drug companies are increasingly turning to “large molecule” biologics. Although biologics represent many of the most promising new therapies for previously intractable diseases, they are extremely expensive. Moreover, the pathway for generic-type competition set up by Congress in 2010 is unlikely to yield significant cost savings. 

In this Article, we provide a fresh diagnosis of, and prescription for, this major public policy problem. We argue that the key cause is pervasive trade secrecy in the complex area of biologics manufacturing. Under the current regime, this trade secrecy, combined with certain features of FDA regulation, not only creates high barriers to entry of indefinite duration but also undermines efforts to advance fundamental knowledge. 

In sharp contrast, offering incentives for information disclosure to originator manufacturers would leverage the existing interaction of trade secrecy and the regulatory state in a positive direction. Although trade secrecy, particularly in complex areas like biologics manufacturing, often involves tacit knowledge that is difficult to codify and thus transfer, in this case regulatory requirements that originator manufacturers submit manufacturing details have already codified the relevant tacit knowledge. Incentivizing disclosure of these regulatory submissions would not only spur competition but it would provide a rich source of information upon which additional research, including fundamental research into the science of manufacturing, could build. 

In addition to provide fresh diagnosis and prescription in the specific area of biologics, the Article contributes to more general scholarship on trade secrecy and tacit knowledge. Prior scholarship has neglected the extent to which regulation can turn tacit knowledge not only into codified knowledge but into precisely the type of codified knowledge that is most likely to be useful and accurate. The Article also draws a link to the literature on adaptive regulation, arguing that greater regulatory flexibility is necessary and that more fundamental knowledge should spur flexibility.

Small-molecule pharmaceutical drugs have long been the poster child for the patent system, but as Allison, Lemley & Schwartz have recently reminded us, pharma and biotech are not the same and may have very different patent ecosystems. For anyone interested in IP policy in the biologics space, this new piece by Price and Rai is highly recommended.

Do Biosimilar Manufacturers Have To Dance? A District Court Answers “No”

In 2010, Congress enacted the Biologics Price Competition and Innovation Act (BPCIA) as part of the Affordable Care Act. BPCIA is, in a broad sense, intended to be the analog of the Hatch-Waxman Act for biologic drugs. Hatch-Waxman provides a pathway for Food and Drug Administration (FDA) approval for small-molecule generic drugs. Vastly simplified, the Hatch-Waxman process comes down to this: if a follow-on (i.e., generic) manufacturer can make an identical copy of the branded drug molecule, it can obtain FDA approval to market the drug without the clinical trials that the drug’s originator had to go through to prove that the drug is safe and effective. This saves costs for the generic manufacturer and, once the generic goes on the market, lowers prices for consumers. Under Hatch-Waxman, a follow-on manufacturer’s act of filing a so-called Abbreviated New Drug Application is an act of patent infringement, and so the originator can try to keep generic drugs off the market using patent law. The Food, Drug, and Cosmetics Act also provides periods of market and data exclusivities even for originator drugs that are not covered by patents. But once those periods end and the generic manufacturer can prove chemical identity to the brand, the generic drug is good to go on the market as far as the FDA is concerned—and the only barrier left is the brand’s potential patent infringement claims.

Guest Post on Dan Burk's "Curious Incident of the Supreme Court in Myriad Genetics"

This is a guest post by Vikram Iyengar, a J.D. student at Stanford Law School. He thanks Prof. Mark Lemley for introducing him to Patent Law, and Prof. Hank Greely for his guidance with this research topic.

Patentable Subject Matter and Non-Patent Innovation Incentives

I just posted my symposium essay from U.C. Irvine's Meaning of Myriad Conference: Patentable Subject Matter and Non-Patent Innovation Incentives. Here is the abstract—comments welcome!

In four patentable subject matter cases in the past five Terms, the Supreme Court has reaffirmed the judicially created prohibitions on patenting “abstract ideas” and “nature,” but the boundaries of these exceptions remain highly contested. The dominant justification for these limitations is utilitarian: courts create exemptions in areas where patents are more likely to thwart innovation than to promote it. The resulting debates thus focus on whether patents are needed to provide adequate innovation incentives in disputed fields such as software or genetic research, or whether private incentives such as reputational gains, first-mover advantages, or competitive pressures are sufficient. These debates frequently overlook a significant fact: the absence of patents does not imply that there would be only private incentives. Rather, federal and state governments facilitate financial transfers to researchers through a host of mechanisms—including tax incentives, direct grants and contracts, prizes, and regulatory exclusivity—which already provide substantial research support in the fields where patents are the most controversial.

Paying attention to non-patent incentives could prevent courts from being misled by the concern that a lack of patents for a certain type of invention would remove all incentives for nonobvious and valuable research in that field. Non-patent innovation incentives could also help ease the tension between utilitarian and moral considerations in the current patentable subject matter debates: if many people find patents on certain inventions (such as “human genes”) morally objectionable, utilitarian goals can still be served by using other transfer mechanisms to substitute for the incentive provided by patents. Indeed, non-patent incentives may be more effective than patents in contested areas, where inventors who share moral objections find little incentive in patents, and those who do not still find the patent incentive to be dulled by the persistent uncertainty that has plagued patentable subject matter doctrine in recent years. Wider appreciation of the range of innovation incentives would help bring patentable subject matter discussions in line with the realities of scientific research, and might even make this doctrinal morass more tractable.

IP Watch Recap of Meaning of Myriad Conference

Last Friday I presented my latest essay, Patentable Subject Matter and Non-Patent Innovation Incentives, at UC Irvine's Meaning of Myriad Conference, which included a terrific line-up of speakers. Brittany Ngo, a 3L at UC Irvine, nicely recapped the conference for IP Watch: Experts Look At The Meaning Of Myriad Case, One Year Later. Her article is paywalled, but it is published under the CC BY-NC-ND license, so I am redistributing the article here (with attribution, for noncommercial use, and without modification).

Arti Rai – Patent Validity Across the Executive Branch: Ex Ante Foundations for Policy Development

What can the recent DNA patent controversies teach us about the role of executive agencies in shaping patent policy? In Professor Arti Rai’s essay: Patent Validity Across the Executive Branch: Ex Ante Foundations for Patent Development, Rai analyzes how systematic interagency debate can facilitate the development of beneficial patent policy ex ante. Professor Rai uses recent Supreme Court holdings to demonstrate that executive agencies like the International Trade Commission (ITC), the National Institute of Health (NIH), and the Department of Justice can work in tandem with the U.S. Patent and Trademark Office (PTO or Patent Office) to avoid some of the policy pitfalls created by the U.S. Court of Appeals for the Federal Circuit (Federal Circuit) and Congress.

Are Biotech Patents Enabled?

Stanford 3L Dmitry Karshtedt, who has guest posted on this blog, has a new post on Stanford's Law and Biosciences Blog about biologics, which are complicated drugs like erythropoietin that are typically made using living cells, as distinct from easily replicated small-molecule drugs like aspirin.

Karshtedt discusses his new paper, Limits on Hard-To-Reproduce Inventions: Process Elements and Biotechnology's Compliance with the Enablement Requirement, in which he argues that claim limitations can help enable biotech patents. I have also discussed the enablement problem for biologics starting at ¶ 106 of Access to Bio-Knowledge: From Gene Patents to Biomedical Materials, which cites Gregory Mandel's argument that many biotech patents fail enablement. What do readers think: is enablement a problem for biotech? Should biotech patents disclose more? I'd like to think about this issue more as I revise my paper on patent disclosure.

Heidi Williams: IP on Genes

How does intellectual property protection for human genes influence the development of products based on these genes? A few weeks ago, Heidi Williams (NBER fellow and incoming MIT econ prof) presented to the Yale Law School Information Society Project about her empirical study of this topic: Intellectual Property Rights and Innovation: Evidence from the Human Genome.

Williams looked at the race to sequence the human genome between the Human Genome Project, whose genes were freely available, and Celera, whose genes were protected through contractual restrictions on redistribution and licenses for commercial uses. (So Williams was not looking at gene patents, but her results may have implications for the gene patent controversy and Myriad case.) Celera's IP protection only lasted until the gene was re-sequenced by the Human Genome Project, which meant a maximum of two years of protection, ending in 2003. To my knowledge, this is the first paper to look at the impact of open access not just on publications, but also on commercial products. The results are very interesting:

Robin Feldman on Owning You

The fourth paper in my review of Stanford's Bilski Symposium is Whose Body Is It Anyway? Human Cells and the Strange Effects of Property & Intellectual Property Law by Robin Feldman (U.C. Hastings Law). Feldman's thought-provoking paper was presented in the same panel as the paper on genetic diagnostic patents by Dreyfuss and Evans, and she expresses a similar concern about genetic patents. Although the title and beginning of the paper led me to believe that it would focus on moral and ethical concerns of patenting DNA (which I have argued are not as significant as potential concerns about healthcare and basic research), Feldman actually presents a "modest and practical approach." She concludes that genes should be patentable, but only under a narrow claim scope.

Part I is about neither patents nor Bilski: Feldman argues that Moore v. Regents of the University of California (holding that a patient who consented to removal of his cells did not have a property interest in those cells) was wrongly decided, and that a person should have a property right in cells that are removed from his or her body. (If I were editing this piece, I might recommend that this Part be cut or reduced to a paragraph in the Introduction: this argument isn't new, and I think it detracts from the more interesting arguments in Part II.)

Part II examines "the extent to which inventors can tie up human genes and related substances" in light of Bilski and Association for Molecular Pathology. Like Dreyfuss and Evans, Feldman focuses on the use of "pre-empt" in Bilski, arguing that "[i]n gene-related inventions, pre-emption problems can emerge ... in the context of attempts to tie up a natural phenomenon." Under this preemption test, inventors should not be allowed to patent "the relationship between elevated blood sugar levels and diabetes" but should be able to patent "personalized medicine diagnostic methods, which may involve hundreds of biomarkers and complex statistical modeling." Considering the breast cancer genes at issue in Molecular Pathology, Feldman argues that the diagnostic claims are closer to personalized medicine, while the therapeutic claims (for "the 'method' of determining whether a cancer therapeutic is effective") have "greater problems."

"The more interesting question," writes Feldman, "involves the claims to particular DNA and cDNA sequences created outside the human body." She argues that the common analogy between gene patents and isolated and purified natural products (like the paper pulp in the 1874 American Wood-Paper case) is outdated because "the modern creation of genetic inventions no longer requires purification"; instead, genes can be built "from the ground up" through chemical synthesis. Feldman argues that genes should be patentable if researchers can develop specific uses for them, and that "the fact that genes exist in a natural form in the human body should not prevent patenting of genes in laboratory form." The subject matter test is related to novelty and utility: "we ask whether the invention allows us to accomplish something that we could not accomplish with the natural product. Applying that yardstick to isolated DNA and cDNA would suggest that such products should be considered human invention, rather than the handiwork of nature."

Feldman says that the problem is not gene patents per se; rather, it is "allowing patent holders to reach beyond the state of knowledge at the time of the invention," and "[t]he solution lies in properly limiting the scope of the allowed claim." But unlike Lemley et al., who argue that § 101 independently limits claim scope, Feldman says that "this limitation could be accomplished through the disclosure requirements of section 112." Myriad's BRCA1 patent claims, for example, should be limited to the BRCA1 sequence "for the purposes of breast cancer diagnosis in a designated patient population." (Feldman doesn't explain what "a designated patient population" would be, but presumably it would be something like "women at risk for breast cancer.") These restrictions might be important in some hypotheticals, but they wouldn't satisfy the Molecular Pathology plaintiffs, since the use of the BRCA1 gene for breast cancer diagnosis is what they care about. But presumably Feldman would argue that under our current patent laws, that makes doctrinal sense.

Dreyfuss & Evans: Bilski and Gene Patents

Does Bilski bar patents on genetic diagnostics? All the Justices in Bilski agreed that patents may not "preempt" (or "pre-empt") something, but what does "preempt" mean? Is a gene patent that can't be designed around preemptive? Rochelle Dreyfuss (NYU Law) and James Evans (UNC Genetics and Medicine) tackle these question in the third paper in Stanford's Bilski symposium: From Bilski Back to Benson: Preemption, Inventing Around, and the Case of Genetic Diagnostics.

Like Lemley et al. and Menell, Dreyfuss and Evans agree that the fractured Bilski opinions were uninformative. (Does anyone think the Bilski opinions were great? That would be a novel argument.) They write that "preempt" is used "entirely within the legal domain" and has no meaning in "technological discourse." (It addition to describing displacement of state law by federal law, the term frequently came up in law review article discussions: a "preempted" piece failed the novelty prong for a good law review article.) In Part I, Dreyfuss and Evans argue that § 101 does not tell us "whether" a new technology can be patented, but rather "how" the technology is claimed: "claims that 'preempt' competitive development—that cover prospects that cannot be efficiently mined by individual rights holders—are barred." This is very similar to the argument by Lemley et al. that § 101 is about claim scope, not gatekeeping.

In Part II, Dreyfuss and Evans apply these ideas to patents on genetic diagnostics, which is a subset of what are often called "gene patents," and I will use the "gene patent" shorthand in this post. Lawyers who are unfamiliar with genetic diagnostics will enjoy II.A on "The Science of Genetics." II.B then reviews the SACGHS report on genetic diagnostic patents (Evans was chair of the SACGHS task force). The piece reports that "when there were patents held exclusively by a single entity, both clinical practice and scientific development were impaired," which is a different message from the SACGHS draft report, which concluded that "patents covering genetic tests ... do not appear to be causing wide or lasting barriers to patient or clinical access," as I quoted in Access to Bio-Knowledge: From Gene Patents to Biomedical Materials. But because the draft report found that patents do little to help the development of new genetic diagnostics, I argued in Access to Bio-Knowledge that the report still supported calls for exempting genetic diagnostics from patentability—a conclusion that the final report makes even stronger.

Dreyfuss and Evans hint in Part III that a legislative carve-out may be unnecessary because patents on genetic diagnostics might "preempt" competitive development for at least four reasons: (1) inventing around gene patents is impossible, (2) gene patents limit interoperability, (3) gene patents create broad unmined prospects, and (4) patentees for genetic diagnostics tend to be academics who are not primarily motivated by patents. (This last factor seems like an important policy concern, but the link to preemption is less obvious than for the other three.) The authors never actually say that they think genetic diagnostic patents are not patentable subject matter under Bilski, but they note that "it is no wonder that courts have begun to question the validity of these patents" (citing Association for Molecular Pathology) and that "one Federal Circuit judge has already suggested that Bilski's preemption test raises serious questions about patents on isolated DNA molecules" (citing Judge Dyk's opinion in Intervet v. Merial).

I wish that the paper had a more explicit conclusion—even if the authors do not feel comfortable claiming that genetic diagnostic patents do preempt development and are thus unpatentable subject matter, they could at least lay out what factors still need to be examined to decide whether this is true—but I still think the paper does a nice job of highlighting the preemption concern and thinking about factors that might be relevant in investigating preemption.