Research and Development of Hepatitis B Drugs: An Analysis Based on Technology Flows Measured by Patent Citations

<div><p>Despite the existence of available therapies, the Hepatitis B virus infection continues to be one of the most serious threats to human health, especially in developing countries such as China and India. To shed light on the improvement of current therapies and development of novel anti-HBV drugs, we thoroughly investigated 212 US patents of anti-HBV drugs and analyzed the technology flow in research and development of anti-HBV drugs based on data from IMS LifeCycle databases. Moreover, utilizing the patent citation method, which is an effective indicator of technology flow, we constructed patent citation network models and performed network analysis in order to reveal the features of different technology clusters. As a result, we identified the stagnant status of anti-HBV drug development and pointed the way for development of domestic pharmaceuticals in developing countries. We also discussed about therapeutic vaccines as the potential next generation therapy for HBV infection. Lastly, we depicted the cooperation between entities and found that novel forms of cooperation added diversity to the conventional form of cooperation within the pharmaceutical industry. In summary, our study provides inspiring insights for investors, policy makers, researchers, and other readers interested in anti-HBV drug development.</p></div

Partial list of current clinical trials evaluating various vaccine therapies for HBV^a^, ^b.

<p>Partial list of current clinical trials evaluating various vaccine therapies for HBV<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164328#t003fn001" target="_blank">^a</a>^, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164328#t003fn002" target="_blank">^b</a>.</p

Information of the main technology clusters in the patent citation network^a.

<p>Information of the main technology clusters in the patent citation network<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164328#t002fn001" target="_blank">^a</a>.</p

Illustration of distribution of patents by patentee.

<p>Note: patentees are listed in descending order from left to right. A portion of the patents are shared by multiple institutions.</p

Illustration of distribution of patents by development phase.

Note: Most patents are in the marketed phase, indicating stagnancy of R&D of anti-HBV drugs.</p

Illustration of distribution of patents by year granted.

<p>Note: a reversed U-shaped curve with fluctuations showed the 1995–2004 bloom period of anti-HBV drug development.</p

Patent information of marketed HBV drugs^a.

<p>Patent information of marketed HBV drugs<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0164328#t001fn001" target="_blank">^a</a>.</p

Patent citation network.

<p>Note: Network model is divided into different clusters and patents worth noticing are annotated with their US patent numbers (the prefix “US” is removed and only the numbers are shown for users to search in the USPTO’s online database).</p

The research framework of this study.

<p>Note: Data were collected from IMS LifeCycle databases and processed for statistical analysis, network modeling, and network analysis.</p

D6D activity is higher in tumor tissue than in adjacent non-tumor tissue.

<p>(<b>a</b>) The activity of biomarkers of D6D in B16 melanoma. <i>Upper:</i> Gas chromatography showing the differences in LA, ETA and AA content between B16 melanoma and adjacent non-tumor tissue. <i>Lower</i>: The ratios of ETA/LA and AA/LA indicate D6D enzyme activity. **<i>P</i><0.01, n = 4. (<b>b</b>) Activity of biomarkers of D6D in LLC tumors. <i>Upper:</i> Gas chromatography showing the differences in LA, ETA and AA content between LLC tumor and adjacent non-tumor tissue. <i>Lower</i>: The ratios of ETA/LA and AA/LA indicate D6D enzyme activity. **<i>P</i><0.01, n = 4. (<b>c</b>) D6D mRNA levels in tumor and adjacent non-tumor tissue. **<i>P</i><0.01, n = 3. (<b>d</b>) Western blot showing D6D protein levels in tumor and adjacent non-tumor tissue. (<b>e</b>) Correlation of the activity of biomarkers of D6D (based on ETA/LA and AA/LA ratios) with tumor size. (<b>f</b>) Correlation of D6D mRNA levels with tumor size.</p