Are Manufacturing Patents to Blame for Biosimilar Market Launch Delays?

OBJECTIVES: Biosimilar market launch delays are likely costing healthcare systems billions of dollars and preventing patients accessing affordable biologic therapies sooner. Many claim these delays are mostly caused by originator biologics' large patent portfolios asserted during litigation against biosimilar developers, particularly that the manufacturing patents filed after the originator is approved is an important driver of these delays. Our objective was to investigate the accuracy of these claims. METHODS: We reviewed US Court document submissions for litigation data, including the details of patents asserted against biosimilar owners, and collated biosimilar market launch dates from publicly available databases. RESULTS: We find that, although approximately half of all patents asserted in litigation were manufacturing patents, a greater proportion of composition, active pharmaceutical ingredient, and treatment patents are associated with longer market launch delays, whereas a greater proportion of manufacturing patents are associated with shorter market launch delays. CONCLUSIONS: Our results suggest that manufacturing patents were having less of an impact on market launch delays than other types of patents. Our findings have implications for both biosimilar and originator developers, as well as patent policy and its association with healthcare accessibility.

A bias of Asparagine to Lysine mutations in SARS-CoV-2 outside the receptor binding domain affects protein flexibility.

Introduction: COVID-19 pandemic has been threatening public health and economic development worldwide for over two years. Compared with the original SARS-CoV-2 strain reported in 2019, the Omicron variant (B.1.1.529.1) is more transmissible. This variant has 34 mutations in its Spike protein, 15 of which are present in the Receptor Binding Domain (RBD), facilitating viral internalization via binding to the angiotensin-converting enzyme 2 (ACE2) receptor on endothelial cells as well as promoting increased immune evasion capacity. Methods: Herein we compared SARS-CoV-2 proteins (including ORF3a, ORF7, ORF8, Nucleoprotein (N), membrane protein (M) and Spike (S) proteins) from multiple ancestral strains. We included the currently designated original Variant of Concern (VOC) Omicron, its subsequent emerged variants BA.1, BA2, BA3, BA.4, BA.5, the two currently emerging variants BQ.1 and BBX.1, and compared these with the previously circulating VOCs Alpha, Beta, Gamma, and Delta, to better understand the nature and potential impact of Omicron specific mutations. Results: Only in Omicron and its subvariants, a bias toward an Asparagine to Lysine (N to K) mutation was evident within the Spike protein, including regions outside the RBD domain, while none of the regions outside the Spike protein domain were characterized by this mutational bias. Computational structural analysis revealed that three of these specific mutations located in the central core region, contribute to a preference for the alteration of conformations of the Spike protein. Several mutations in the RBD which have circulated across most Omicron subvariants were also analysed, and these showed more potential for immune escape. Conclusion: This study emphasizes the importance of understanding how specific N to K mutations outside of the RBD region affect SARS-CoV-2 conformational changes and the need for neutralizing antibodies for Omicron to target a subset of conformationally dependent B cell epitopes.

A structural biology community assessment of AlphaFold2 applications.

Most proteins fold into 3D structures that determine how they function and orchestrate the biological processes of the cell. Recent developments in computational methods for protein structure predictions have reached the accuracy of experimentally determined models. Although this has been independently verified, the implementation of these methods across structural-biology applications remains to be tested. Here, we evaluate the use of AlphaFold2 (AF2) predictions in the study of characteristic structural elements; the impact of missense variants; function and ligand binding site predictions; modeling of interactions; and modeling of experimental structural data. For 11 proteomes, an average of 25% additional residues can be confidently modeled when compared with homology modeling, identifying structural features rarely seen in the Protein Data Bank. AF2-based predictions of protein disorder and complexes surpass dedicated tools, and AF2 models can be used across diverse applications equally well compared with experimentally determined structures, when the confidence metrics are critically considered. In summary, we find that these advances are likely to have a transformative impact in structural biology and broader life-science research.

Assessment of the Urinary Microbiome in Children Younger Than 48 Months.

BACKGROUND: The urinary tract was once thought to be sterile, and little is known about the urinary microbiome in children. This study aimed to examine the urinary microbiome of young children across demographic and clinical factors. METHODS: Children <48 months, undergoing a urinary catheterization for clinical purposes in the Pediatric Emergency Department were recruited and urine samples collected. Detailed demographic and clinical information were recorded. Urine samples underwent DNA extraction and 16S ribosomal RNA gene sequencing, urinalysis and urine culture. RESULTS: Eighty-five children were included; a urinary microbiome was identified in every child. Nine children had Escherichia coli urinary tract infections (UTIs) identified. Those with UTIs had a significantly decreased alpha diversity (t test, P < 0.001) and the composition of the microbiome clustered separately (P = 0.001) compared with those without UTIs. CONCLUSIONS: A urinary microbiome was identified in every child, even neonates. Differences in microbiome diversity and composition were observed in patients with a standard culture positive UTI. The urinary microbiome has just begun to be explored, and the implications on long-term disease processes deserve further investigation.

Diagnosis of D-Bifunctional Protein Deficiency through Whole-Genome Sequencing: Implications for Cost-Effective Care.

D-Bifunctional protein deficiency, caused by recessive mutations in HSD17B4, is a severe disorder of peroxisomal fatty acid oxidation. Nonspecific clinical features may contribute to diagnostic challenges. We describe a newborn female with infantile-onset seizures and nonspecific mild dysmorphisms who underwent extensive genetic workup that resulted in the detection of a novel homozygous mutation (c.302+1_4delGTGA) in the HSD17B4 gene, consistent with a diagnosis of D-bifunctional protein deficiency. By comparing the standard clinical workup to diagnostic analysis performed through research-based whole-genome sequencing (WGS), which independently identified the causative mutation, we demonstrated the ability of genomic sequencing to serve as a timely and cost-effective diagnostic tool for the molecular diagnosis of apparent and occult newborn diseases. As genomic sequencing becomes more available and affordable, we anticipate that WGS and related omics technologies will eventually replace the traditional tiered approach to newborn diagnostic workup.

International adoptions by military families: a reexamination.

The adoption of foreign-born children by U.S. families is an increasingly common occurrence, having tripled in the past 15 years. The demographic features of international adoption have changed dramatically over the same time period. Today's foreign-born adoptees originate from a myriad of nations and cultures and present challenging medical and social problems to the practitioners faced with caring for these children and advising their adoptive families. Military families, cosmopolitan and often stationed overseas, adopt a large proportion of these children from foreign lands. Consequently, military health care providers require a familiarity with the special needs of international adoptees and the unique aspects of international adoption, as practiced by military families. We previously reported on this topic more than a decade ago. Much has changed since then, prompting this update.