Exhausted or Unlicensed: Can Field-of-Use Restrictions in Biotech License Agreements Still Prevent Off-Label Use Promotion After Quanta Computer?

[Excerpt] “In the biotechnology (biotech) industry, companies must be increasingly aware of their intellectual property and how their licensing strategies can impact their rights. When licensing patented technology, it is common practice for biotech companies to include restricted field-of-use provisions in their license agreements. Such provisions permit a licensee to only use licensed technology in a defined field and restrict use or development in another field. This licensing strategy plays an important role within the biotech industry because it allows companies to more effectively control their intellectual property and to more efficiently research and develop pharmaceutical products. A problem that occurs in the biotech industry is when a company promotes the ―off-label use of an already-approved drug—a use that may be covered by another‘s patent, though perhaps undeveloped or unlicensed. This problem can be an unforeseen side effect of utilizing biological material to develop drugs that may have many, and often unknown, indications for disease treatments. One way to control off-label use promotion is through patent license agreements. Unfortunately, for many biotech licensors, patent licenses may not always prevent off-label use promotion. To illustrate, a licensee (or a third party downstream of the license agreement) could promote a drug approved by the Food and Drug Administration (FDA), developed from licensed technology, for an unapproved treatment covered by the licensor‘s patent that the party was not given the right to develop. The U.S. Supreme Court has held that activity outside of the licensed field can constitute patent infringement because the patent owner has not transferred the rights for use or product development in that field. However, in 2008, the Supreme Court, in Quanta Computer, Inc. v. LG Electronics, Inc., implied that the patent holder in this situation may have exhausted its rights by licensing the technology and, therefore, cannot sue a third party for infringement even if the use being promoted is covered by the patent. This Note discusses how Quanta should be interpreted and applied in the context of field-of-use restrictions in biotech license agreements and how a biotech licensor may sue for patent infringement as a remedy for downstream off-label use promotion when it licenses technology to be developed within a restricted field. Section I provides an overview of the biotech industry and how patent licensing plays an essential role in the growth and continuation of the industry. Section II highlights the problem of off-label use promotion and how the FDA appears to fall short of adequate regulation in this area. Section III outlines how the doctrine of exhaustion affects patent license agreements, specifically in the wake of Quanta. Section IV discusses the post-Quanta application of the doctrine of exhaustion to biotech licenses that incorporate field-of-use restrictions and how licensors should respond to Quanta when drafting license agreements to prevent off-label use.

The biopsychology of maternal behavior in nonhuman mammals

The term “maternal behavior,” when applied to nonhuman mammals, includes the behaviors exhibited in preparation for the arrival of newborn, in the care and protection of the newly arrived young, and in the weaning of those young, and represents a complex predictable pattern that is often regarded as a single, comprehensive, species-specific phenomenon. Although the delivering first-time mammalian mother is immediately and appropriately maternal, a maternal “virgin” with no prior exposure to young does not show immediate and appropriate behavior toward foster young. Nevertheless, the virgin female, and indeed the male, possess the neural circuitry that underlies the pattern referred to as maternal behavior, despite not exhibiting the pattern under normal circumstances. At parturition, or after extensive exposure to young, what emerges appears to be a single stereotyped maternal behavior pattern. However, it is actually a smoothly coordinated constellation of simpler actions with proximate causes that, when sequenced properly, have the appearance of a motivated, purposive, adaptive, pattern of caretaking. Over the past 50 years, much research has focused on finding the principal external and internal factors that convert the nonmaternal behavior patterns of the nonpregnant nullipara, the virgin, to the almost immediate and intense maternal behavior characteristic of the puerpera, the mother. This review is an attempt to summarize the many comprehensive, even encyclopedic, reviews of these factors, with an emphasis on brain mechanisms, and to highlight the gaps that remain in understanding the processes involved in the almost immediate onset of maternal caretaking behaviors observed in mammals at delivery. Where possible, the reader is directed to some of those excellent reviews

Effects of Lateral Hypothalamic Lesions on Placentophagia in Virgin, Primiparous, and Multiparous Rats

Lesions of the lateral hypothalamus (LH) were produced in pregnant and nonpregnant female rats through chronically implanted electrodes to investigate the effect of LH damage on placentophagia. Other variables investigated were prior parturitional experience and stimulus properties of the placenta. Lesions were produced under ether anesthesia 24 hr. prior to parturition in pregnant females and 24 hr. prior to placenta presentation in nonpregnant females.\ud The LH lesions produced aphagia to a liquid diet. Pregnancy was not a significant variable in the initiation of placentophagia, but prior parturitional experience was a critical variable. Virgin and primiparous females did not exhibit placentophagia following LH damage, but multiparous females would eat placenta whenever the opportunity arose, independently of LH damage and pregnancy

Perinatal maternal and neonatal behaviour in\ud the captive reticulated giraffe

A captive reticulated giraffe was observed constantly for three weeks prior to, and periodically for 90 days subsequent to, the birth of her calf. Extensive observations were made of the birth sequence, feeding, drinking, sleeping and one instance of an infant distress call, as well as observations of the initiation of maternal behaviour (including licking, nursing, placentophagia, and what appeared to be helping the calf to stand, guiding the calf's movements, and attempts to respond to the calf's distress call)

Opioid stimulation in the ventral tegmental area facilitates the onset of maternal behavior in rats

This research investigated the effect of an increase or decrease in opioid activity in the ventral tegmental area (VTA) on the onset of maternal behavior in rats. In Experiment 1, the latency to show maternal behavior toward foster rat pups (sensitization latency) was determined in maternally naive female rats given either nothing or a unilateral intra-VTA injection of morphine sulfate (MS) (0.0, 0.01, 0.03, 0.1 or 0.3 µg), on the first three days of a 10-day period of constant exposure to pups. Rats treated with 0.03 µg MS had significantly shorter sensitization latencies than did rats treated with 0.0 µg MS, 0.01 µg MS, or receiving no treatment (higher doses of morphine produced intermediate results). The facilitating effect of intra-VTA MS on the onset of maternal behavior was blocked by pretreatment with naltrexone hydrochloride and was found to have a specific site of action in the VTA (MS injections dorsal to the VTA were ineffective). In Experiment 2, sensitization latencies were determined in periparturitional rats given a bilateral intra-VTA injection of either the opioid antagonist naltrexone methobromide (quaternary naltrexone), its vehicle, a sham injection, or left untreated 40 min after delivery of the last pup. The mothers' own pups were removed at delivery; mothers were nonmaternal at the time of testing. Quaternary naltrexone treatment produced significantly slower sensitization to foster pups than did control conditions. Total activity and pup-directed activity did not differ significantly with treatment. The results demonstrate that increased opioid activity in the VTA facilitates the onset of maternal behavior in inexperienced nonpregnant female rats, and decreased opioid activity in the VTA disrupts the rapid onset of maternal behavior at parturition

Next steps for understanding the selective relevance of female-female competition

After decades of neglect, recent empirical research on exaggerated female traits (e.g., ornaments, armaments, aggression, acoustic signals, etc.) has revived interest in this widespread but poorly understood phenomenon, and shown that these traits often function in the context of female-female competition (West-Eberhard, 1983; Amundsen, 2000; Clutton-Brock, 2009; Rosvall, 2011a; Stockley and Bro-Jørgensen, 2011; Rubenstein, 2012 [Theme issue]; Stockley and Campbell, 2013 [Theme issue]). However, recent reviews have emphasized the applicability of sexual vs. social selection, rather than rigorously examining the role of different ecological contexts in shaping the evolution of traits used in competitive contexts (hereafter, “competitive traits”) in females. Thus, we still lack a solid understanding of the ecological and evolutionary mechanisms driving the evolution of female trait expression, in particular whether, how, and why these mechanisms vary among species, and between the sexes

The effects of strain, reproductive condition, and strain of placenta donor on placentophagia in nonpregnant mice

The effects on placentophagia of strain, reproductive condition, and strain of placenta donor were observed in nonpregnant mice. Mice of the C57BL/6By and BALB/cBy strains were exposed to placentas of either strain after either no previous parturitional experience, one parturitional experience without nursing experience, or one parturitional experience with nursing experience. There was a significant effect of strain, a significant effect of reproductive condition, but no significant effect of strain of placenta donor. There was a significant interaction between strain and reproductive condition, but no significant interactions with placenta strain. It was inferred that the ability of a mouse to acquire and utilize relevant stimuli during and after parturition, in order to produce an emancipation of placentophagia from the physiological controls associated with parturition, is influenced by genotype

Effects of Medial Preoptic Lesions on\ud Placentophagia and on the Onset of Maternal\ud Behavior in the Rat

Lesions of the medial preoptic area (MPO) were produced through permanently indwelling electrodes 24 hr prior to parturition in pregnant rats, or 24 hr prior to donor-placenta presentation in virgin rats determined in a pretest to be placentophages. The lesions had no disruptive effect on placentophagia in the virgin females. However, MPO lesions did delay the onset of placentophagia, pup-retrieval, and nestbuilding in some parturient rats. In others, lesions produced an impairment (in latency and quality) only of nest-building. None showed any impairment of pup-licking, or in the clear tendency to leave excreted waste away from the gathered pups. These results suggest the possibility of at least semi-independent mechanisms for the various components of maternal behavior

Costs and benefits of competitive traits in females: aggression, maternal care and reproductive success

Recent research has shown that female expression of competitive traits can be advantageous, providing greater access to limited reproductive resources. In males increased competitive trait expression often comes at a cost, e.g. trading off with parental effort. However, it is currently unclear whether, and to what extent, females also face such tradeoffs, whether the costs associated with that tradeoff overwhelm the potential benefits of resource acquisition, and how environmental factors might alter those relationships. To address this gap, we examine the relationships between aggression, maternal effort, offspring quality and reproductive success in a common songbird, the dark-eyed junco (Junco hyemalis), over two breeding seasons. We found that compared to less aggressive females, more aggressive females spent less time brooding nestlings, but fed nestlings more frequently. In the year with better breeding conditions, more aggressive females produced smaller eggs and lighter hatchlings, but in the year with poorer breeding conditions they produced larger eggs and achieved greater nest success. There was no relationship between aggression and nestling mass after hatch day in either year. These findings suggest that though females appear to tradeoff competitive ability with some forms of maternal care, the costs may be less than previously thought. Further, the observed year effects suggest that costs and benefits vary according to environmental variables, which may help to account for variation in the level of trait expression.Research was supported by National Science Foundation (NSF) grants to EK (BSC 05-19211 and IOS 08-20055) and an NSF Doctoral Dissertation Improvement Grant to KC (09-10036). KC was also supported by NSF Graduate Research Fellowship (www.nsfgrfp.org)

Placentophagia in Nonpregnant Rats:\ud Influence of Estrous Cycle Stage and Birthplace

Prior parturitional experience and genotype have previously been found to affect the proportion of nonpregnant female rats and mice that will eat foster placenta. The present series of experiments was designed to investigate the influence of estrous cycle stage on placentophagia in rats. Foster placenta was presented to nonpregnant Long-Evans females, purchased from a commercial breeder, for 15 min on 5 consecutive days. We found that virgin placentophages were most likely to have eaten placenta on the first presentation, unless the first presentation occurred during proestrus. In fact, virgins would not eat placenta for the first time during proestrus, regardless of test-day. However, once they had eaten placenta, either in a nonproestrus stage, or, in the case of primiparae, during parturition, they would eat placenta during proestrus. Long-Evans rats born in our laboratory differed from the purchased rats, manifesting an incidence of placentophagia that was too low to be analyzed by stage of the estrous cycle; when tested as primiparae, however, there were no differences between the two groups