What’s So Special About Patent Law?

The widespread belief that patent law is special has shaped the development of patent law into one of the most specialized areas of the law today. The belief in patent law’s exceptionalism manifests itself as two related presumptions with respect to the judiciary: first, that generalist judges who do not have patent law expertise cannot effectively decide patent cases, and second, that judges can develop necessary expertise through repeated experience with patent cases. Congress showed that it acquiesced to both views when it created the Federal Circuit and the Patent Pilot Program. In recent years, however, the Supreme Court has reminded us that the judiciary’s difficulty with patent cases is not the law, but is instead that patent cases often involve difficult subject matter, which sometimes requires technical or scientific expertise. While Congress’s early attempts to deal with these difficulties focused on courts with legal―rather than technical―expertise, the Supreme Court’s recent pronouncements suggest that they should have been doing the reverse. Moreover, to the extent that it is the underlying technology that makes patent cases difficult, that commends the use of an administrative, rather than a judicial, solution. One potentially viable answer to the judiciary’s problem with patent law has already been partly implemented in the form of the recently created Patent Trial and Appeal Board. This Article proposes expansion of that solution by making that new entity the exclusive forum for deciding issues of patent validity

Coumarins as factor XIIa inhibitors:Potency and selectivity improvements using a fragment-based strategy

Previously, we described weak coumarin inhibitors of factor XIIa, a promising target for artificial surface-induced thrombosis and various inflammatory diseases. In this work, we used fragment-based drug discovery approach to improve our coumarin series. First, we screened about 200 fragments for the S1 pocket. The S1 pocket of trypsin-like serine proteases, such as factor XIIa, is highly conserved and is known to drive a major part of the association energy. From the screening, we selected fragments displaying a micromolar activity and studied their selectivity on other serine proteases. Then, these fragments were merged to our coumarin templates, leading to the generation of nanomolar inhibitors. The mechanism of inhibition was further studied by mass spectrometry demonstrating the covalent binding through the formation of an acyl enzyme complex. The most potent compound was tested in plasma to evaluate its stability and efficacy on coagulation assays. It exhibited a plasmatic half-life of 1.9 h and a good selectivity for the intrinsic coagulation pathway over the extrinsic one.</p

Gasdermin D membrane pores orchestrate IL-1α secretion from necrotic macrophages after NFS-rich silica exposure.

IL-1α is an intracellular danger signal (DAMP) released by macrophages contributing to the development of silica-induced lung inflammation. The exact molecular mechanism orchestrating IL-1α extracellular release from particle-exposed macrophages is still unclear. To delineate this process, murine J774 and bone-marrow derived macrophages were exposed to increasing concentrations (1-40 cm/ml) of a set of amorphous and crystalline silica particles with different surface chemical features. In particular, these characteristics include the content of nearly free silanols (NFS), a silanol population responsible for silica cytotoxicity recently identified. We first observed de novo stocks of IL-1α in macrophages after silica internalization regardless of particle physico-chemical characteristics and cell stress. IL-1α intracellular production and accumulation were observed by exposing macrophages to biologically-inert or cytotoxic crystalline and amorphous silicas. In contrast, only NFS-rich reactive silica particles triggered IL-1α release into the extracellular milieu from necrotic macrophages. We demonstrate that IL-1α is actively secreted through the formation of gasdermin D (GSDMD) pores in the plasma membrane and not passively released after macrophage plasma membrane lysis. Our findings indicate that the GSDMD pore-dependent secretion of IL-1α stock from macrophages solely depends on cytotoxicity induced by NFS-rich silica. This new regulated process represents a key first event in the mechanism of silica toxicity, suitable to refine the existing adverse outcome pathway (AOP) for predicting the inflammatory activity of silicas

Distinct Pro-Inflammatory Mechanisms Elicited by Short and Long Amosite Asbestos Fibers in Macrophages

International audienceWhile exposure to long amphibolic asbestos fibers (L &gt; 10 µm) results in the development of severe diseases including inflammation, fibrosis, and mesothelioma, pathogenic activity associated with short &lt; 5 is less clear. By exposing murine macrophages (SFA) or (LFA) amosite different size surface chemistry, we observed that SFA internalization resulted pyroptotic-related immunogenic cell death (ICD) characterized by release pro-inflammatory damage signal (DAMP) IL-1α after inflammasome activation gasdermin D (GSDMD)-pore formation. In contrast, macrophage responses non-internalizable LFA were tumor necrosis factor alpha (TNF-α) release, caspase-3 -7 activation, apoptosis. effects exclusively from Toll-like receptor 4 (TLR4), a pattern-recognition (PRR) recognized for its ability sense particles, while response was elicited multifactorial ignition system involving collagenous structure (SR-A6 MARCO), reactive oxygen species (ROS) cascade, TLR4. Our findings indicate fiber features play major roles modulating ICD inflammatory pathways. They also suggest are biologically vitro and, therefore, their toxic vivo should not be underestimated

Effects of different amosite preparations on macrophages, lung damages, and autoimmunity

International audienceThe underlying mechanisms of asbestos-related autoimmunity are poorly understood. As the size, surface reactivity, and free radical activity of asbestos particles are considered crucial regarding the health effects, this study aims to compare the effects of exposure to pristine amosite (pAmo) or milled amosite (mAmo) particles on lung damage, autoimmunity, and macrophage phenotype. Four months after lung exposure to 0.1 mg of amosite, BAL levels of lactate dehydrogenase, protein, free DNA, CCL2, TGF-β1, TIMP-1, and immunoglobulin A of pAmo-exposed C57Bl/6 mice were increased when compared to fluids from control- and mAmo-exposed mice. Effects in pAmo-exposed mice were associated with lung fibrosis and autoimmunity including anti-double-strand DNA autoantibody production. mAmo or pAmo at 20 µg/cm(2) induced a pro-inflammatory phenotype characterized by a significant increase in TNFα and IL-6 secretion on human monocyte-derived macrophages (MDMs). mAmo and pAmo exposure induced a decrease in the efferocytosis capacities of MDMs, whereas macrophage abilities to phagocyte fluorescent beads were unchanged when compared to control MDMs. mAmo induced IL-6 secretion and reduced the percentage of MDMs expressing MHCII and CD86 markers involved in antigen and T-lymphocyte stimulation. By contrast, pAmo but not mAmo activated the NLRP3 inflammasome, as evaluated through quantification of caspase-1 activity and IL-1β secretion. Our results demonstrated that long-term exposure to pAmo may induce significant lung damage and autoimmune effects, probably through an alteration of macrophage phenotype, supporting in vivo the higher toxicity of entire amosite (pAmo) with respect to grinded amosite. However, considering their impact on efferocytosis and co-stimulation markers, mAmo effects should not be neglected. KEY MESSAGES: Lung fibrosis and autoimmunity induced by amosite particles depend on their physicochemical characteristics (size and surface) Inhalation exposure of mice to pristine amosite fibers is associated with lung fibrosis and autoimmunity Anti-dsDNA antibody is a marker of autoimmunity in mice exposed to pristine amosite fibers Activation of lung mucosa-associated lymphoid tissue, characterized by IgA production, after exposure to pristine amosite fibers Pristine and milled amosite particle exposure reduced the efferocytosis capacity of human-derived macrophages