Patents, Ethics and Stem Cell Research : The Case of hESC Innovation in Australia, Europe and the United States

Embryonic stem cells offer potentially a ground-breaking insight into health and diseases and are said to offer hope in discovering cures for many ailments unimaginable few years ago. Human embryonic stem cells are undifferentiated, immature cells that possess an amazing ability to develop into almost any body cell such as heart muscle, bone, nerve and blood cells and possibly even organs in due course. This remarkable feature, enabling embryonic stem cells to proliferate indefinitely in vitro (in a test tube), has branded them as a so-called miracle cure . Their potential use in clinical applications provides hope to many sufferers of debilitating and fatal medical conditions. However, the emergence of stem cell research has resulted in intense debates about its promises and dangers. On the one hand, advocates hail its potential, ranging from alleviating and even curing fatal and debilitating diseases such as Parkinson s, diabetes, heart ailments and so forth. On the other hand, opponents decry its dangers, drawing attention to the inherent risks of human embryo destruction, cloning for research purposes and reproductive cloning eventually. Lately, however, the policy battles surrounding human embryonic stem cell innovation have shifted from being a controversial research to scuffles within intellectual property rights. In fact, the ability to obtain patents represents a pivotal factor in the economic success or failure of this new biotechnology. Although, stem cell patents tend to more or less satisfy the standard patentability requirements, they also raise serious ethical and moral questions about the meaning of the exclusions on ethical or moral grounds as found in European and to an extent American and Australian patent laws. At present there is a sort of a calamity over human embryonic stem cell patents in Europe and to an extent in Australia and the United States. This in turn has created a sense of urgency to engage all relevant parties in the discourse on how best to approach patenting of this new form of scientific innovation. In essence, this should become a highly favoured patenting priority. To the contrary, stem cell innovation and its reliance on patent protection risk turmoil, uncertainty, confusion and even a halt on not only stem cell research but also further emerging biotechnology research and development. The patent system is premised upon the fundamental principle of balance which ought to ensure that the temporary monopoly awarded to the inventor equals that of the social benefit provided by the disclosure of the invention. Ensuring and maintaining this balance within the patent system when patenting human embryonic stem cells is of crucial contemporary relevance. Yet, the patenting of human embryonic stem cells raises some fundamental moral, social and legal questions. Overall, the present approach of patenting human embryonic stem cell related inventions is unsatisfactory and ineffective. This draws attention to a specific question which provides for a conceptual framework for this work. That question is the following: how can the investigated patent offices successfully deal with patentability of human embryonic stem cells? This in turn points at the thorny issue of application of the morality clause in this field. In particular, the interpretation of the exclusions on ethical or moral grounds as found in Australian, American and European legislative and judicial precedents. The Thesis seeks to compare laws and legal practices surrounding patentability of human embryonic stem cells in Australia and the United States with that of Europe. By using Europe as the primary case study for lessons and guidance, the central goal of the Thesis then becomes the determination of the type of solutions available to Europe with prospects to apply such to Australia and the United States. The Dissertation purports to define the ethical implications that arise with patenting human embryonic stem cells and intends to offer resolutions to the key ethical dilemmas surrounding patentability of human embryonic stem cells and other morally controversial biotechnology inventions. In particular, the Thesis goal is to propose a functional framework that may be used as a benchmark for an informed discussion on the solution to resolving ethical and legal tensions that come with patentability of human embryonic stem cells in Australian, American and European patent worlds. Key research questions that arise from these objectives and which continuously thread throughout the monograph are: 1. How do common law countries such as Australia and the United States approach and deal with patentability of human embryonic stem cells in their jurisdictions? These practices are then compared to the situation in Europe as represented by the United Kingdom (first two chapters), the Court of Justice of the European Union and the European Patent Office decisions (Chapter 3 onwards) in order to obtain a full picture of the present patenting procedures on the European soil. 2. How are ethical and moral considerations taken into account at patent offices investigated when assessing patentability of human embryonic stem cell related inventions? In order to assess this part, the Thesis evaluates how ethical issues that arise with patent applications are dealt with by: a) Legislative history of the modern patent system from its inception in 15th Century England to present day patent laws. b) Australian, American and European patent offices presently and in the past, including other relevant legal precedents on the subject matter. c) Normative ethical theories. d) The notion of human dignity used as the lowest common denominator for the interpretation of the European morality clause. 3. Given the existence of the morality clause in form of Article 6(1) of the Directive 98/44/EC of the European Parliament and of the Council of 6 July 1998 on the legal protection of biotechnological inventions which corresponds to Article 53(a) European Patent Convention, a special emphasis is put on Europe as a guiding principle for Australia and the United States. Any room for improvement of the European morality clause and Europe s current manner of evaluating ethical tensions surrounding human embryonic stem cell inventions is examined. 4. A summary of options (as represented by Australia, the United States and Europe) available as a basis for the optimal examination procedure of human embryonic stem cell inventions is depicted, whereas the best of such alternatives is deduced in order to create a benchmark framework. This framework is then utilised on and promoted as a tool to assist Europe (as represented by the European Patent Office) in examining human embryonic stem cell patent applications. This method suggests a possibility of implementing an institution solution. 5. Ultimately, a question of whether such reformed European patent system can be used as a founding stone for a potential patent reform in Australia and the United States when examining human embryonic stem cells or other morally controversial inventions is surveyed. The author wishes to emphasise that the guiding thought while carrying out this work is to convey the significance of identifying, analysing and clarifying the ethical tensions surrounding patenting human embryonic stem cells and ultimately present a solution that adequately assesses patentability of human embryonic stem cell inventions and related biotechnologies. In answering the key questions above, the Thesis strives to contribute to the broader stem cell debate about how and to which extent ethical and social positions should be integrated into the patenting procedure in pluralistic and morally divided democracies of Europe and subsequently Australia and the United States.

Packing in molten globules and native states

Close packing of hydrophobic residues in the protein interior is an important determinant of protein stability. Cavities introduced by large to small substitutions are known to destabilize proteins. Conversely, native states of proteins and protein fragments can be stabilized by filling in existing cavities. Molten globules (MGs) were initially used to describe a state of protein which has well-defined secondary structure but little or no tertiary packing. Subsequent studies have shown that MGs do have some degree of native-like topology and specific packing. Wet molten globules (WMGs) with hydrated cores and considerably decreased packing relative to the native state have been studied extensively. Recently there has been renewed interest in identification and characterization of dry molten globules (DMGs). These are slightly expanded forms of the native state which show increased conformational flexibility, native-like main-chain hydrogen bonding and dry interiors. The generality of occurrence of DMGs during protein unfolding and the extent and nature of packing in DMGs remain to be elucidated. Packing interactions in native proteins and MGs can be probed through mutations. Next generation sequencing technologies make it possible to determine relative populations of mutants in a large pool. When this is coupled to phenotypic screens or cell-surface display, it becomes possible to rapidly examine large panels of single-site or multi-site mutants. From such studies, residue specific contributions to protein stability and function can be estimated in a highly parallelized fashion. This complements conventional biophysical methods for characterization of packing in native states and molten globules.

Marine flora and fauna of the northeastern United States. Echinodermata: Echinoidea

The echinoid fauna from littoral to abyssal depths off the northeastern United States (Cape Hatteras, NC, to northern Nova Scotia) comprises 31 species, in 26 genera and 19 families. An introduction to the external morphology, distribution, and natural history is given along with an illustrated key to the species, an annotated systematic list, and an index. The fauna Includes 17 species with wide-ranging distributions on continental slopes or abyssal plains. The remaining 14 species occur in shallower waters on the continental shelf or upper slope. Of these, eight are tropical in distribution with their northern range extending to the northeastern United States and three are mainly boreal with the northeastern United States at the southern limit of their range. Two species occur only off the eastern United States and one species is cosmopolitan. (PDF file contains 33 pages.)

I. Electronic states of heavily-doped molecular crystals--naphthalene. I. Theoretical. II. Experimental. II. Lowest singlet and triplet excited states of pyrazine

PART I

The energy spectrum of heavily-doped molecular crystals was treated in the Green’s function formulation. The mixed crystal Green’s function was obtained by averaging over all possible impurity distributions. The resulting Green’s function, which takes the form of an infinite perturbation expansion, was further approximated by a closed form suitable for numerical calculations. The density-of-states functions and optical spectra for binary mixtures of normal naphthalene and deuterated naphthalene were calculated using the pure crystal density-of-state functions. The results showed that when the trap depth is large, two separate energy bands persist, but when the trap depth is small only a single band exists. Furthermore, in the former case it was found that the intensities of the outer Davydov bands are enhanced whereas the inner bands are weakened. Comparisons with previous theoretical calculations and experimental results are also made.

PART II

The energy states and optical spectra of heavily-doped mixed crystals are investigated. Studies are made for the following binary systems: (1) naphthalene-h₈ and d₈, (2) naphthalene--h₈ and αd₄, and (3) naphthalene--h₈ and βd₁, corresponding to strong, medium and weak perturbations. In addition to ordinary absorption spectra at 4˚K, band-to-band transitions at both 4˚K and 77˚K are also analyzed with emphasis on their relations to cooperative excitation and overall density-of-states functions for mixed crystals. It is found that the theoretical calculations presented in a previous paper agree generally with experiments except for cluster states observed in system (1) at lower guest concentrations. These features are discussed semi-quantitatively. As to the intermolecular interaction parameters, it is found that experimental results compare favorably with calculations based on experimental density-of-states functions but not with those based on octopole interactions or charge-transfer interactions. Previous experimental results of Sheka and the theoretical model of Broude and Rashba are also compared with present investigations.

PART III

The phosphorescence, fluorescence and absorption spectra of pyrazine-h₄ and d₄ have been obtained at 4˚K in a benzene matrix. For comparison, those of the isotopically mixed crystal pyrazine-h₄ in d₄ were also taken. All these spectra show extremely sharp and well-resolved lines and reveal detailed vibronic structure.

The analysis of the weak fluorescence spectrum resolves the long-disputed question of whether one or two transitions are involved in the near-ultraviolet absorption of pyrazine. The “mirror-image relationship” between absorption and emission shows that the lowest singlet state is an allowed transition, properly designated as ¹B_3u ← ¹A_1g. The forbidden component ¹B_2g, predicted by both “exciton” and MO theories to be below the allowed component, must lie higher. Its exact location still remains uncertain.

The phosphorescence spectrum when compared with the excitation phosphorescence spectra, indicates that the lowest triplet state is also symmetry allowed, showing a strong 0-0 band and a “mirror-image relationship” between absorption and emission. In accordance with previous work, the triplet state is designated as ³B_3u.

The vibronic structure of the phosphorescence spectrum is very complicated. Previous work on the analysis of this spectrum all concluded that a long progression of v_6a exists. Under the high resolution attainable in our work, the supposed v_6a progression proves to have a composite triplet structure, starting from the second member of the progression. Not only is the v_9a hydrogen-bending mode present as shown by the appearance of the C-D bending mode in the d₄ spectrum, but a band of 1207 cm^-1 in the pyrazine in benzene system and 1231 cm^-1 in the mixed crystal system is also observed. This band is assigned as 2v_6b and of a_1g symmetry. Its anonymously strong intensity in the phosphorescence spectrum is interpreted as due to the Fermi resonance with the 2v_6a and v_9a band.

To help resolve the present controversy over the crystal phosphorescence spectrum of pyrazine, detailed vibrational analyses of the emission spectra were made. The fluorescence spectrum has essentially the same vibronic structure as the phosphorescence spectrum.

A study of T = 2 states in ^(12)B, ^(12)C, ^(20)F and ^(28)Al

The lowest T = 2 states have been identified and studied in the nuclei ¹²C, ¹²B, ²⁰F and and ²⁸Al. The first two of these were produced in the reactions ¹⁴C(p,t)¹²C and ¹⁴C (p,³He)¹²B, at 50.5 and 63.4 MeV incident proton energy respectively, at the Oak Ridge National Laboratory. The T = 2 states in ²⁰F and ²⁸Al were observed in (³He,p) reactions at 12-MeV incident energy, with the Caltech Tandem accelerator.

The results for the four nuclei studied are summarized below:

(1) ¹²C: the lowest T = 2 state was located at an excitation energy of 27595 ± 20 keV, and has a width less than 35 keV.

(2) ¹²B: the lowest T = 2 state was found at an excitation energy of 12710 ± 20 keV. The width was determined to be less than 54 keV and the spin and parity were confirmed to be 0⁺. A second ¹²B state (or doublet) was observed at an excitation energy of 14860 ± 30 keV with a width (if the group corresponds to a single state) of 226 ± 30 keV.

(3) ²⁰F: the lowest T = 2 state was observed at an excitation of 6513 ± 5 keV; the spin and parity were confirmed to be 0⁺. A second state, tentatively identified as T = 2 from the level spacing, was located at 8210 ± 6 keV.

(4) ²⁸Al: the lowest T = 2 state was identified at an excitation of 5997 ± 6 keV; the spin and parity were confirmed to be 0⁺. A second state at an excitation energy of 7491 ± 11 keV is tentatively identified as T = 2, with a corresponding (tentative) spin and parity assignment J^π = 2⁺.

The results of the present work and the other known masses of T = 2 states and nuclei for 8 ≤ A ≤ 28 are summarized, and massequation coefficients have been extracted for these multiplets. These coefficients were compared with those from T = 1 multiplets, and then used to predict the mass and stability of each of the unobserved members of the T = 2 multiplets.

Growth dynamics of the spinner shark (Carcharhinus brevipinna) off the United States southeast and Gulf of Mexico coasts: a comparison of methods

The age and growth dynamics of the spinner shark (Carcharhinus brevipinna) in the northwest Atlantic Ocean off the southeast United States and in the Gulf of Mexico were examined and four growth models were used to examine variation in the ability to fit size-at-age data. The von Bertalanffy growth model, an alternative equation of the von Bertalanffy growth model with a size-at-birth intercept, the Gompertz growth model, and a logistic model were fitted to sex-specific observed size-at-age data. Considering the statistical criteria (e.g., lowest mean square error [MSE], high coefficient-of-determination, and greatest level of significance) we desired for this study, the logistic model provided the best overall fit to the size-at-age data, whereas the von Bertalanffy growth model gave the worst. For “biological validity,” the von Bertalanffy model for female sharks provided estimates similar to those reported in other studies. However, the von Bertalanffy model was deemed inappropriate for describing the growth of male spinner sharks because estimates of theoretical maximum size (L∞) indicated a size much larger than that observed in the field. However, the growth coefficient (k= 0.14/yr) from the Gompertz model provided an estimate most similar to that reported for other large coastal species. The analysis of growth for spinner shark in the present study demonstrates the importance of fitting alternative models when standard models fit the data poorly or when growth estimates do not appear to be realistic.

Collaborative Pacific Halibut, Hippoglossus stenolepis, Bycatch Control by Canada and the United States

ABSTRACT—Bycatch mortality of Pacific halibut, Hippoglossus stenolepis, in nontarget fisheries is composed primarily of immature fish, and substantial reductions in yield to directed halibut fisheries result from this bycatch. Distant-water bottomtrawl fleets operating off the North American coast, beginning in the mid 1960’s, experienced bycatch mortality of over 12,000 t annually. Substantial progress on reducing this bycatch was not achieved until the of extension fisheries jurisdictions by the United States and Canada in 1977. Bycatch began to increase again during the expansion of domestic catching capacity for groundfish, and by the early 1990’s it had returned to levels seen during the period of foreign fishing. Collaborative action by Canada and the United States through the International Pacific Halibut Commission has resulted in substantial reductions in bycatch mortality in some areas. Methods of control have operated at global, fleet, and individual vessel levels. We evaluate the hierarchy of effectiveness for these control measures and identify regulatory needs for optimum effects. New monitoring technologies offer the promise of more cost-effective approaches to bycatch reduction.

Gap states of hydrogenated amorphous silicon near and above the threshold of microcrystallinity with subtle boron compensation

The effects of hydrogen dilution, subtle boron compensation, and light-soaking on the gap states of hydrogenated amorphous silicon films (a-Si:H) near and above the threshold of microcrystallinity have been investigated in detail by the constant photocurrent method and the improved phase-shift analysis of modulated photocurrent technique. It is shown that high hydrogen dilution near the threshold of microcrystallinity leads to a more ordered network structure and to the redistribution of gap states; it gives rise to a small peak at about 0.55 eV and a shoulder at about 1.2 eV below the conduction band edge, which are associated with the formation of microcrystallites embedded in the amorphous silicon host matrix. A concurrent subtle boron compensation is demonstrated to prevent excessive formation of microcrystallinity, and to help promote the growth of the ordered regions and reduce the density of gap defect states, particularly those associated with microcrystallites. Hydrogen-diluted and appropriately boron-compensated a-Si:H films deposited near the threshold of microcrystallinity show the lowest density of the defects in both the annealed and light-soaked states, and hence, the highest performance and stability. (C) 2001 American Institute of Physics.

Degenerate four-wave-mixing signals from dc- and ac-driven semiconductor superlattice

Within the one-dimensional tight-binding model;rnd chi-3 approximation, we have calculated four-wave-mixing (FWM) signals for a semiconductor superlattice in the presence of both static and high-frequency electric fields. When the exciton effect is negligible, the time-periodic field dynamically delocalizes the otherwise localized Wannier-Stark states, and accordingly quasienergy band structures are formed, and manifest in the FWM spectra as a series of equally separated continua. The width of each continuum is proportional to the joint width of the valence and conduction minibands and is independent of the Wannier-Stark index. The realistic homogeneous broadening blurs the continua into broad peaks, whose line shapes, far from the Lorentzian, vary with the delay time in the FWM spectra. The swinging range of the peaks is just the quasienergy bandwidth. The dynamical delocalization (DDL) also induces significant FWM signals well beyond the excitation energy window. When the Coulomb interaction is taken into account, the unequal spacing between the excitonic Wannier-Stark levels weakens the DDL effect, and the FWM spectrum is transformed into groups of discrete lines. Strikingly, the groups are evenly spaced by the ac field frequency, reflecting the characteristic of the quasienergy states. The homogeneous broadening again smears out the line structures, leading to the excitonic FWM spectra quite similar to those without the exciton effect. However, all these features predicted by the dynamical theory do not appear in a recent experiment [Phys. Rev. Lett. 79, 301 (1997)], in which, by using the static approximation the observed Wannier-Stark ladder with delay-time-dependent spacing in the FWM spectra is attributed to a temporally periodic dipole field, produced by the Bloch oscillation of electrons in real space. The contradiction between the dynamical theory and the experiments is discussed. In addition, our calculation indicates that the dynamical localization coherently enhances the time-integrated FWM signals. The feasibility of using such a technique to study the dynamical localization phenomena is shown. [S0163-1829(99)10607-6].

Energy spectrum and persistent currents in finite-width mesoscopic ring with radial potential barrier threading a magnetic flux through its hole

The energy spectrum and the persistent currents are calculated for a finite-width mesoscopic annulus with radial potential barrier, threading a magnetic flux through the hole of the ring. Owing to the presence of tunneling barrier, the coupling effect leads to the splitting of each radial energy subband of individual concentrical rings into two one. Thus, total currents and currents carried by single high-lying eigenstate as a function of magnetic flux exhibit complicated patterns. However, periodicity and antisymmetry of current curves in the flux still preserve.

Restudy on the wave functions of Gamma(nS) states in the light-front quark model and the radiative decays of Gamma(nS) -> eta(b) + gamma

The light-front quark model has been applied to calculate the transition matrix elements of heavy hadron decays. However, it is noted that using the traditional wave functions of the light-front quark model given in the literature, the theoretically determined decay constants of the Gamma(nS) obviously contradict the data. This implies that the wave functions must be modified. Keeping the orthogonality among the nS states and fitting their decay constants, we obtain a series of the wave functions for Gamma(nS). Based on these wave functions and by analogy with the hydrogen atom, we suggest a modified analytical form for the Gamma(nS) wave functions. Using the modified wave functions, the obtained decay constants are close to the experimental data. Then we calculate the rates of radiative decays of Gamma(nS) -> eta(b) + gamma. Our predictions are consistent with the experimental data on decays Gamma(3S) -> eta(b) + gamma within the theoretical and experimental errors.

Alpha-decay for heavy nuclei in the ground and isomeric states

The alpha-decay half-lives of nuclei in the ground states and Isomeric states have been calculated within the WKB approximation and Royer's formulas. The barrier in the quasimolecular shape path is determined within a generalized liquid drop model (GLDM). in which the centrifugal potential energy has been introduced to study the unfavored a-decay The agreement between the calculated results and experimental data indicates the reliability of studying alpha-decay of isomeric states with the generalized liquid drop model We find that their is no significant difference of preformation probability between Isomeric states and the corresponding ground states generally in favored alpha-decay Additionally. we extended Royer's formulas by taking account of the role of centrifugal harrier to study the unfavored alpha-decay, and some predicts oil the a decay half-lives of Isomers are made Finally. the effects of angular momontum transfer and Q(alpha) on alpha-decay half-life have been discussed Crown Copyright (C) 2009 Published by Elsevier B.V. All rights reserved

Synthesis and characteristics of the human serum albumin-triazine chiral stationary phase

Human serum albumin (HSA) was successfully bonded to silica with s-triazine as activator. The coupling reaction by this method was rapid and effective. The triazine-activated silica is relatively stable and can be installed for at least 1 month without obvious loss of reactivity when stored below 30 degreesC, pH below 7. It was observed that the amount of bound HSA reached 120 mg/g silica calculated from the UV absorbance difference of the HSA solution. d,l-tryptophan was selected as the probe solute to characterize the properties of HSA bonded s-triazine chiral stationary phase, and separation factor of 9.4 was obtained for d,l-tryptophan. Furthermore, the amount of effective HSA on silica was measured by high-performance frontal analysis, and only 16.8 mg/g silica was responsible for the resolution of d,l-tryptophan. These results indicate that the amount of both the bound and effective HSA on silica with triazine as activator was much higher than those by the Schiff base coupling method. Different kinds of enantiomers were resolved successfully on the aminopropylsilica-bonded HSA s-triazine chiral stationary phase. (C) 2000 Wiley-Liss, Inc.

Evolution of the interfacial tension between polydisperse "immiscible" polymers in the absence and in the presence of a compatibilizer

The interfacial tension sigma between two polyisobutylenes (PIB) of dissimilar polydispersity and two polydisperse samples of poly(dimethylsiloxane) (PDMS) was measured as a function of time by means of a pendent drop apparatus at different temperatures ranging from 30 to 110 degreesC. In addition to three of the four possible binary blends, the time evolution of sigma was also determined for one ternary system, where the PIB phase contained 0.03 wt % of a diblock copolymer poly(isobutylene-b-dimethylsiloxane). The pronounced decrease of sigma with advancing time, observed in all cases, is attributed to the migration of the interfacially active lower molecular weight components of the homopolymers and of the compatibilizer into the interphase. Several days are normally required until a becomes constant. These time independent values are not considered as equilibrium data, but accredited to stationary states. A kinetic model is established for sigma(t), which enables a detailed investigation of the rates of transport of the different migrating species of average molar mass of M.

Gas chromatographic enantiomer separation on single and mixed cyclodextrin derivative chiral stationary phases

Capillary gas chromatographic enantiomer separation of some polar compounds, including alpha-phenylethylamine, styrene oxide, pyrethroid insecticides and other carboxylates, was investigated on modified cyclodextrin (CD) chiral stationary phases. The chiral stationary phases studied included permethylated beta-CD (PMBCD), heptakis (2,6-di-O-butyl-3-O-butyryl)-beta-CD (DBBBCD), heptakis (2,6-di-O-nonyl-3-O-trifluoroacetyl)-beta-CD (DNTBCD), the mixture of PMBCD and DBBBCD, and the mixture of PMBCD and DNTBCD. On the mixed chiral stationary phases containing the mixtures of derivatized cyclodextrins, enantiomer separation was improved significantly for some compounds as compared to the single cyclodextrin derivative chiral stationary phases, and synergistic effects were observed for some compounds on the mixed cyclodextrin derivative chiral stationary phases.