The New Cybersquatters: The Evolution of Trademark Enforcement in the Domain Name Space

The domain name space has become a particularly contentious area of trademark enforcement as a result of the growth of online commerce, an intense competition for popular domain names, and new conceptual challenges stemming from the borderless and textual nature of the medium. In response, the Internet Corporation for Assigned Names and Numbers (“ICANN”), a global non-profit which oversees the domain-name space, has implemented a highly sophisticated set of rights-protection mechanisms. This Article examines the scope of trademark protections applied under ICANN’s rights protection mechanisms to demonstrate that they have evolved far beyond their traditional consumer protection function; indeed, they have morphed into offensive brand management tools, whose application in the global domain name space vastly exceeds the protections that are available under domestic legal frameworks. The Article begins by introducing ICANN and its main trademark protection instruments, namely the Uniform Dispute Resolution Policy, the Uniform Rapid Suspension, and the Trademark Clearinghouse, before demonstrating the divergence between protections under these systems and the protections under domestic legal frameworks. The result is that trademark owners turn to ICANN for rights and remedies that would not be available from ordinary sovereigns, embodying a major expansion of trademark protections. The Article concludes by outlining the contours of ongoing discussions re-examining these mechanisms, and the challenges in curbing this maximalist view of trademark law

Subverting Democracy to Save Democracy: Canada’s Extra-Constitutional Approaches to Battling “Fake News”

Nearly a decade after the first Twitter and Facebook revolutions, the early narratives pointing to social media as a great agent of democratization1 have given way to a more nuanced understanding of the impact of the Internet on our political discourse. While there is no question that Internet access provides tremendous expressive benefits, scholars are increasingly questioning whether this information diet is ultimately healthy for society. An analogy to sugars, fats and salts has emerged, where just as an appetite for rich foods served our species well when resources were scarce, but have become a liability in an age of plenty, our natural curiosity and hunger for new ideas has led to problems in an online world teeming with misinformation and extremism. The potential for mischief was illustrated in stark terms in 2016, when well documented campaigns of foreign interference, including social media manipulation, impacted both the Brexit referendum and the United States presidential race. In response to these, and other high profile cases of the Internet being used as a vector to distribute manipulative content, many countries around the world are re-examining their approach to regulating online speech, as well as their specific posture on electrion speech. However, while there is no question that the Internet has created a raft of new regulatory challenges, it is important not to lose sight of the foundational importance of freedom of expression to an effective democracy. Solutions which attempt to address the challenges posed by online speech, but which do this by undermining core freedom of expression principles, are ultimately destined to be counter-productive. Any victory against forces that threaten our democracy will be hollow if it comes at the cost of the human rights principles which undergird our democratic system

Squaring the Circle Between Freedom of Expression and Platform Law

Among the greatest emerging challenges to global efforts to promote and protect human rights is the role of private sector entities in their actualization, since international human rights rules were designed to apply primarily, and in many cases solely, to the actions of governments. This paradigm is particularly evident in the expressive space, where private sector platforms play an enormously influential role in determining the boundaries of acceptable speech online, with none of the traditional guardrails governing how and when speech should be restricted. Many governments now view platform-imposed rules as a neat way of sidestepping legal limits on their own exercise of power, pressuring private sector entities to crack down on content which they would be constitutionally precluded from targeting directly. For their part, the platforms have grown increasingly uncomfortable with the level of responsibility they now wield, and in recent years have sought to modernize and improve their moderation frameworks in line with the growing global pressure they face. At the heart of these discussions are debates around how traditional human rights concepts like freedom of expression might be adapted to the context of “platform law.” This Article presents a preliminary framework for applying foundational freedom of expression standards to the context of private sector platforms, and models how the three-part test, which lies at the core of understandings of freedom of expression as a human right, could be applied to platforms’ moderation functions

Understanding the Internet as a Human Right

Around the world, fundamental human rights have undergone a dramatic conceptual shift as a result of the spread of the Internet. The right to freedom of expression, once largely limited to printing, has exploded in a digital world that provides users with an unprecedented megaphone to broadcast their views. The right to political participation and the right to free assembly have similarly been reborn in an age of instant communication, allowing activists to mobilise hundreds of thousands of followers with a single email, text or tweet. Although these are the most notable examples, the Internet has also had a transformative impact on several other recognised human rights, including the right to education, to healthcare and to work. The Internet’s role in the enabling and delivery of human rights has led some to claim that access to the Internet itself should be considered a human right, an idea that has deep implications for both international law and domestic legal frameworks. If, indeed, access to the Internet is a human right, it adds an additional dimension to regulatory issues, since overly restrictive laws that compromise access or damage the vitality or utility of the Internet become more than just bad policy. In some cases, they may constitute violations of international human rights standards. This Paper discusses the Internet’s recognition as a human right and the implications that spring from this recognition in domestic and international law

Computational Design of Affinity and Specificity at Protein-Protein Interfaces

The computer-based design of protein-protein interactions is a rigorous test of our understanding of molecular recognition and an attractive approach for creating novel tools for cell and molecular research. Considerable attention has been placed on redesigning the affinity and specificity of naturally occurring interactions. Several studies have shown that reducing the desolvation costs for binding while preserving shape complimentarity and hydrogen bonding is an effective strategy for improving binding affinities. In favorable cases specificity has been designed by focusing only on interactions with the target protein, while in cases with closely related off-target proteins, it has been necessary to explicitly disfavor unwanted binding partners. The rational design of protein-protein interactions from scratch is still an unsolved problem, but recent developments in flexible backbone design and energy functions hold promise for the future

Overseeing Oversight

Accountability is at the core of democratic governance. In the United States, the administrative state is formally situated within the executive branch, but the unelected nature of agency officials, combined with the vast power they wield, has long been cause for concern. A crucial tool for establishing accountability within this so-called “Fourth Branch” is the Freedom of Information Act (FOIA), which provides ordinary members of the public with a mechanism for direct oversight of how administrative agencies function. Similar right-to-information laws have been implemented in over one hundred countries. However, in contrast to most of its international counterparts, the FOIA system is severely undermined by its own lack of institutional oversight. Apart from the rare case that makes it to court, agency decisions against releasing records to the public generally are not subject to meaningful review. While there has been no shortage of scholarship documenting the practical challenges with FOIA, this Article is the first to connect these problems to the institutional design choice at the root of FOIA’s oversight deficit. The Article traces the history of FOIA, including the most recent reforms that introduced a FOIA ombudsman office, and documents how the remedies for agency recalcitrance are inadequate to protect the public’s right to information. It then presents a comparative survey of global right-to-information models to pinpoint precisely what design aspects are essential to an effective oversight regime. It argues that the strongest models rely on an independent administrative body, such as an information commission, which is located outside of the executive branch entirely and has the power to order administrative agencies to release records when the commission’s review results in a conclusion that withholding is unjustified under the law. At a time when abuses of executive power have jolted the nation’s collective consciousness, and when the United States’ democratic institutions have faced their most serious threat since the Civil War, there is enormous urgency to improve our mechanisms for democratic oversight, namely through developing oversight of these very structures. This Article documents the democratic deficit underlying our current FOIA remedies and analyzes better institutional design alternatives

Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.This work was supported by grants from the National Center for Research Resources (5P30RR030926) and the National Institute of General Medical Sciences (1R01GM099959 and 8P30GM103495) of the National Institutes of Health, and the Alfred P. Sloan Fellowship (JK)

Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations

Small-molecules that inhibit interactions between specific pairs of proteins have long represented a promising avenue for therapeutic intervention in a variety of settings. Structural studies have shown that in many cases, the inhibitor-bound protein adopts a conformation that is distinct from its unbound and its protein-bound conformations. This plasticity of the protein surface presents a major challenge in predicting which members of a protein family will be inhibited by a given ligand. Here, we use biased simulations of Bcl-2-family proteins to generate ensembles of low-energy conformations that contain surface pockets suitable for small molecule binding. We find that the resulting conformational ensembles include surface pockets that mimic those observed in inhibitor-bound crystal structures. Next, we find that the ensembles generated using different members of this protein family are overlapping but distinct, and that the activity of a given compound against a particular family member (ligand selectivity) can be predicted from whether the corresponding ensemble samples a complementary surface pocket. Finally, we find that each ensemble includes certain surface pockets that are not shared by any other family member: while no inhibitors have yet been identified to take advantage of these pockets, we expect that chemical scaffolds complementing these “distinct” pockets will prove highly selective for their targets. The opportunity to achieve target selectivity within a protein family by exploiting differences in surface fluctuations represents a new paradigm that may facilitate design of family-selective small-molecule inhibitors of protein-protein interactions.This work was supported by a grant from the National Institute of General Medical Sciences of the National Institutes of Health (R01GM099959), the National Science Foundation through XSEDE allocation MCB130049, and the Alfred P. Sloan Fellowship (JK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

DARC 2.0: Improved Docking and Virtual Screening at Protein Interaction Sites

Over the past decade, protein-protein interactions have emerged as attractive but challenging targets for therapeutic intervention using small molecules. Due to the relatively flat surfaces that typify protein interaction sites, modern virtual screening tools developed for optimal performance against “traditional” protein targets perform less well when applied instead at protein interaction sites. Previously, we described a docking method specifically catered to the shallow binding modes characteristic of small-molecule inhibitors of protein interaction sites. This method, called DARC (Docking Approach using Ray Casting), operates by comparing the topography of the protein surface when “viewed” from a vantage point inside the protein against the topography of a bound ligand when “viewed” from the same vantage point. Here, we present five key enhancements to DARC. First, we use multiple vantage points to more accurately determine protein-ligand surface complementarity. Second, we describe a new scheme for rapidly determining optimal weights in the DARC scoring function. Third, we incorporate sampling of ligand conformers “on-the-fly” during docking. Fourth, we move beyond simple shape complementarity and introduce a term in the scoring function to capture electrostatic complementarity. Finally, we adjust the control flow in our GPU implementation of DARC to achieve greater speedup of these calculations. At each step of this study, we evaluate the performance of DARC in a “pose recapitulation” experiment: predicting the binding mode of 25 inhibitors each solved in complex with its distinct target protein (a protein interaction site). Whereas the previous version of DARC docked only one of these inhibitors to within 2 Å RMSD of its position in the crystal structure, the newer version achieves this level of accuracy for 12 of the 25 complexes, corresponding to a statistically significant performance improvement (p < 0.001). Collectively then, we find that the five enhancements described here – which together make up DARC 2.0 – lead to dramatically improved speed and performance relative to the original DARC method

Atomic accuracy in predicting and designing non-canonical RNA structure

We present a Rosetta full-atom framework for predicting and designing the non-canonical motifs that define RNA tertiary structure, called FARFAR (Fragment Assembly of RNA with Full Atom Refinement). For a test set of thirty-two 6-to-20-nucleotide motifs, the method recapitulated 50% of the experimental structures at near-atomic accuracy. Additionally, design calculations recovered the native sequence at the majority of RNA residues engaged in non-canonical interactions, and mutations predicted to stabilize a signal recognition particle domain were experimentally validated