Comparison of Chinese and U.S. Patent Reform Legislation: Which, If Either, Got it Right?, 11 J. Marshall Rev. Intell. Prop. L. 567 (2012)

Chinese patent law has a short history whereas the United States ( U.S. ) system has a more robust history. This article chronicles important remaining differences between Chinese and U.S. patent laws including the utility model successfully employed at State Intellectual Property Office of the People’s Republic of China ( SIPO ) and in the Chinese courts, but not available under U.S. law. Some differences are discussed in regard of patent appeals, reexaminations for invalidity, China’s lack of a reissue process to correct major errors, China’s inventors remuneration process and compulsory licensing of patents, and China’s unique requirement of post termination compensation to support a covenant not to compete. This article further discusses recent changes in U.S. Patent law, as a result of the American Invents Act, that have no counterpart in China. This includes a discussion on changes in the rules governing when prior art applies against applications, new misjoinder rules and elimination of qui tam patent suits rules. This article discusses the new procedure in the United States Patent and Trademark Office ( USPTO ) called post grant review and a companion process for review of validity of granted patents called inter partes review. These new proceedings have the potential for invalidation of patents in a manner far less expensive than in court. However, the devil will be in the details of the regulations and fees yet to be promulgated by the USPTO or reviewed by the public. Whether China or the United States got it right is too early to tell and is anyone’s guess

Contribution of complement‐stimulated hepatic macrophages and neutrophils to endotoxin‐induced liver injury in rats

The role of complement as potential activator for tissue macrophages and neutrophils was investigated in an experimental model of endotoxin‐induced liver injury in male Fischer rats. Injection of Salmonella enteritidis endotoxin (1 mg/kg) into Corynebacterium parvum‐pretreated animals (7 mg/kg; single dose 6 days before endotoxin) resulted in severe oxidant stress, as indicated by a 37‐fold increase of plasma levels of glutathione disulfide (basal concentration, 0.36 ± 14 μmol/L), accumulation of neutrophils in the liver (600 ± 31 neutrophils/50 high‐power fields) and liver injury (plasma ALT, 1184 ± 185 U/l; necrosis; 19% ± 3%) 10 hr after endotoxin. The oxidant stress induced by 1 mg/kg endotoxin in the C. parvum‐treated animals was always significantly higher than that in control animals receiving the same dose of endotoxin. Inhibition of complement activation with the soluble complement receptor type 1 attenuated the oxidant stress and liver injury by 50% to 65% but had no effect on hepatic neutrophil accumulation or plasma tumor necrosis factor‐α levels. Treatment with a monoclonal antibody directed against the α‐chain of CD11b/CD18 adhesion proteins (clone 17), which was highly effective in attenuating ischemia‐reperfusion injury in the liver by reducing the number of neutrophils and functionally inactivating these cells, neither protected against parenchymal cell injury nor affected hepatic neutrophil infiltration in the C. parvum model. We conclude that reactive oxygen derived from complement‐stimulated macrophages is critical for the development of liver injury in the C. parvum/endotoxin model. (HEPATOLOGY 1994; 19:973–979.) Copyright © 1994 American Association for the Study of Liver Disease

Sequestration of neutrophils in the hepatic vasculature during endotoxemia is independent of β2 integrins and intercellular adhesion molecule-1

Antibodies against cellular adhesion molecules protect against neutrophil-induced hepatic injury during ischemia-reperfusion and endotoxemia. To test if β2 integrins on neutrophils and intercellular adhesion molecule-1 (ICAM-1) on endothelial cells are involved in neutrophil sequestration in the hepatic vasculature, neutrophil accumulation in the liver was characterized during the early phase of endotoxemia. Intravenous injection of Salmonella enteritidis endotoxin induced a dose-dependent activation of complement, tumor necrosis factor-α (TNF-α) formation, and an increase of hepatic neutrophils with maximal numbers at 5 mg/kg (90 min: 339 ± 14 cells/50 high power fields; controls: 18 ± 2). Administration of 15 Mg/kg TNF-α and intravascular complement activation with cobra venom factor (75 μg/kg) had additive effects on hepatic neutrophil accumulation compared with each mediator alone. Monoclonal antibodies (2 mg/kg) to ICAM-1 and the α-chain (CD11 a, CD11b) or the β-chain (CD18) of β2 integrins had no significant effect on hepatic neutrophil count after endotoxin. In contrast, these antibodies inhibited peritoneal neutrophil infiltration in response to glycogen administration by 28% (CD11b), 60% (CD11a, ICAM-1), and 92% (CD18). Our data suggest that TNF-α and complement factors contribute to hepatic neutrophil sequestration during the early phase of endotoxemia. Despite the fact that these inflammatory mediators can up-regulate integrins and ICAM-1, these adhesion molecules are not necessary for neutrophil accumulation in hepatic sinusoids. The protective effect of these antibodies against neutrophil-induced liver injury appears to be due to inhibition of transendothelial migration and adherence to parenchymal cells

Activation of kupffer cells and neutrophils for reactive oxygen formation is responsible for endotoxin-enhanced liver injury after hepatic ischemia

The potential role of reactive oxygen species generated by Kupffer cells and neutrophils was investigated in a model of endotoxin-enhanced liver injury after hepatic ischemia. Male Fischer rats were subjected to 20 min ischemia and reperfusion of up to 24 h; .5 mg/kg Salmonella enteritidis endotoxin was injected at 30 min of reperfusion. The animals developed severe liver injury resulting in 50% hepatocellular necrosis at 24 h. Isolated Kupffer cells and neutrophils from the postischemic liver generated 10-fold more Superoxide than cells from control livers. Treatment with gadolinium chloride (GdCl3) selectively reduced the capacity of Kupffer cells to generate Superoxide by 65% and attenuated liver injury by 73% at 4 h and 58-69% at 24 h. Monoclonal antibodies against neutrophil adhesion molecules (CD11/CD18) had no effect on the early injury but reduced hepatocellular necrosis by 90-95% at 24 h. The antioxidant Trolox and the iron-chelator deferoxamine attenuated liver injury by 71 and 80%, respectively. It is concluded that Kupffer cells are mainly responsible for the initial injury, and neutrophils are the dominant cytotoxic cell type during the later phase. Reactive oxygen generated by both cell types is critical for this pathogenesis. © 1995 The Shock Society

Functional inactivation of neutrophils with a Mac‐1 (CD11b/CD18) monoclonal antibody protects against ischemia‐reperfusion injury in rat liver

The role of neutrophil CD11b/CD18 (Mac‐1) adhesion proteins in the pathogenesis of hepatic reperfusion injury was investigated in an experimental model. Male Fischer rats were treated with a CD11b monoclonal antibody or an isotype‐matched IgM control antibody and subjected to 45 min of hepatic ischemia followed by 24 hr of reperfusion. Large numbers of neutrophils were present in postischemic liver lobes (1,241 ± 64 polymorphonuclear cells/50 high‐power fields) compared with numbers in baseline measurements (14 ± 3 polymorphonuclear cells/50 high‐power fields), and severe liver injury was observed after 24 hr of reperfusion (hepatic necrosis: 88% ± 2%). Pretreatment with the CD11b antibody (two doses of 2 mg/kg each) significantly attenuated liver injury and reduced the number of polymorphonuclear cells in the postischemic liver by 59%. Selective treatment with the antibody only during reperfusion was similarly effective. The increased spontaneous superoxide formation of neutrophils isolated from postischemic liver (1.05 ± 0.11 nmol O2−/hr/106 cells) was reduced by 56% in neutrophils from CD11b antibody‐treated animals. Flow cytometric analysis of CD11b/CD18 expression on circulating neutrophils demonstrated significant upregulation at all time points during reperfusion. Clone 17 also effectively inhibited neutrophil extravasation in a glycogen peritonitis model. Our data are consistent with a dual protective effect of the CD11b antibody in hepatic reperfusion injury in vivo (i.e., reduced accumulation of neutrophils and their functional inactivation). (HEPATOLOGY 1993;17:915–923.) Copyright © 1993 American Association for the Study of Liver Disease

Release of soluble intercellular adhesion molecule 1 into bile and serum in murine endotoxin shock

Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecules Mac-1 (CD11b/CD18) on neutrophils and its counterreceptor on endothelial cells and hepatocytes, intercellular adhesion molecule 1 (ICAM-1). To investigate a potential release of a soluble form of ICAM-1 (sICAM-1), animals received 100 μg/kg Salmonella abortus equi endotoxin alone or in combination with 700 mg/kg galactosamine. In endotoxin-sensitive mice (C3Heb/FeJ), injection of endotoxin did not cause liver injury but induced a time-dependent increase of sICAM-1 in serum (300%) and in bile (615%) without affecting bile flow. In galactosamine/endotoxin-treated animals, which developed liver injury, the increase in both compartments was only 97% and 104%, respectively. In either case, the increase in sICAM-1 concentrations paralleled the enhanced ICAM-1 expression in the liver. The endotoxin-resistant strain (C3H/HeJ) did not show elevated sICAM-1 levels in serum or bile after endotoxin administration. In contrast, the intravenous injection of murine tumor necrosis factor α (TNF-α), interleukin-1α (IL- 1α) or IL-1β (13-23 μg/kg) into endotoxin-resistant mice induced a 225% to 364% increase in serum sICAM-1 and a 370% elevation of the biliary efflux of sICAM-1, again independent of changes in bile flow. These data indicate that cytokines are major inducers of sICAM-1 formation during endotoxemia in vivo. The described experimental model can be used to investigate the cole of sICAM-1 in the pathophysiology of inflammatory liver disease

Cytokine-induced upregulation of hepatic intercellular adhesion molecule-1 messenger RNA expression and its role in the pathophysiology of murine endotoxin shock and acute liver failure

Neutrophil-induced liver injury during endotoxemia is dependent on the adhesion molecule Mac-1 (CD11b/CD18) on neutrophils. The potential involvement of its counterreceptor, intercellular adhesion molecule-1 (ICAM-1), in the pathogenesis was investigated after administration of 100 μg/kg Salmonella abortus equi endotoxin (ET) in galactosamine-sensitized mice (Gal). In ETsensitive mice (C3Heb/FeJ), which generated large amounts of tumor necrosis factor-alpha (TNF-α), massive neutrophil infiltration and severe liver injury were observed. In an ET-resistant strain (C3H/HeJ), which did not generate TNF-α, Gal/ET failed to cause neutrophil accumulation or injury. ICAM-1 messenger RNA (mRNA), negligible in control livers, was selectively induced by Gal/ET in ET-sensitive mice. Intravenous injection of murine TNF-α, interleukin-1 alpha (IL-1α) or IL-1β (13 to 23 μg/kg) strongly induced the ICAM-1 message in both strains, showing a comparable capacity for ICAM-1 mRNA synthesis. All cytokines caused similar neutrophil accumulation in the liver; however, only Gal/ TNF-α also caused upregulation of Mac-1 on circulating neutrophils and liver injury. The anti-murine ICAM-1 monoclonal antibody YN.1 (3 mg/kg) attenuated liver injury in ET-sensitive mice by 67% to 90% compared with isotype-matched control antibody-treated animals but did not reduce neutrophil accumulation in hepatic sinusoids. Our data suggest that the cytokines TNF-α and IL-1 are the main mediators responsible for upregulation of ICAM-1 mRNA in the liver during endotoxemia. The upregulation of both adhesion molecules, ICAM-1 and Mac-1, is necessary for a neutrophil-induced liver injury to occur. Blocking ICAM-1 and/or interfering with ICAM1 induction could be a successful therapeutic strategy to prevent sepsis-related inflammatory liver injury. © 1995

Pathophysiologic importance of E- and L-selectin for neutrophil-induced liver injury during endotoxemia in mice

Neutrophils can cause parenchymal cell injury in the liver during ischemia-reperfusion and endotoxemia. Neutrophils relevant for the injury accumulate in sinusoids, transmigrate, and adhere to hepatocytes. To investigate the role of E- and L-selectin in this process, C3Heb/FeJ mice were treated with 700 mg/kg galactosamine and 100 μg/kg endotoxin (Gal/ET). Immunogold labeling verified the expression of E-selectin on sinusoidal endothelial cells 4 hours after Gal/ET injection. In addition, Gal/ET caused up-regulation of Mac-1 (CD11b/CD18) and shedding of L-selectin from circulating neutrophils. Gal/ET induced hepatic neutrophil accumulation (422 ± 32 polymorphonuclear leukocytes [PMN]/50 high power fields [HPF]) and severe liver injury (plasma alanine transaminase [ALT] activities: 4,120 ± 960 U/L; necrosis: 44 ± 3%) at 7 hours. Treatment with an anti-E-selectin antibody (3 mg/kg, intravenously) at the time of Gal/ET administration did not significantly affect hepatic neutrophil accumulation and localization. However, the anti-E-selectin antibody significantly attenuated liver injury as indicated by reduced ALT levels (-84%) and 43% less necrotic hepatocytes. In contrast, animals treated with an anti-L-selectin antibody or L-selectin gene knock out mice were not protected against Gal/ET-induced liver injury. However, E-, L-, and P-selectin triple knock out mice showed significantly reduced liver injury after Gal/ET treatment as indicated by lower ALT levels (-65%) and reduced necrosis (-68%). Previous studies showed that circulating neutrophils of E-selectin-overexpressing mice are primed and activated similar to neutrophils adhering to E-selectin in vitro. Therefore, we conclude that blocking E-selectin or eliminating this gene may have protected against Gal/ET-induced liver injury in vivo by inhibiting the full activation of neutrophils during the transmigration process