Inter Partes Review: Patent Killer No More?

Inter Partes review (IPR) can efficiently invalidate drug patents and potentially convey strategic advantages to follow-on drug makers. However, recent changes in the IPR system foretell a tectonic shift in the landscape. Here we summarize these major changes and discuss the implications for the biopharmaceutical community.

China: The Next Pharmacy of the World?

The manufacturing success in China has not yet radiated to the pharmaceutical sector. Recently, China released a policy guideline to foster its follow-on drug industry, revealing its ambition to become a great power in the field. Here, I briefly discuss how this guideline may change the industry landscape, and its associated challenges and opportunities.

Patent trend and competitive analysis of cancer immunotherapy in the United States.

Immunotherapy has brought high hopes for cancer treatment, and attracted tremendous resources from the biopharmaceutical community. Here we analyze cancer immunotherapy-related patents granted by the United States Patent and Trademark Office in the past decade (2006-2016). A total of 2,229 patents were identified in 13 subfields.

NMD Classifier: A reliable and systematic classification tool for nonsense-mediated decay events.

Nonsense-mediated decay (NMD) degrades mRNAs that include premature termination codons to avoid the translation and accumulation of truncated proteins. This mechanism has been found to participate in gene regulation and a wide spectrum of biological processes. However, the evolutionary and regulatory origins of NMD-targeted transcripts (NMDTs) have been less studied, partly because of the complexity in analyzing NMD events.

The challenges of joint performance to method patents.

Biotech patents are facing increasingly stern challenges. The patent statue holds that a multi-step method patent is not directly infringed unless all steps are carried out and attributed to a single entity. When separate steps are performed jointly by two or more parties, those parties are liable for divided infringement if there exists a direct infringement.

Invalidation of Atorvastatin Patent Highlights Complex Chinese Patent Law.

Pfizer's atorvastatin (Lipitor) is a blockbuster drug for the treatment of cardiovascular diseases. In China, a critical polymorph patent of this drug has been recently invalidated by the Supreme People's Court for insufficiency of disclosure. Here, we discuss the particularities in patent litigation in China worth attention from the community.

Non-small-cell lung cancer cells combat epidermal growth factor receptor tyrosine kinase inhibition through immediate adhesion-related responses.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, and afatinib, have greatly improved treatment efficacy in non-small cell lung cancer (NSCLC) patients with drug-sensitive EGFR mutations. However, in some TKI responders, the benefits of such targeted therapies are limited by the rapid development of resistance, and strategies to overcome this resistance are urgently needed. Studies of drug resistance in cancer cells typically involve long term in vitro induction to obtain stably acquired drug-resistant cells followed by elucidation of resistance mechanisms, but the immediate responses of cancer cells upon drug treatment have been ignored.

Divided Infringement in the Limelight of the Patent Battle Field.

Diagnostic patents usually comprise multiple steps and can be jointly implemented by different parties. However, in the USA, joint implementation may render diagnostic patents unenforceable in light of recent court opinions. Here, I explain how inappropriate claim drafting may render a diagnostic patent vulnerable to joint implementation.

NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance.

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients.

Functional divergence and convergence between the transcript network and gene network in lung adenocarcinoma.

Introduction: Alternative RNA splicing is a critical regulatory mechanism during tumorigenesis. However, previous oncological studies mainly focused on the splicing of individual genes. Whether and how transcript isoforms are coordinated to affect cellular functions remain underexplored.

Triple-layer dissection of the lung adenocarcinoma transcriptome: regulation at the gene, transcript, and exon levels.

Lung adenocarcinoma is one of the most deadly human diseases. However, the molecular mechanisms underlying this disease, particularly RNA splicing, have remained underexplored. Here, we report a triple-level (gene-, transcript-, and exon-level) analysis of lung adenocarcinoma transcriptomes from 77 paired tumor and normal tissues, as well as an analysis pipeline to overcome genetic variability for accurate differentiation between tumor and normal tissues.

Functional Implications of RNA Splicing for Human Long Intergenic Noncoding RNAs.

Long intergenic noncoding RNAs (lincRNAs) have been suggested as playing important roles in human gene regulation. The majority of annotated human lincRNAs include multiple exons and are alternatively spliced. However, the connections between alternative RNA splicing (AS) and the functions/regulations of lincRNAs have remained elusive.

Alternative RNA structure-coupled gene regulations in tumorigenesis.

Alternative RNA structures (ARSs), or alternative transcript isoforms, are critical for regulating cellular phenotypes in humans. In addition to generating functionally diverse protein isoforms from a single gene, ARS can alter the sequence contents of 5'/3' untranslated regions (UTRs) and intronic regions, thus also affecting the regulatory effects of these regions. ARS may introduce premature stop codon(s) into a transcript, and render the transcript susceptible to nonsense-mediated decay, which in turn can influence the overall gene expression level.

Pros and cons of the tuberculosis drugome approach--an empirical analysis.

Drug-resistant Mycobacterium tuberculosis (MTB), the causative pathogen of tuberculosis (TB), has become a serious threat to global public health. Yet the development of novel drugs against MTB has been lagging. One potentially powerful approach to drug development is computation-aided repositioning of current drugs.

The evolution of the coding exome of the Arabidopsis species--the influences of DNA methylation, relative exon position, and exon length.

Background: The evolution of the coding exome is a major driving force of functional divergence both between species and between protein isoforms. Exons at different positions in the transcript or in different transcript isoforms may (1) mutate at different rates due to variations in DNA methylation level; and (2) serve distinct biological roles, and thus be differentially targeted by natural selection. Furthermore, intrinsic exonic features, such as exon length, may also affect the evolution of individual exons.

Draft Genome Sequence of NDM-1-Producing Klebsiella pneumoniae Clinical Isolate 303K.

Multidrug-resistant New Delhi metallo-β-lactamase 1 (NDM-1)-producing bacteria have spread globally and become a major clinical and public health threat. We report here the draft genome sequence of the Klebsiella pneumoniae clinical isolate 303K, harboring an NDM-1 coding sequence.

DNA methylation is associated with an increased level of conservation at nondegenerate nucleotides in mammals.

DNA methylation at CpG dinucleotides can significantly increase the rate of cytosine-to-thymine mutations and the level of sequence divergence. Although the correlations between DNA methylation and genomic sequence evolution have been widely studied, an unaddressed yet fundamental question is how DNA methylation is associated with the conservation of individual nucleotides in different sequence contexts. Here, we demonstrate that in mammalian exons, the correlations between DNA methylation and the conservation of individual nucleotides are dependent on the type of exonic sequence (coding or untranslated), the degeneracy of coding nucleotides, background selection pressure, and the relative position (first or nonfirst exon in the transcript) where the nucleotides are located.

Are all of the human exons alternatively spliced?

Alternative mRNA splicing (AS) is a major mechanism for increasing regulatory complexity. A key concept in AS is the distinction between alternatively and constitutively spliced exons (ASEs and CSEs, respectively). ASEs and CSEs have been reported to be differentially regulated, and to have distinct biological properties.

The evolutionary landscape of the Mycobacterium tuberculosis genome.

Mycobacterium tuberculosis is one of the most deadly human pathogens. The major mechanism for the adaptations of M. tuberculosis is nucleotide substitution.

Selective constraint on the upstream open reading frames that overlap with coding sequences in animals.

Upstream open reading frames (uORFs) are translational regulatory elements located in 5' untranslated regions. They can significantly repress the translation of the downstream coding sequences (CDS), and participate in the spatio-temporal regulations of protein translation. Notwithstanding this biological significance, the selective constraint on uORFs remains underexplored.

Position-dependent correlations between DNA methylation and the evolutionary rates of mammalian coding exons.

DNA cytosine methylation is a central epigenetic marker that is usually mutagenic and may increase the level of sequence divergence. However, methylated genes have been reported to evolve more slowly than unmethylated genes. Hence, there is a controversy on whether DNA methylation is correlated with increased or decreased protein evolutionary rates.

Selective constraint on human pre-mRNA splicing by protein structural properties.

Alternative splicing (AS) is a major mechanism of increasing proteome diversity in complex organisms. Different AS transcript isoforms may be translated into peptide sequences of significantly different lengths and amino acid compositions. One important question, then, is how AS is constrained by protein structural requirements while peptide sequences may be significantly changed in AS events.

Determinants of exon-level evolutionary rates in Arabidopsis species.

What causes the variations in evolutionary rates is fundamental to molecular evolution. However, in plants, the causes of within-gene evolutionary rate variations remain underexplored. Here we use the principal component regression to examine the contributions of eleven exon features to the within-gene variations in nonsynonymous substitution rate (d(N)), synonymous substitution rate (d(S)), and the d(N)/d(S) ratio in Arabidopsis species.