Patent Institutions: Shifting Interactions Between Legal Actors

This contribution to the Research Handbook on Economics of Intellectual Property Rights (Vol. 1 Theory) addresses interactions between the principal legal institutions of the U.S. patent system. It considers legal, strategic, and normative perspectives on these interactions as they have evolved over the last 35 years. Early centralization of power by the U.S. Court of Appeals for the Federal Circuit, newly created in 1982, established a regime dominated by the appellate court\u27s bright-line rules. More recently, aggressive Supreme Court and Congressional intervention have respectively reinvigorated patent law standards and led to significant devolution of power to inferior tribunals, including newly created tribunals like the USPTO\u27s Patent Trial and Appeals Board. This new era in institutional interaction creates a host of fresh empirical and normative research questions for scholars. The contribution concludes by outlining a research agenda

Simultaneous administration of adjuvant donor bone marrow in pancreas transplant recipients

Objective: The effect of donor bone marrow was evaluated for its potentially favorable effect in the authors' simultaneous pancreas/kidney transplant program. Methods: From July 1994 to January 1999, 177 pancreas transplants were performed, 151 of which were simultaneous pancreas/kidney transplants. All patients received tacrolimus, mycophenolate mofetil, and steroids for immunosuppression (azathioprine was used in the first year of the program). Fifty-three simultaneous pancreas/kidney transplant recipients received perioperative unmodified donor bone marrow, 3 to 6 x 108 cells/kg. Results: Overall actuarial survival rates at 1 and 3 years were 98% and 95% (patient), 95% and 87% (kidney), and 86% and 80% (pancreas), respectively. In the adjuvant bone marrow group, 1- and 3-year survival rates were 96% and 91% (patient), 95% and 87% (kidney), and 83% and 83% (pancreas), respectively. For 98 recipients who did not receive bone marrow, survival rates at 1 and 3 years were 100% and 98% (patient), 96% and 86% (kidney), and 87% and 79% (pancreas), respectively. No pancreas allografts were lost after 3 months in bone marrow recipients, and seven in the non-bone marrow recipients were lost to rejection at 0.7, 6.7, 8.8, 14.6, 24.1, 24.3, and 25.5 months. Twenty-two percent of bone marrow patients were steroid-free at 1 year, 45% at 2 years, and 67% at 3 years. Nineteen percent of the non-bone marrow recipients were steroid-free at 1 year, 38% at 2 years, and 45% (p = 0.02) at 3 years. The mean acute cellular rejection rate was 0.94 ± 1.1 in the bone marrow group and 1.57 ± 1.3 (p = 0.003) in the non-bone marrow group (includes borderline rejection and multiple rejections). The level of donor cell chimerism in the peripheral blood of bone marrow patients was at least two logs higher than in controls. Conclusion: In this series, which represents the largest experience with adjuvant bone marrow infusion in pancreas recipients, there was a higher steroid withdrawal rate (p = 0.02), fewer rejection episodes, and no pancreas graft loss after 3 months in bone marrow recipients compared with contemporaneous controls. All pancreas allografts lost to chronic rejection (n = 6) were in the non-bone marrow group. Donor bone marrow administered around the time of surgery may have a protective effect in pancreas transplantation

Gamma-ray Observations Under Bright Moonlight with VERITAS

Imaging atmospheric Cherenkov telescopes (IACTs) are equipped with sensitive photomultiplier tube (PMT) cameras. Exposure to high levels of background illumination degrades the efficiency of and potentially destroys these photo-detectors over time, so IACTs cannot be operated in the same configuration in the presence of bright moonlight as under dark skies. Since September 2012, observations have been carried out with the VERITAS IACTs under bright moonlight (defined as about three times the night-sky-background (NSB) of a dark extragalactic field, typically occurring when Moon illumination > 35%) in two observing modes, firstly by reducing the voltage applied to the PMTs and, secondly, with the addition of ultra-violet (UV) bandpass filters to the cameras. This has allowed observations at up to about 30 times previous NSB levels (around 80% Moon illumination), resulting in 30% more observing time between the two modes over the course of a year. These additional observations have already allowed for the detection of a flare from the 1ES 1727+502 and for an observing program targeting a measurement of the cosmic-ray positron fraction. We provide details of these new observing modes and their performance relative to the standard VERITAS observations

Gamma-ray observations of Tycho's SNR with VERITAS and Fermi

High-energy gamma-ray emission from supernova remnants (SNRs) has provided a unique perspective for studies of Galactic cosmic-ray acceleration. Tycho's SNR is a particularly good target because it is a young, type Ia SNR that is well-studied over a wide range of energies and located in a relatively clean environment. Since the detection of gamma-ray emission from Tycho's SNR by VERITAS and Fermi-LAT, there have been several theoretical models proposed to explain its broadband emission and high-energy morphology. We report on an update to the gamma-ray measurements of Tycho's SNR with 147 hours of VERITAS and 84 months of Fermi-LAT observations, which represents about a factor of two increase in exposure over previously published data. About half of the VERITAS data benefited from a camera upgrade, which has made it possible to extend the TeV measurements toward lower energies. The TeV spectral index measured by VERITAS is consistent with previous results, but the expanded energy range softens a straight power-law fit. At energies higher than 400 GeV, the power-law index is $2.92 \pm 0.42_{\mathrm{stat}} \pm 0.20_{\mathrm{sys}}$. It is also softer than the spectral index in the GeV energy range, $2.14 \pm 0.09_{\mathrm{stat}} \pm 0.02_{\mathrm{sys}}$, measured by this study using Fermi--LAT data. The centroid position of the gamma-ray emission is coincident with the center of the remnant, as well as with the centroid measurement of Fermi--LAT above 1 GeV. The results are consistent with an SNR shell origin of the emission, as many models assume. The updated spectrum points to a lower maximum particle energy than has been suggested previously.Comment: Accepted for publication in The Astrophysical Journa

Very-high-energy observations of the binaries V 404 Cyg and 4U 0115+634 during giant X-ray outbursts

Transient X-ray binaries produce major outbursts in which the X-ray flux can increase over the quiescent level by factors as large as $10^7$. The low-mass X-ray binary V 404 Cyg and the high-mass system 4U 0115+634 underwent such major outbursts in June and October 2015, respectively. We present here observations at energies above hundreds of GeV with the VERITAS observatory taken during some of the brightest X-ray activity ever observed from these systems. No gamma-ray emission has been detected by VERITAS in 2.5 hours of observations of the microquasar V 404 Cyg from 2015, June 20-21. The upper flux limits derived from these observations on the gamma-ray flux above 200 GeV of F $< 4.4\times 10^{-12}$ cm$^{-2}$ s$^{-1}$ correspond to a tiny fraction (about $10^{-6}$) of the Eddington luminosity of the system, in stark contrast to that seen in the X-ray band. No gamma rays have been detected during observations of 4U 0115+634 in the period of major X-ray activity in October 2015. The flux upper limit derived from our observations is F $< 2.1\times 10^{-12}$ cm$^{-2}$ s$^{-1}$ for gamma rays above 300 GeV, setting an upper limit on the ratio of gamma-ray to X-ray luminosity of less than 4%.Comment: Accepted for publication in the Astrophysical Journa

Direct measurement of stellar angular diameters by the VERITAS Cherenkov Telescopes

The angular size of a star is a critical factor in determining its basic properties. Direct measurement of stellar angular diameters is difficult: at interstellar distances stars are generally too small to resolve by any individual imaging telescope. This fundamental limitation can be overcome by studying the diffraction pattern in the shadow cast when an asteroid occults a star, but only when the photometric uncertainty is smaller than the noise added by atmospheric scintillation. Atmospheric Cherenkov telescopes used for particle astrophysics observations have not generally been exploited for optical astronomy due to the modest optical quality of the mirror surface. However, their large mirror area makes them well suited for such high-time-resolution precision photometry measurements. Here we report two occultations of stars observed by the VERITAS Cherenkov telescopes with millisecond sampling, from which we are able to provide a direct measurement of the occulted stars' angular diameter at the $\leq0.1$ milliarcsecond scale. This is a resolution never achieved before with optical measurements and represents an order of magnitude improvement over the equivalent lunar occultation method. We compare the resulting stellar radius with empirically derived estimates from temperature and brightness measurements, confirming the latter can be biased for stars with ambiguous stellar classifications.Comment: Accepted for publication in Nature Astronom

Thyroid carcinomas that occur in familial adenomatous polyposis patients recurrently harbor somatic variants in APC, BRAF, and KTM2D

Background: Familial adenomatous polyposis (FAP) is a condition typically caused by pathogenic germline mutations in the APC gene. In addition to colon polyps, individuals with FAP have a substantially increased risk of developing papillary thyroid cancer (PTC). Little is known about the events underlying this association, and the prevalence of somatic "second-hit" mutations in APC is controversial. Methods: Whole-genome sequencing was performed on paired thyroid tumor and normal DNA from 12 FAP patients who developed PTC. Somatic mutation profiles were compared with clinical characteristics and previously sequenced sporadic PTC cases. Germline variant profiling was performed to assess the prevalence of variants in genes previously shown to have a role in PTC predisposition. Results: All 12 patients harbored germline mutations in APC, consistent with FAP. Seven patients also had somatic mutations in APC, and seven patients harbored somatic mutations in KMT2D, which encodes a lysine methyl transferase. Mutation of these genes is extremely rare in sporadic PTCs. Notably, only two of the tumors harbored the somatic BRAF p.V600E mutation, which is the most common driver mutation found in sporadic PTCs. Six tumors displayed a cribriform-morular variant of PTC (PTC-CMV) histology, and all six had somatic mutations in APC. Additionally, nine FAP-PTC patients had rare germline variants in genes that were previously associated with thyroid carcinoma. Conclusions: Our data indicate that FAP-associated PTCs typically have distinct mutations compared with sporadic PTCs. Roughly half of the thyroid cancers that arise in FAP patients have somatic "second-hits" in APC, which is associated with PTC-CMV histology. Somatic BRAF p.V600E variants also occur in some FAP patients, a novel finding. We speculate that in carriers of heterozygous pathogenic mutations of tumor suppressor genes such as APC, a cooperating second-hit somatic variant may occur in a different gene such as KTM2D or BRAF, leading to differences in phenotypes. The role of germline variance in genes other than APC (9 of the 12 patients in this series) needs further research.Peer reviewe