Patent Landscape of Influenza A Virus Prophylactic Vaccines and Related Technologies

Executive Summary: This report focuses on patent landscape analysis of technologies related to prophylactic vaccines targeting pandemic strains of influenza. These technologies include methods of formulating vaccine, methods of producing of viruses or viral subunits, the composition of complete vaccines, and other technologies that have the potential to aid in a global response to this pathogen. The purpose of this patent landscape study was to search, identify, and categorize patent documents that are relevant to the development of vaccines that can efficiently promote the development of protective immunity against pandemic influenza virus strains. The search strategy used keywords which the team felt would be general enough to capture (or “recall”) the majority of patent documents which were directed toward vaccines against influenza A virus. After extensive searching of patent literature databases, approximately 33,500 publications were identified and collapsed to about 3,800 INPADOC families. Relevant documents, almost half of the total, were then identified and sorted into the major categories of vaccine compositions (about 570 families), technologies which support the development of vaccines (about 750 families), and general platform technologies that could be useful but are not specific to the problems presented by pandemic influenza strains (about 560 families). The first two categories, vaccines and supporting technologies, were further divided into particular subcategories to allow an interested reader to rapidly select documents relevant to the particular technology in which he or she is focused. This sorting process increased the precision of the result set. The two major categories (vaccines and supporting technologies) were subjected to a range of analytics in order to extract as much information as possible from the dataset. First, patent landscape maps were generated to assess the accuracy of the sorting procedure and to reveal the relationships between the various technologies that are involved in creating an effective vaccine. Then, filings trends are analyzed for the datasets. The country of origin for the technologies was determined, and the range of distribution to other jurisdictions was assessed. Filings were also analyzed by year, by assignee, and by inventor. Finally, the various patent classification systems were mapped to find which particular classes tend to hold influenza vaccine-related technologies. Besides the keywords developed during the searches and the landscape map generation, the classifications represent an alternate way for further researchers to identify emerging influenza technologies. The analysis included creation of a map of keywords, as shown above, describing the relationship of the various technologies involved in the development of prophylactic influenza A vaccines. The map has regions corresponding to live attenuated virus vaccines, subunit vaccines composed of split viruses or isolated viral polypeptides, and plasmids used in DNA vaccines. Important technologies listed on the map include the use of reverse genetics to create reassortant viruses, the growth of viruses in modified cell lines as opposed to the traditional methods using eggs, the production of recombinant viral antigens in various host cells, and the use of genetically-modified plants to produce virus-like particles. Another major finding was that the number of patent documents related to influenza being published has been steadily increasing in the last decade, as shown in the figure below. Until the mid-1990s, there were only a few influenza patent documents being published each year. The number of publications increased noticeably when TRIPS took effect, resulting in publication of patent applications. However, since 2006 the number of vaccine publications has exploded. In each of 2011 and 2012, about 100 references disclosing influenza vaccine technologies were published. Thus, interest in developing new and more efficacious influenza vaccines has been growing in recent years. This interest is probably being driven by recent influenza outbreaks, such as the H5N1 (bird flu) epidemic that began in the late 1990s and the 2009 H1N1 (swine flu) pandemic. The origins of the vaccine-related inventions were also analyzed. The team determined the country in which the priority application was filed, which was taken as an indication of the country where the invention was made or where the inventors intended to practice the invention. By far, most of the relevant families originated with patent applications filed in the United States. Other prominent priority countries were the China and United Kingdom, followed by Japan, Russia, and South Korea. France was a significant priority country only for supporting technologies, not for vaccines. Top assignees for these families were mostly large pharmaceutical companies, with the majority of patent families coming from Novartis, followed by GlaxoSmithKline, Pfizer, U.S. Merck (Merck, Sharpe, & Dohme), Sanofi, and AstraZeneca. Governmental and nonprofit institutes in China, Japan, Russia, South Korea and the United States also are contributing heavily to influenza vaccine research. Lastly, the jurisdictions were inventors have sought protection for their vaccine technologies were determined, and the number of patent families filing in a given country is plotted on the world map shown on page seven. The United States, Canada, Australia, Japan, South Korea and China have the highest level of filings, followed by Germany, Brazil, India, Mexico and New Zealand. However, although there are a significant number of filings in Brazil, the remainder of Central and South America has only sparse filings. Of concern, with the exception of South Africa, few other African nations have a significant number of filings. In summary, the goal of this report is to provide a knowledge resource for making informed policy decisions and for creating strategic plans concerning the assembly of efficacious vaccines against a rapidly-spreading, highly virulent influenza strain. The team has defined the current state of the art of technologies involved in the manufacture of influenza vaccines, and the important assignees, inventors, and countries have been identified. This document should reveal both the strengths and weaknesses of the current level of preparedness for responding to an emerging pandemic influenza strain. The effects of H5N1 and H1N1 epidemics have been felt across the globe in the last decade, and future epidemics are very probable in the near future, so preparations are necessary to meet this global health threat

Seasonal Variations of Relative Neutral Densities between 45 and 90 km Determined from USU Rayleigh Lidar Observations

A Rayleigh-scatter lidar operated at the Atmospheric Lidar Observatory (ALO; 41.7°N, 111.8°W), part of Center for Atmospheric and Space Sciences (CASS) on the campus of Utah State University (USU), collected extensive data between 1993 and 2004. From the Rayleigh lidar photon-count profiles, relative densities were determined throughout the mesosphere, from 45 to 90 km. Using these relative densities three climatologies were derived, each using a different density normalization at 45 km. The first normalized the relative densities to a constant; the second to the NRL-MSISe00 empirical model which has a strong annual component; and the third to the CPC analyses model, which is similar to MSIS in that it has a strong annual oscillation. In each case the density profile for every night of a composite year was found by averaging the nighttime density profiles over a 31-day by 11-year window centered on that day. For each of the cases, the average annual density profile was found by averaging all the days. Then the daily percent differences were found relative to the annual density profile. Despite the different normalizations at 45 km, many common features were found in the seasonal behavior of the density profiles, a large seasonal variation maximizing in June at ~70 km, Another above 80 km is a large shift in the maximum to earlier in the year, and lastly sharp density fall off at almost all altitudes in early October. While these density normalizations provide initial information about mesospheric behavior, the current lidar upgrade will enable us to add an absolute scale to the density profiles

Long-term bird colonization and turnover in restored woodlands

The long-term effectiveness of restored areas for biodiversity is poorly known for the majority of restored ecosystems worldwide. We quantified temporal changes in bird occurrence in restoration plantings of different ages and geometries, and compared observed patterns with a reference dataset from woodland remnants on the same farms as our plantings. Over time, bird species richness remained unchanged in spring but exhibited modest increases in winter. We found that wider plantings supported significantly greater bird species richness in spring and winter than narrow plantings. There was no evidence of a significant interaction between planting width and time. We recorded major temporal changes in the occurrence of a range of individual species that indicated a clear turnover of species as plantings matured. Our results further revealed marked differences in individual species occurrence between plantings and woodland remnants. Life-history attributes associated with temporal changes in the bird assemblage were most apparent in winter survey data, and included diet, foraging and nesting patterns, movement behaviour (e.g. migratory vs. dispersive), and body size. Differences in bird assemblages between plantings of different ages suggest that it is important that farms support a range of age classes of planted woodland, if the aim is to maximize the number of native bird species in restored areas. Our data also suggest that changes in the bird species occupying plantings of different ages can be anticipated in a broadly predictable way based on planting geometry (especially width) and key life-history attributes, particularly movement patterns and habitat and diet specialisation. © 2016, Springer Science+Business Media Dordrecht. **Please note that there are multiple authors for this article therefore only the name of the first 5 including Federation University Australia affiliate “Philip Barton” is provided in this record*

Mesospheric Density Climatologies Determined at Midlatitudes Using Rayleigh Lidar

The original Rayleigh-scatter lidar that operated at the Atmospheric Lidar Observatory (ALO; 41.7°N, 111.8°W) in the Center for Atmospheric and Space Sciences (CASS) on the campus of Utah State University (USU), collected 11 years of data between 1993 and 2004. From Rayleigh lidar photon-count returns, relative densities throughout the mesosphere, from 45 to 90 km, were determined. Using these relative densities, three climatologies are derived, each using a different density normalization method at 45 km: the first method normalized the relative densities to a constant; the second normalized them to the NRLMSISe00 empirical model; and the third normalized them to the CPC analyses, a first principles, assimilative, meteorological model. From there, the average density profile for each night of the composite year is found by averaging the nighttime density profiles in a multi-year, 31-day window centered on that particular night. From these three density climatologies, some different and many common features in the mesospheric densities are evident. In the future, with improvements to the lidar, it will be possible to provide an absolute normalization for the density profiles

Analytic approach to the evolutionary effects of genetic exchange

We present an approximate analytic study of our previously introduced model of evolution including the effects of genetic exchange. This model is motivated by the process of bacterial transformation. We solve for the velocity, the rate of increase of fitness, as a function of the fixed population size, $N$. We find the velocity increases with $\ln N$, eventually saturated at an $N$ which depends on the strength of the recombination process. The analytical treatment is seen to agree well with direct numerical simulations of our model equations

Environment-Sensitive Intrusion Detection

Abstract. We perform host-based intrusion detection by constructing a model from a program’s binary code and then restricting the program’s execution by the model. We improve the effectiveness of such model-based intrusion detection systems by incorporating into the model knowledge of the environment in which the program runs, and by increasing the accuracy of our models with a new dataflow analysis algorithm for context-sensitive recovery of static data. The environment—configuration files, command-line parameters, and environment variables—constrains acceptable process execution. Environment dependencies added to a program model update the model to the current environment at every program execution. Our new static data-flow analysis associates a program’s data flows with specific calling contexts that use the data. We use this analysis to differentiate systemcall arguments flowing from distinct call sites in the program. Using a new average reachability measure suitable for evaluation of call-stackbased program models, we demonstrate that our techniques improve the precision of several test programs ’ models from 76 % to 100%

Adaptations of Lumbar Biomechanics after Four Weeks of Running Training with Minimalist Footwear and Technique guidance: Implications for Running-Related Lower Back Pain

Objectives To investigate the changes in lumbar kinematic and paraspinal muscle activation before, during, and after a 4-week minimalist running training. Design Prospective cohort study. Setting University research laboratory. Participants Seventeen habitually shod recreational runners who run 10–50 km per week. Main outcome measures During stance phases of running, sagittal lumbar kinematics was recorded using an electrogoniometer, and activities of the lumbar paraspinal muscles were assessed by electromyography. Runners were asked to run at a prescribed speed (3.1 m/s) and a self-selected speed. Results For the 3.1 m/s running speed, significant differences were found in the calculated mean lumbar posture (p = 0.001) during the stance phase, including a more extended lumbar posture after minimalist running training. A significant reduction in the contralateral lumbar paraspinal muscle activation was also observed (p = 0.039). For the preferred running speed, similar findings of a more extended lumbar posture (p = 0.002) and a reduction in contralateral lumbar paraspinal muscle activation (p = 0.047) were observed. Conclusion A 4-week minimalist running training program produced significant changes in lumbar biomechanics during running. Specifically, runners adopted a more extended lumbar posture and reduced lumbar paraspinal muscle activation. These findings may have clinical implications for treating individuals with running-related lower back pain

Effects of a large wildfire on vegetation structure in a variable fire mosaic

Management guidelines for many fire-prone ecosystems highlight the importance of maintaining a variable mosaic of fire histories for biodiversity conservation. Managers are encouraged to aim for fire mosaics that are temporally and spatially dynamic, include all successional states of vegetation, and also include variation in the underlying "invisible mosaic" of past fire frequencies, severities, and fire return intervals. However, establishing and maintaining variable mosaics in contemporary landscapes is subject to many challenges, one of which is deciding how the fire mosaic should be managed following the occurrence of large, unplanned wildfires. A key consideration for this decision is the extent to which the effects of previous fire history on vegetation and habitats persist after major wildfires, but this topic has rarely been investigated empirically. In this study, we tested to what extent a large wildfire interacted with previous fire history to affect the structure of forest, woodland, and heath vegetation in Booderee National Park in southeastern Australia. In 2003, a summer wildfire burned 49.5% of the park, increasing the extent of recently burned vegetation (<10 yr post-fire) to more than 72% of the park area. We tracked the recovery of vegetation structure for nine years following the wildfire and found that the strength and persistence of fire effects differed substantially between vegetation types. Vegetation structure was modified by wildfire in forest, woodland, and heath vegetation, but among-site variability in vegetation structure was reduced only by severe fire in woodland vegetation. There also were persistent legacy effects of the previous fire regime on some attributes of vegetation structure including forest ground and understorey cover, and woodland midstorey and overstorey cover. For example, woodland midstorey cover was greater on sites with higher fire frequency, irrespective of the severity of the 2003 wildfire. Our results show that even after a large, severe wildfire, underlying fire histories can contribute substantially to variation in vegetation structure. This highlights the importance of ensuring that efforts to reinstate variation in vegetation fire age after large wildfires do not inadvertently reduce variation in vegetation structure generated by the underlying invisible mosaic.This research was financially supported by the Aus-tralian Research Council, the Long Term Ecological ResearchNetwork and the National Environmental Science Program. P.S. Barton was supported by an ARC DECRA Fellowship. D. B.Lindenmayer was supported by an ARC Laureate Fellowship

WZW-like Action for Heterotic String Field Theory

We complete the construction of the Neveu-Schwarz sector of heterotic string field theory begun in hep-th/0406212 by giving a closed-form expression for the action and gauge transformations. Just as the Wess-Zumino-Witten (WZW) action for open superstring field theory can be constructed from pure-gauge fields in bosonic open string field theory, our heterotic string field theory action is constructed from pure-gauge fields in bosonic closed string field theory. The construction involves a simple alternative form of the WZW action which is consistent with the algebraic structures of closed string field theory.Comment: 22 pages, no figures, LaTeX2