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

Intraventricular Septation in the Context of Dilated Cardiomyopathy Associated With TTN Mutation

A 6-month-old infant boy presented with symptomatic heart failure. Dilated cardiomyopathy was found in association with a mutation in TTN. Structural heart disease included novel septation of the left ventricle with a fenestrated membrane resulting from aberrant congenital mitral valve apparatus formation. (Level of Difficulty: Advanced.)

Processing and Transmission of Information

Contains research objectives and summary of research on three research projects and reports on two research projects.National Aeronautics and Space Administration (Grant NGL 22-009-013)National Science Foundation (Grant GK-41464)National Science Foundation (Grant GK-41098)Joint Services Electronics Program (Contract DAAB07-74-C-0630)National Science Foundation (Grant GK-37582

Optical Propagation and Communication

Contains research objectives and summary of research on three research projects, and reports on three research projects.National Aeronautics and Space Administration (Grant NGL 22-009-013)National Science Foundation (Grant ENG74-00131-A01)National Science Foundation (Grant ENG74-03996-A01

Cooperative Origin of Low-Density Domains in Liquid Water

We study the size of clusters formed by water molecules possessing large enough tetrahedrality with respect to their nearest neighbors. Using Monte Carlo simulation of the SPC/E model of water, together with a geometric analysis based on Voronoi tessellation, we find that regions of lower density than the bulk are formed by accretion of molecules into clusters exceeding a minimum size. Clusters are predominantly linear objects and become less compact as they grow until they reach a size beyond which further accretion is not accompanied by a density decrease. The results suggest that the formation of "ice-like" regions in liquid water is cooperative.Comment: 16 pages, 6 figure

Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis receiving abatacept

Background Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections. We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011–2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs). Methods Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of ≥3 months’ SC abatacept. All patients received fixed-dose abatacept 125 mg/week with background DMARDs. A pre-vaccination blood sample was taken, and after 28 ± 3 days a final post- vaccination sample was collected. The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as ≥2-fold increase in post-vaccination titers to ≥3 of 5 antigens and protective antibody level of ≥1.6 μg/mL to ≥3 of 5 antigens; influenza: defined as ≥4-fold increase in post-vaccination titers to ≥2 of 3 antigens and protective antibody level of ≥1:40 to ≥2 of 3 antigens). Safety and tolerability were evaluated throughout the sub-studies. Results Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively. Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline. Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively. In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer ≥1.6 μg/mL to ≥3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer ≥1:40 to ≥2 of 3 antigens) at Day 28 post-vaccination. Vaccines were well tolerated with SC abatacept with background DMARDs. Conclusions In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines. Trial registration NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008)

On positivity of Ehrhart polynomials

Ehrhart discovered that the function that counts the number of lattice points in dilations of an integral polytope is a polynomial. We call the coefficients of this polynomial Ehrhart coefficients, and say a polytope is Ehrhart positive if all Ehrhart coefficients are positive (which is not true for all integral polytopes). The main purpose of this article is to survey interesting families of polytopes that are known to be Ehrhart positive and discuss the reasons from which their Ehrhart positivity follows. We also include examples of polytopes that have negative Ehrhart coefficients and polytopes that are conjectured to be Ehrhart positive, as well as pose a few relevant questions.Comment: 40 pages, 7 figures. To appear in in Recent Trends in Algebraic Combinatorics, a volume of the Association for Women in Mathematics Series, Springer International Publishin

A Transect Through the Pre-Silurian Rocks of Central Vermont; The Lincoln Massic and Its Immediate Cover; The Pre-Silurian Hinterland Along the Valleys of the White and Mad Rivers, Central Vermont; Metamorphism of Pre-Silurian Rocks, Central Vermont; Regional Geochemical Variations in Greenstones from the Central Vermont Appalachians

Guidebook for field trips in Vermont: New England Intercollegiate Geological Conference, 79th annual meeting, October 16, 17 and 18, 1987: Trips B-8; C-

Brief cognitive behavioral therapy in primary care: a hybrid type 2 patient-randomized effectiveness-implementation design

BACKGROUND: Despite the availability of evidence-based psychotherapies for depression and anxiety, they are underused in non-mental health specialty settings such as primary care. Hybrid effectiveness-implementation designs have the potential to evaluate clinical and implementation outcomes of evidence-based psychotherapies to improve their translation into routine clinical care practices. METHODS: This protocol article discusses the study methodology and implementation strategies employed in an ongoing, hybrid, type 2 randomized controlled trial with two primary aims: (1) to determine whether a brief, manualized cognitive behavioral therapy administered by Veterans Affairs Primary Care Mental Health Integration program clinicians is effective in treating depression and anxiety in a sample of medically ill (chronic cardiopulmonary diseases) primary care patients and (2) to examine the acceptability, feasibility, and preliminary outcomes of a focused implementation strategy on improving adoption and fidelity of brief cognitive behavioral therapy at two Primary Care-Mental Health Integration clinics. The study uses a hybrid type 2 effectiveness/implementation design to simultaneously test clinical effectiveness and to collect pilot data on a multifaceted implementation strategy that includes an online training program, audit and feedback of session content, and internal and external facilitation. Additionally, the study engages the participation of an advisory council consisting of stakeholders from Primary Care-Mental Health Integration, as well as regional and national mental health leaders within the Veterans Administration. It targets recruitment of 320 participants randomized to brief cognitive behavioral therapy (n = 200) or usual care (n = 120). Both effectiveness and implementation outcomes are being assessed using mixed methods, including quantitative evaluation (e.g., intent-to-treat analyses across multiple time points) and qualitative methods (e.g., focus interviews and surveys from patients and providers). Patient-effectiveness outcomes include measures of depression, anxiety, and physical health functioning using blinded independent evaluators. Implementation outcomes include patient engagement and adherence and clinician brief cognitive behavioral therapy adoption and fidelity. CONCLUSIONS: Hybrid designs are needed to advance clinical effectiveness and implementation knowledge to improve healthcare practices. The current article describes the rationale and challenges associated with the use of a hybrid design for the study of brief cognitive behavioral therapy in primary care. Although trade-offs exist between scientific control and external validity, hybrid designs are part of an emerging approach that has the potential to rapidly advance both science and practice. TRIAL REGISTRATION: NCT01149772 at http://www.clinicaltrials.gov/ct2/show/NCT0114977

Liver Cancer Disparities in New York City: A neighborhood wiew of risk and harm reduction factors

Introduction: Liver cancer is the fastest increasing cancer in the United States and is one of the leading causes of cancer-related death in New York City (NYC), with wide disparities among neighborhoods. The purpose of this cross-sectional study was to describe liver cancer incidence by neighborhood and examine its association with risk factors. This information can inform preventive and treatment interventions. Materials and methods: Publicly available data were collected on adult NYC residents (n = 6,407,022). Age-adjusted data on liver and intrahepatic bile duct cancer came from the New York State Cancer Registry (1) (2007-2011 average annual incidence); and the NYC Vital Statistics Bureau (2015, mortality). Data on liver cancer risk factors (2012-2015) were sourced from the New York City Department of Health and Mental Hygiene: (1) Community Health Survey, (2) A1C registry, and (3) NYC Health Department Hepatitis surveillance data. They included prevalence of obesity, diabetes, diabetic control, alcohol-related hospitalizations or emergency department visits, hepatitis B and C rates, hepatitis B vaccine coverage, and injecting drug use. Results: Liver cancer incidence in NYC was strongly associated with neighborhood poverty after adjusting for race/ethnicity (β = 0.0217, p = 0.013); and with infection risk scores (β = 0.0389, 95% CI = 0.0088-0.069, p = 0.011), particularly in the poorest neighborhoods (β = 0.1207, 95% CI = 0.0147-0.2267, p = 0.026). Some neighborhoods with high hepatitis rates do not have a proportionate number of hepatitis prevention services. Conclusion: High liver cancer incidence is strongly associated with infection risk factors in NYC. There are gaps in hepatitis prevention services like syringe exchange and vaccination that should be addressed. The role of alcohol and metabolic risk factors on liver cancer in NYC warrants further study