Summary Extrapolation of conventional paradigms to unconventional reservoirs can lead to disappointment and poor performance. Careful analysis of the reservoir and application of the correct stimulation design are critical when dealing with marginally economic developments. This approach includes adequate characterization of the reservoir and an understanding of the factors that control flow capacity and deliverability. One of the biggest practical problems with unconventional-stimulation-design optimization is estimating post-fracture rate, production decline, and ultimate recovery. Without a realistic prediction of the decline resulting from a given completion, it is impossible to assign value to one design over another and equally impossible to optimize the treatment for whichever goal is sought, either acceleration of recovery or increase in reserves. It is often the first—inadequate reservoir characterization—that leads to the second—unrealistic post-treatment predictions. For instance, assuming that core-derived permeability fully represents the reservoir's total flow capacity or that stimulated reservoir volumes represent the effective producing volumes can lead to incorrect diagnosis of the reservoir capability and, consequently, can lead to an inefficient treatment design. This paper presents methods for production forecasting that give reasonable post-treatment predictions that have been found useful for economic planning. The proposed methodology, backed by field observations and laboratory work, provides an economically viable plan for optimizing lateral length, fracture spacing, and treatment design. The methodology focuses on the post-stimulation effective reservoir volume. Results show that increasing apparent fracture length rarely impacts long-term recovery. Likewise, adding more fractures within the same reservoir volume may increase early-time production rate (initial production) and decline rate, without contacting more reservoir volume or adding to long-term recovery. Such practices lead to acceleration of reserves recovery, which has economic value and should be considered in the design process, but does not increase the ultimate recovery of the well once a sufficient number of contributing fractures are in place. The economically preferred completion designs may be more driven by the net present value derived in the first 5 years of production rather than the ultimate recovery of the well. This early 5-year period represents most of the useful economic life of the well, can be estimated more accurately from early performance, and is a good benchmark for completion optimization.

Abstract Decline curve analysis in unconventional reservoirs is challenging due to the extremely low reservoir flow capacity coupled with the completion techniques and production practices used to achieve economic rates. The primary flow regimes for these wells include transient bilinear flow, transient linear flow, boundary-influenced flow and possibly long-term linear flow. It is commonly believed that the dominant flow regime in unconventional developments will be transient linear flow; however, boundary-influenced flow may be even more important. Classical decline curve analysis techniques are applicable only during the boundary-influenced flow period. Frequently, a hyperbolic form equation is utilized and this practice used by the industry over the entire life of the well results in excessively high decline exponents which can lead to optimistic forecasts of future performance. This technique can be improved for unconventional plays by imposing limits to the final decline. However, current methods to constrain the final decline are based on historical vertical well performance and rules of thumb which introduce a high degree of uncertainty. A number of these plays have now reached a level of maturity that will allow characterization of their long term decline performance. This paper presents a comprehensive technique to analyze production history using a flow regime based workflow to guide classic decline curve analysis. The technique identifies the onset of boundary-influenced flow and thus provides a consistent approach to evaluate late time decline characteristics which will improve the forecast results. In addition to providing guidance for decline curve analysis, the proposed workflow can also be used to evaluate completion efficiency by relating the time to boundary-influenced flow to the stimulated reservoir volume. The practical application of this this technique will be presented using field studies of active unconventional developments.

Abstract Although not all analytical, empirical, and statistical techniques are applicable at all stages of field maturity, their concurrent and consistent application was indispensable in justifying the Woodford as a World-Class Tier 2 Resource play (SPEE Criteria 2010) and added multiple Proved-Undeveloped (PUD) locations in 2011 that were not direct offsets. Introduction of the "Modernized SEC Rules" greatly expanded the scope of tools available for evaluating and justifying PUD locations more than one offset away from the existing producers. Shale Plays - with their monumental extent, number of wellbores, drilling activity, and in-place volumes - provide a quintessential laboratory to test application of advanced statistical approaches, in conjunction with analytical and empirical protocols for the play evaluation. The starting point for the PUD evaluation was the protocol advocated in the recently published SPEE Monograph 3. The employment of statistics required the development of a large dataset of projected EURs, which was generated using an inhouse decline curve analysis protocol and validated using an empirical model. Analytical correlations were also employed to achieve the sample size dictated by uncertainty analysis of the data. Then, this synthesized dataset was benchmarked against G&G parameters to determine if the entire area met the SEC definition of "analogous formation." Finally, advanced statistical techniques were applied to define the "Reliable Technology Area" (RTA) in the play and the Proved volume. The resulting statistics for the RTA established using this protocol were found to be remarkably consistent and reproducible, thus meeting the SEC's definition of "Reliable Technology." The resulting Proved area was further refined using PVT data and economics. The scope of this paper is limited to the elucidation of the successful application of this integrated Technique to the Anadarko-Woodford. Additional results would likely be presented in future papers as this methodology appears to be highly transferable to other resource plays.

Abstract The production of natural gas from shales traces back to the first well drilled in New York in 1821. Over the past 25 years, access to this resource has grown. Recent advancements in drilling and completion technology has enhanced well production rates and production from shales has increased to where it currently supplies 20% of the gas produced by all gas wells in the United States. Well performance data from these shale plays has been compiled and analyzed to develop insight into these tight reservoirs. These results are compared and contrasted to determine similarities and differences among the plays. Comparisons with classical gas reservoirs and tight gas reservoirs are made to provide additional insight.

Abstract Unconventional resource plays can provide a long-term supply of oil and gas to help supplement the North American energy demands. However, obtaining a good economic return from these developments can be challenging. A successful entry into an unconventional play requires careful pre-entry analysis in order to develop meaningful production profiles and set realistic expectations. Wells completed in unconventional plays typically exhibit limited drainage areas and produce a majority of recoverable reserves at low rates. Due to the limited flow capacity of these reservoirs typical development strategies include some form of horizontal completion. When considering a potential entry into a "new" resource play there are a number of important questions that must be answered such as "What is an appropriate range of initial production rates and reserves for the development?" or "What is the most cost effective completion method?" and "How will post drill completion efficiency be determined?". This paper will present one operator's approach to answer these questions for its entry into the Bakken Shale development of North Dakota. The paper focuses on the effective use of existing public information to frame expectations for the development. It will also present the completion design considerations and initial implementation results from the development.

Abstract Proppant selection in hydraulic fracturing is a critical economic and technical decision that affects stimulation and field development economics. In many cases the selection is based on laboratory data from standardized API conductivity tests on clean packs at specified stress and temperature. These tests predict conductivities that are optimistic compared to observed field performance. Often a laboratory measured conductivity difference of only 5-10% is considered a significant variance when applied to the producing life of a well. The significance of these small differences, however, is often overwhelmed by other factors affecting fracture performance in the field. The selection of a particular proppant should be based on an identifiable difference in performance under field conditions. This requires an accurate assessment of all the damage mechanisms that can and do occur during fracturing and their impact on final conductivity. This paper outlines the primary damage mechanisms and their effect on conductivity, fracture cleanup and ultimate stimulation response. The expected variance in laboratory measurements of conductivity is also quantified.

Research since 1983 has demonstrated that human hepatocytes can be isolated, cultured, and used for biological investigations, including studies of gene transcription and drug metabolism (1,2). In addition, the ability to cyropreserve hepatocytes has facilitated clinical research of hepatitic cell transplantation (3). We have used primary human heptocytes as host tissue for viral infection with hepatitis C. The availability of HCV-infected livers has also allowed for the culturing and analysis of HCV-positive cells. Our laboratory (4) and others (5) have confirmed the ability of these cells to display molecular markers of HCV replication. This chapter will review the basic steps of hepatocyte isolation and culturing and analysis for HCV by RT-PCR. We have also attempted to indicate alternative techniques that may be better suited to an individual investigator's needs.

SCH 43478 and analogs are a class of non-nucleoside antiviral agents that have potent and selective activity against herpes simplex virus type 2 (HSV-2). The IC50 for these compounds in plaque reduction analysis using Vero cells ranges from 0.8 to 2.0 microg/ml. All compounds have a LC50 > 100 microg/ml in cytotoxicity analysis. Mechanism of action studies suggest that these molecules have an effect on the transactivation of viral immediate early (alpha) gene expression. Time of addition studies indicate that antiviral activity of these analogs is limited to the initial 2-3 h after infection and is not due to inhibition of viral adsorption or penetration. Analysis of HSV protein expression demonstrates that SCH 49286 inhibits the accumulation of viral immediate early (alpha) gene products. SCH 43478 demonstrates statistically significant efficacy (P < 0.05) in the guinea pig genital model of HSV infection. Following subcutaneous administration in a therapeutic treatment regimen, SCH 43478 (90 mg/kg/day) is efficacious in reducing the number and severity of lesions and the neurological complications of acute HSV infection. Thus, SCH 43478 and analogs are anti-herpesvirus agents with a unique mechanism of action.

SCH 48973 is a novel molecule with potent, selective, antienterovirus activity. In assays of the cytopathic effect against five picornaviruses, SCH 48973 had antiviral activity (50% inhibitory concentrations [IC50s]) of 0.02 to 0.11 microg/ml, with no detectable cytotoxicity at 50 microg/ml. SCH 48973 inhibited 80% of 154 recent human enterovirus isolates at an IC50 of 0.9 microg/ml. The antiviral activity of SCH 48973 is derived from its specific interaction with viral capsid, as confirmed by competition binding studies. The affinity constant (Ki) for SCH 48973 binding to poliovirus was 8.85 x 10(-8) M. In kinetic studies, a maximum of approximately 44 molecules of SCH 48973 were bound to poliovirus capsid. SCH 48973 demonstrated efficacy in a murine poliovirus model of enterovirus disease. SCH 48973 increased the survival of infected mice when it was administered orally at dosages of 3 to 20 mg/kg of body weight/day. Oral administration of SCH 48973 also reduced viral titers in the brains of infected mice. On the basis of its in vitro and in vivo profiles, SCH 48973 represents a potential candidate for therapeutic intervention against enterovirus infections.

Background: Polioviruses are human pathogens and the causative agents of poliomyelitis. Polioviruses are icosahedral single-stranded RNA viruses, which belong to the picornavirus family,and occur as three distinct serotypes. All three serotypes of poliovirus can infect primates, but only type 2 can infect mice. The crystal structures of a type 1 and a type 3 poliovirus are already known. Structural studies of poliovirus type 2 Lansing (PV2L) were initiated to try to enhance our understanding of the differences in host range specificity, antigenicity and receptor binding among the three serotypes of poliovirus.Results: The crystal structure of the mouse neurovirulent PV2L complexed with a potent antiviral agent, SCH48973, was determined at 2.9 Angstrom resolution. Structural differences among the three poliovirus serotypes occur primarily in the loop regions of the viral coat proteins (VPs), most notably in the loops of VPI that cluster near the fivefold axes of the capsid, where the BC loop of PV2L is disordered. Unlike other known structures of enteroviruses, the entire polypeptide chain of PV2L VP4 is visible in the electron density and RNA bases are observed stacking with conserved aromatic residues (Tyr4020 and Phe4046) of VP4. The broad-spectrum antiviral agent SCH48973 is observed binding in a pocket within the beta-barrel of VP1, in approximately the same location that natural 'pocket factors' bind to polioviruses. SCH48973 forms predominantly hydrophobic interactions with the pocket residues.Conclusions: Some of the conformational changes required for infectivity and involved in the control of capsid stability and neurovirulence in mice may occur in the vicinity of the fivefold axis of the poliovirus, where there are significant structural differences among the three poliovirus serotypes in the surface exposed loops of VPI (BC, DE, and HI), A surface depression is located at the fivefold axis of PV2L that is not present in the other two poliovirus serotypes. The observed interaction of RNA with VP4 supports the observation that loss of VP4 ultimately leads to the loss of Viral RNA. A model is proposed that suggests dual involvement of the Virion fivefold and pseudo-threefold axes in receptor-mediated initiation of infection by picornaviruses.

SCH 47802 and its derivatives are potent inhibitors of enteroviruses in vitro. The IC50 for SCH 47802 ranges from 0.03 to 10 μg/ml when tested against a spectrum of enteroviruses in plaque reduction assays. The compounds have in vitro therapeutic indices of at least 81 based on viral cytopathic effect (CPE) assays. The in vitro activity of SCH 47802 translates into in vivo activity in the murine model of poliovirus encephalitis. In an oral dosing regimen, SCH 47802 protects mice from mortality at 60 mg/kg per day. Consistent with the in vivo efficacy, pharmacokinetic analyses after oral dosing with SCH 47802 demonstrate serum levels of the compound above the in vitro IC50 for poliovirus for at least 4 h. SCH 47802 and its active analogs stabilize poliovirus to thermal inactivation indicating that the compounds bind to the virus capsid. Mechanistic studies with poliovirus indicate that SCH 47802 acts early in viral infection. This series of molecules represents potential candidates for the treatment of human enterovirus infections.

SCH 38057 (1-[6-(2-chloro-4-methoxyphenoxy)-hexyl]imidazole hydrochloride) is a new, water-soluble antiviral that has inhibitory activities against a number of picornavirus infections. The structure of the human rhinovirus 14 (HRV14) complex with SCH 38057 was determined at 3·0 Å resolution by single-crystal diffraction techniques using synchrotron X-radiation. SCH 38057 was found to bind at the innermost end of the hydrophobic pocket within the capsid protein VP1, a locus of binding of other antipicornaviral agents; however, the complex differs from previously reported complexes in two important aspects. It leaves a considerable volume near entrance to the binding pocket unoccupied. In addition, the alterations in the conformation of the VP1 polypeptide are similar to, but more extensive than those observed in HRV14 complexes with other antiviral agents. Although only 9 amino acids of VP1 have close contacts with the SCH 38057 molecule (within 3·6 Å), at least 36 amino acids from both VP1 and VP3 have significantly altered conformations (Cα movement >0·5 Å versus native). The structures of complexes of HRV14 with SCH 38057 and WIN 51711 are compared. Aromatic ring interactions between picornavirus capsid residues and antiviral inhibitors are proposed to be among the major determinants for positioning of these compounds.

The activity of a new water-soluble molecule, SCH 38057, against picornaviruses is described. SCH 38057 inhibited plaque formation of selected entero- and rhinoviruses in a range of 10.2 to 29.1 microM (50% endpoint) and had a therapeutic index of 10 against poliovirus type 2 (polio 2) in HeLa cells. When administered orally or subcutaneously, SCH 38057 protected mice infected with either coxsackievirus B3 (CVB3) or echovirus-9 from mortality. The molecule provided a low level of protection against thermal inactivation of virus, indicating that SCH 38057 interacts with the picornavirus capsid. Binding studies with [3H]SCH 38057 revealed that the molecule binds to CVB3 and human rhinovirus 14 (HRV14) in a ratio of 29 and 19 molecules per viral particle, respectively. The affinity constant for SCH 38057 binding to CVB3 was 7.0 x 10(-4) M. When added to cultures of infected cells at 3 h after infection, SCH 38057 markedly inhibited viral RNA synthesis. This finding with lack of inhibition of attachment and loss of infectious virus after attachment were interpreted to indicate that, although SCH 38057 binds to the viral capsid, the molecule exerts its antiviral effect after the initial stage of picornavirus uncoating, i.e., after conversion of the 156S infectious viral particle to smaller subviral species.

We have expressed the 3C protease of coxsackievirus B3 (CVB3) in a cell-free system. This expression system employs the translational initiation signal of an insect virus RNA, black beetle virus (BBV) RNA 1, to direct CVB3-specific protein synthesis. Using this expression system, we demonstrate that a biologically active 3C protease is synthesized which possesses both cis and trans processing capabilities. This in vitro-synthesized 3C protease is analogous to the native 3C, which was obtained from cytoplasmic extracts of CVB3-infected HeLa cells, in all biological parameters that were evaluated. In addition, antibody prepared against the 3C protease purified from extracts of CVB3-infected HeLa cells cross-reacts with the 3C protease produced in this cell-free system. Using the translational initiation signal from BBV RNA 1, we also have expressed the CVB3 capsid precursor and part of the P2 region in vitro, and have shown that the capsid precursor is cleaved between 1C (VP3) and 1D (VP1) by the proteolytic activity of in vitro-synthesized 3C in trans. Evidence also is presented to implicate the 2A protein of CVB3 as having proteolytic function.

Studies show a radical transformation in the ranks and numbers of the homeless, now including large numbers of young, severely disturbed and disabled street people. Without decent, safe, accessible shelter, therapeutic efforts are doomed.