Patent production is a prerequisite for successful exit of a biopharmaceutical company.

Patents are especially important for the business of drug discovery; however, their importance for biopharmaceutical companies has not been revealed quantitatively yet. To examine the correlation between patents and long-term business outcome of biopharmaceutical companies we analyze annual number of patent families and business conditions of 123 public-listed biopharmaceutical companies established from 1990 to 1995 in the USA. Our results show the number of patent families per year correlates well with the business condition: average of the bankruptcy group is significantly smaller than those of the continuing and the merger and acquisitions (M&A) groups. In the M&A by big pharma group, the acquisition cost correlates with the number of annual patent families. However, patentability and strategy of foreign patent application are not different among the groups. Therefore, the productivity of invention is the key factor for success of biopharmaceutical companies.

Attenuation and immunogenicity in mice of temperature-sensitive influenza viruses expressing truncated NS1 proteins.

It was previously shown that two mutant influenza A viruses expressing C-terminally truncated forms of the NS1 protein (NS1-81 and NS1-110) were temperature sensitive in vitro. These viruses contain HA, NA and M genes derived from influenza A/WSN/33 H1N1 virus (mouse-adapted), and the remaining five genes from human influenza A/Victoria/3/75 virus. Mice intranasally infected with the NS1 mutant viruses showed undetectable levels of virus in lungs at day 3, whereas those infected with the NS1 wild-type control virus still had detectable levels of virus at this time. Nevertheless, the temperature-sensitive mutant viruses induced specific cellular and humoral immune responses similar to those induced by the wild-type virus. Mice immunized with the NS1 mutant viruses were protected against a lethal challenge with influenza A/WSN/33 virus. These results indicate that truncations in the NS1 protein resulting in temperature-sensitive phenotypes in vitro correlate with attenuation in vivo without compromising viral immunogenicity, an ideal characteristic for live attenuated viral vaccines.

Induction of cellular immune responses to simian immunodeficiency virus gag by two recombinant negative-strand RNA virus vectors.

A recombinant Newcastle disease virus (rNDV) expressing simian immunodeficiency virus (SIV) Gag protein (rNDV/SIVgag) was generated. The rNDV/SIVgag virus induced Gag-specific cellular immune responses in mice, leading to a specific anti-Gag antiviral immunity. This was evidenced by the inhibition of growth of recombinant vaccinia virus expressing an identical Gag antigen (rVac/SIVgag) but not of wild-type vaccinia virus in rNDV/SIVgag-immunized mice. Among intravenous, intraperitoneal, or intranasal immunization routes, intranasal administration induced the strongest protective response against challenge with rVac/SIVgag. We further demonstrated that these immune responses were greatly enhanced after booster immunization with recombinant influenza viruses expressing immunogenic portions of SIV Gag. The magnitude of the protective immune response correlated with the levels of cellular immune responses to Gag, which were still evident 9 weeks after immunization. These results suggest that rNDV and influenza virus vectors are suitable candidate vaccines against AIDS as well as against other infectious diseases.

Induction of protective immunity against malaria by priming-boosting immunization with recombinant cold-adapted influenza and modified vaccinia Ankara viruses expressing a CD8+-T-cell epitope derived from the circumsporozoite protein of Plasmodium yoelii.

We immunized mice with an attenuated (cold-adapted) influenza virus followed by an attenuated vaccinia virus (modified vaccinia virus Ankara), both expressing a CD8(+)-T-cell epitope derived from malaria sporozoites. This vaccination regimen elicited high levels of protection against malaria. This is the first time that the vaccine efficacy of a recombinant cold-adapted influenza virus vector expressing a foreign antigen has been evaluated.

Enhanced cellular immune responses to SIV Gag by immunization with influenza and vaccinia virus recombinants.

An effective vaccination strategy against human immunodeficiency virus type 1 (HIV-1) should include the induction of potent cellular immune responses against conserved HIV-1 antigens. We have generated five replication competent recombinant influenza viruses (rFlu/SIV Gag nos. 1-5) expressing different portions of Gag of simian immunodeficiency virus (SIV). Single intranasal immunizations in mice with each rFlu/SIV Gag viruses resulted in different degrees of protection against a challenge with recombinant vaccinia virus expressing SIV Gag. Immunized BALB/c mice had detectable CD8+ T cell responses specific for Gag peptide 185-199 when mice were vaccinated with rFlu/SIV Gag no. 3 virus, and for Gag peptides 281-295 and 285-299 when vaccinated with rFlu/SIV Gag no. 4 virus. Cellular immune responses against SIV Gag were further enhanced by a booster with a recombinant vaccinia virus expressing SIV Gag in both the spleen and local lymph node tissues, resulting in the induction of robust Gag-specific CD8+ T cell responses at both systemic and mucosal levels. We suggest that a prime-boost immunization regimen using recombinant influenza and vaccinia viruses expressing HIV Gag might represent an effective means to induce potent HIV-specific, protective CD8+ T cell responses.