The instant invention comprises a process for the solid phase synthesis of directed epitope peptide mixtures useful in the modulation of unwanted immune responses, such process defined by a set of rules regarding the identity and the frequency of occurrence of amino acids that substitute a base or native amino acid of a known epitope. The resulting composition is a mixture of related peptides for therapeutic use.

Immunomodulation.
Many disease conditions are, at least in part, a result of an unwanted or excessive immune response within an organism. The rejection of a transplanted organ is axiomatic example of an unwanted immune response. The rejection of the graft is emblematic of a condition in which an organism's inability to control an immune response results in a pathology. In organ transplantation, the unwanted immune response that results in graft rejection is triggered by: (1) "direct recognition," where the T cells of the graft recipient recognize foreign major histocompatibility complex ("MHC") molecules on the graft tissue, already presenting some peptides, via their T-cell receptor ("TCR") directly, or "indirect recognition," where the recipient T cells recognize the antigenic determinants derived from the graft after the determinants are processed and presented by recipient MHC; (2) the generation of antibodies directed against the graft, more specifically, the human leukocyte antigens ("HLA") molecules present on the cells of the graft tissue, caused by the exposure of the recipient to the graft; and (3) binding of preformed anti-graft antibodies in the circulation of the recipient to the graft. Studies have shown that these immune responses are directed to three types of donor derived antigens: MHC (through direct or indirect recognition), minor histocompatibility antigens ("mH"), and organ derived antigens.
Successful transplantation depends on preventing the unwanted immune responses, inducing sustained chimerism. Sustained chimerism is a phenomenon in which the recipient develops tolerance for a foreign graft, enabling the grafted tissue to survive in the recipient without being subjected to immune responses. Under experimental conditions, sustained chimerism can be induced by peptides that are closely related to those that stimulate graft-rejecting immune responses, albeit for short periods of time. (B. Murphy et al., J. Am. Soc. Nephrol., 2003, 14:1053-1065; C. LeGuern, Trends Immunol., 2003, 24:633-638). The difficulty lies with the likelihood of the broadening of the offending epitopes via the process of epitope spreading (N. Suciu-Foca et al., Immunol. Rev., 1998, 164:241).
Transplant physicians have long recognized the need both to inhibit the immune response generated by the presence of what the recipient's immune system views as foreign, without also compromising the patient's ability to fight opportunistic infection. Currently, transplantation patients are often treated with immunosuppressive therapies that depress the overall immune response and reactivity in a patient. Immunosuppressive therapies attempt to attenuate the reaction of the body to an already-triggered immune response, and are accompanied by numerous undesirable side effects. Because of the significant undesirable side effects, a single immunosuppressant cannot be used continuously to treat a transplant recipient, and a course of treatment comprises using one immunosuppressant having one set of side effect, changing to second immunosuppressant with a different set of side effect, and to third, and so on, to limit the exposure of the recipient to each immunosuppressant and its side effects. For example, steroids such as prednisone or methylprednisone are powerful immunosuppressants but can induce cataracts, hyperglycemia, hirstutism, bruising, acne, bone growth suppression, and ulcerative oesophagitis. Long term use of steroids has also been associated with bone loss. Cyclosporin A (CsA), a widely used immunosuppressant, is nephrotoxic, and often replaced with tacrolimus (TAC) after a period of treatment. For the treatment of non-acute rejection, azathioprine is used, the side effect of which include leucopenia, anemia, fever, chills, nausea and vomiting. Regardless of what immunosuppressant is used, one of the most substantial side effects related to longer term treatment with immunosuppressives in addition to the general compromise of the immune system leaving the patient vulnerable to any type of infections, is the generation of transplant related malignancies such as Kaposi's sarcoma. There is a strong desire on the part of physician and patient to decrease or cease the use of these current front line therapies. (Pharmacotherapy: A pathophysiologic Approach, Fifth Edition. 2002, McGraw Hill.) It would be difficult to state that they have met the clinical goal of sustained chimerism without ongoing immunosuppressive therapy.
Immunomodulation, in contrast to immunosuppression, targets the cause of unwanted immune responses. Immunomodulation can be attempted in an antigen/epitope non-specific fashion by targeting the body's mechanism for immunity, or in an antigen/epitope specific manner. As an example of antigen/epitope non-specific treatment, therapies directly targeted at controlling T lymphocytes or their functions have been developed using biotechnological tools. The therapeutic agents useful for such treatment include Muromonab-CD3 (OKT3), antilymphocyte globulin (ALG), antithymocyte globulin (ATG), or interleukin-2 receptor monoclonal antibody ("mAb") daclizumab or basiliximab. Other agents include soluble CTLA-4, an anti-CD154 mAb; anti-CD11a; a humanized mAb which inhibits VLA-4; anti-CD2, 3, or 4 antibodies; and anti-CD152 antibodies (J. B. Matthews et al., Amer. J. Transplantation, 2003, 3: 794-80). While all of these therapeutic agents may induce a state of non-responsiveness of the recipient's immune system to the transplanted tissue with a reduction in side effects, as compared to e.g. prednisone, the therapies still do not meet the clinical goal of sustained chimerism without ongoing immunosuppressive therapy, except for limited reports, such as immunosuppressive withdrawal after combination therapy of total lymphoid irradiation followed by ATG administration (S. Strober et al., Transplantation, 2004 Mar. 27; 77(6): 932-936). Further, these therapies also suffer from the unattractive side effects of compromised overall immune function.
In contrast to the antigen non-specific immunomodulatory approach, the immune system can also be retuned, or modulated in an antigen/epitope specific manner. Such a type of immunomodulation is the process of increasing or decreasing the immune system's ability to mount a response against a particular antigenic determinant through either the TCR's recognition of complexes formed by MHC and antigens, or through the B cell receptor's ("BCR") recognition of the epitope itself. Because of the specificity of the process toward a particular antigenic determinant and not toward the immune system as a whole, antigen specific immunomodulation has advantages such as fewer undesirable side effects compared to current treatment modalities such as immunosuppressive therapies, which affects the overall immune system.
Antigenic determinant-specific immunomodulatory treatments can help establish such sustained chimerism by inducing donor-specific tolerance in host T lymphocytes. Immunomodulation of the reaction toward any and all of these antigens help attenuate or alleviate graft rejection and establish sustained chimerism. Studies indicate that one mechanism of action of immunomodulation by certain immunomodulatory peptides may be through their binding to T cells that would otherwise bind to the donor-derived antigens and resulting in differential activation of T cell functions. This mechanism has been suggested to be centrally induced tolerance involving the thymus (G. Benichou et al. Immunol. Today, 1997, 18(2):67-72). The demonstration of achieving sustained chimerism without immunosuppressive treatment via induction of donor-specific tolerance in host T lymphocytes through immunomodulation was performed by a group of investigators who, using mice, induced tolerance to the subsequent graft by intrathymic injection of a series of determinants from 3M KCl-extracted donor MHC-derived peptides. Two doses of anti-T cell antibody were given first to eliminate circulating T cells. Then eight peptide sequences extracted from the donor MHC were delivered in combination. The treated mice tolerated subsequent transplants. As a control, the investigators performed thymectomy, which caused graft rejection. The study is an example of importance of centrally-induced tolerance (T. Hamashima et al., Transplantation, 1994 Jul. 15; 58(1):105-7). Thus, designing appropriate peptides similar to T cell-stimulating antigens that bind to the T cells is beneficial to achieving sustained chimerism.
However, the difficulty lies with the likelihood of the broadening of the offending epitopes via the process of epitope spreading. (N. Suciu-Foca et al., Immunol. Rev. 1998, 164:241). Thus, in transplantation, the axiomatic example where certain immune response is unwanted, it is clear that, in the absence of the ability to modulate the relevant antigenic determinants over time, the only alternatives are non-specific immunomodulatory, or immunosuppressive therapies.
Other examples of unwanted immune responses are autoimmune diseases. One important contextual difference between autoimmune diseases and transplantation rejection is that the offending antigenic determinant(s) is/are generally more restricted and definable. While the trigger of an autoimmune disease is undefined and may be dictated by pre-existing and/or environmental factors, the direct causes of the pathological condition have been identified in many autoimmune diseases. An autoimmune disease results from an inappropriate immune response directed against a self antigen (an autoantigen), which is a deviation from the normal state of self-tolerance. Self-tolerance arises when the generation of T cells and B cells capable of reacting against autoantigens has been prevented or altered centrally by events that occur either in their early development or after maturation in the periphery. The cell surface proteins that play a central role in regulation of immune responses through their ability to bind and present processed peptides to T cells via the T cell receptor (TCR) are class I and class II MHC (J. B. Rothbard et al., Annu. Rev. Immunol., 1991, 9:527).
Thus, an attractive point of intervention for the amelioration of an autoimmune response is via the set of lymphocyte surface protein MHC molecules for example, HLA-DR, -DQ and -DP, themselves or in combination with the peptides they present. Different HLA alleles generate a diversity of responses via antigenic-determinant specificities by variable affinities for protein fragments found in the extra- and intra-cellular milieu because of differences in the amino acids which are directly involved in the binding of the peptides. There are large numbers of alternative or allelic forms within a mammalian population, but only a few of these allelic forms are associated with disease-related antigenic determinants. It is well understood to one with ordinary skill in the art the genomes of subjects affected with certain autoimmune diseases, for example MS and RA, are more likely to carry one or more such characteristic MHC class II alleles, to which that disease is linked. For example, HLA-DR2 (DRB1*1501) is associated with multiple sclerosis and HLA-DR1 (DRBI*0101) or HLA-DR4 (DRB1*0401) are associated with rheumatoid arthritis.
The disease-related antigenic determinants derive from proteins which have been described as being simply associated with an autoimmune response, or as being part of the pathogenesis of the disease process itself. There are highly conserved sequences within HLA that may play a role in either the generation or regulation of immunologic tolerance when processed into peptides and presented by intact HLA (reviewed in B. Murphy and A. M. Krensky, J. Am. Soc. Nephroi., 1999, 10:1346-55). A. Snijders et al. discuss one particular sequence (KDILEDERAAVDTYC) (SEQ ID NO: 206) presented by HLA-DRB1 as being protective against rheumatoid arthritis, with the most relevant portion of the peptide being DERAA (SEQ ID NO: 207) (J. Immunol., 2001, 166:4987-93), while others have promoted what is known as the 'shared epitope hypothesis' (P. K. Gregersen et al., Arthritis Rheumatism 1987 November; 30(11):1205-13) where those individuals that carry HLA-DRB1 alleles having the sequence QKRAA (SEQ ID NO: 208) are predisposed to rheumatoid arthritis. Other investigators have demonstrated that heat shock proteins (hsp) and the peptides derived from them can have immunomodulatory properties (S. M. Anderton et al., J. Exp. Med., 1995, 181:943-952; J. A. van Roon et al., J. Clin. Invest., 1997, 100:459-063). One peptide in particular, dubbed p277, derives from hsp60, VLGGGVALLRVIPALDSLTPANED (SEQ ID NO: 147), has demonstrated apparent activity in the context of Type I diabetes (I. Raz et al., Lancet, 2001, 358:1749-52). Further sources of epitope sequence may be derived from a pathogen-derived mimic of a sequence within mammalian MHC proteins such as the DNAjP1 peptide, or related peptides (QKRAAYDQYGHAAFE (SEQ ID NO: 209); Proc. Nat. Acad. Sci. USA, 101:4228-33; U.S. Pat. No. 6,989,146). Other proteins and the peptides that derive from them having disease association are: glutamate decarboxylase (GAD) with diabetes (M. A. Atkinson et al. J. Clin. Invest., 1994, 94:2125-29; D. B. Wilson J. Autoimmun., 2003, 20:199-201); myelin associated proteins such as myelin basic protein (MBP), myelin-associated glycoprotein (MAG), proteolipid protein (PLP), and myelin oligodendrite glycoprotein (MOG) with multiple sclerosis (reviewed in P. Fontoura et al., Int. Rev. Immunol., 2005, 24:415-46); Ro60, SmD and other ribonucleoprotein antigens with lupus (R. Pal, et al., J. Immunol., 2005, 175:7669-77; Seshmukh et al., J. Immunol., 2000, 164:6655-61; R. R. Singh, Mol. Immunol., 2004, 40:1137-45); or the acetylcholine receptor (AChR) with myasthenia gravis (MG) (S. L. Kirshner, et al. Scand. J. Immunol., 1996, 44:512-21); or desmoglein 3 (DsG3) with pemphigus vulgaris (PV) (Wucherpfennig et al., Proc. Nat. Acad. Sci. USA, 1995, 92:11935-9; Lin et al., J. Clin. Invest., 1997, 99:31-40; Veldman et al., J. Immunol., 2004 172:3883-92; Angelini et al., J. Translational Med., 2006, 4:43; U.S. Pat. No. 5,874,531; U.S. Pat. No. 7,084,247).
Despite the attraction of using HLA alleles and their associated antigenic determinants that have been linked to many autoimmune diseases as a point of intervention, therapeutic agents based on this knowledge have not been developed fully. Instead, a number of immunomodulatory therapeutic agents that are not specific to any particular antigenic determinant have been developed and being used to treat autoimmune diseases, including general anti-inflammatory drugs such as cyclooxygenase-2 (COX-2) inhibitors that can prevent formation of low molecular weight inflammatory compounds; inhibitors of a protein mediator of inflammation such as tumor necrosis factor (TNF), such as an anti-TNF specific monoclonal antibody or antibody fragment, or a soluble form of the TNF receptor that sequester TNF; and agents that target a protein on the surface of a T cell and generally prevent interaction with an antigen presenting cell (APC), for example by inhibiting the CD4 receptor or the cell adhesion receptor ICAM-1. However, these types of antigenic-determinant non-specific immunomodulatory therapeutic agents have residual immunosuppressive-like side-effects which diminish their attractiveness as chronic first line therapies. Additionally, compositions having natural folded proteins (such as antibodies) as therapeutic agents can encounter problems in production, formulation, storage, and delivery. Several of these problems necessitate delivery to the patient in a hospital setting.
Strategy for Creating Synthetic Therapeutic Peptides
Drug discovery can be generalized into two major elements, lead generation and lead optimization. The development and exploitation of combinatorial chemistry (CC) has seen the divergence of the uses of rational design versus random generation on a very fundamental level. On one side we find the use of CC to assist a researcher in the rational design of molecules. An example of which can be seen in the discovery of structure/activity relationships (SAR) between two or more active molecules of therapeutic interest. On the other side we find researchers using CC to define for them the design of new molecules discovered based on a specific activity. An example of which would be the generation of random libraries used in lead generation, whereby the lead is singled out and further optimized.
The level of expertise in the state of the art of combinatorial chemistry as applied to the synthesis of peptide libraries has risen, producing highly reliable and pure mixtures of peptides of great diversity. The use of these diverse peptide libraries has focused on lead generation and optimization. This strategy entails screening the vast numbers of individual peptide sequences in the library against a target of interest with the intention of defining a single, or limited set of peptides which demonstrate a particular activity. That single peptide, or the limited set of peptides, then become candidates which are modified to increase activity against the target. This process is schematically represented in FIG. 1A.
The challenge for practitioners in this art has been to deconvolute, or accurately define the single or limited set of peptides that were responsible for the observed activity. The difficulties associated with deconvolution have spawned great efforts on the part of practitioners to create synthesis methods which inherently increase the resolution of individual peptides, as well as the identity of individual amino acids within peptides.
In order to efficiently identify the target peptide from myriad of candidates presented by a library created by combinatorial chemistry, a variety of synthesis methods and approaches have been developed. These synthesis methods aim to provide a large number of candidates, and yet when a positive result is obtained, to quickly determine the identity of the peptide without having to laboriously isolate the positive species from the rest. The effort put forth by practitioners in this art in this regard is an indication of the industry-wide vision of the method's ultimate utility, which is to allow the random complexity of these libraries perform the screening process for the desired activity.
Examples of the resulting evolution of subtypes of combinatorial methods include: multiple synthesis, iterative synthesis, positional scanning, and one-compound-one-bead post assay identification design.
Multiple synthesis" provides for any method whereby distinct compounds are synthesized simultaneously to create a library of isolated compounds. The identity of these compounds would be known from the rules of the synthesis. H. M. Greysen et al., Proc. Nat. Acad. Sci. USA, 1984, 81:3998, used the multiple synthesis method to identify peptides that bound to an antibody raised against VPI protein of foot-and-mouth disease virus. The investigators identified GDLQVL (SEQ ID NO: 210) as the epitope recognized by the antibody. In this case the authors synthesized 108 overlapping peptides representing the VPI sequence on pins in a 96-well microplate array.
"Iterative synthesis/screening" involves methods of peptide synthesis which allow for a determination of the identity of individual residues within peptide sequences. An example of iterative synthesis can be seen in R. A. Houghten et al., Nature, 1991, 354:84-86, also to determine antibody binding epitopes. These investigators identified the sequence YPYDVPDYASLRS (SEQ ID NO: 211) using an ELISA type assay format. The first library consisted of 324 pools of peptides with the first two residues fixed, which peptides can be shown as O1O2XXXX, wherein O1 and O2 are the fixed residues and X is randomly selected. The process identified DV as the fix residues. The next step was to do the same for position three, by synthesizing peptides that can be shown as DV O1XXX, wherein O1 again is a fixed residue. When the process identified which residue at the third position would elicit the desired binding, that residue was adopted as the unchanging third residue, and the fourth position was explored in a similar manner. The process continued until the native sequence DVPDYA (SEQ ID NO: 212) was identified.
"Positional scanning" is a synthesis method producing complex mixtures of peptides that allows for the determination of the activity of each individual peptide. Based on the screening results, the derived peptide can then be separately synthesized for optimization. As seen in C. Pinilla et al., Biochem J., 1994, 301:847-853, positional scanning libraries were used to identify decapeptides which bound the same YPYDVPDYASLRS-binding (SEQ ID NO: 211) antibody. In this case ten different libraries each containing 20 pools with a defined amino acid at each of the ten positions in the peptide. Fifteen peptides were identified.
Each of the above methods were also employed to identify enzyme substrates (J. H. Till et al., J. Biol. Chem., 1994, 269:7423-7428, J. Wu et al, Biochemistry, 1994, 33:14825-14833, W. Tegge et al., Biochemistry, 1995, 34:10569-10577), or enzyme inhibitors (M. Bastos et al., Proc. Nat. Acad. Sci. USA, 1995, 92:6738-6742, Meldal et al., Proc. Nat. Acad. Sci. USA, 1994, 91:3314-3318), R. A. Owens et al., Biomed Biophys. Res. Commun., 1994, 181:402-408, J. Eichler. et al., Pept. Res., 1994, 7:300-7). These powerful tools allow investigators to rationally design combinatorial peptide libraries to identify a single species which has a desired activity.
As powerful and clear cut the identification of a specific peptide from a combinatorial library may be, it may only serve as a starting point and identification of a lead peptide that is not itself therapeutically useful. The identified epitope may be ignored by the immune system if it resembles a self protein or possibly exacerbate the very condition that the therapy aims to relieve. Such peptide is not directly therapeutically useful. However, one may create, based on such peptide, epitope reactive analogs that would act as modifiers of the unwanted immune response.
One such approach is creation of altered peptide ligands (APL). This approach is schematically represented in FIG. 1B. An APL is defined as an analog peptide which contains a small number of amino acid changes from the native immunogenic peptide ligand. Some of such APLs act as an antagonist to the T cell receptor, blocking the stimulating binding by the antigens causing the unwanted immune effect. Evabold et al., Proc. Nat. Acad. Sci. USA, 1994 Mar. 15; 91(6):2300-4. However, while recognition of the native response may induce an angonist like reaction, an APL might induce a partial agonist response, or induce a state of energy in the reactive T cell population. In discussing APL in the context of allograft rejection therapy, Fairchild et al., Curr. Topics Peptide Protein Res., 2004, 6:237-44, note that an APL acting as an antagonist for one TCR, may become an agonist for another, complicating the rational design of an APL. Compounding the obstacle of the development of APL is the difficulty in translating a response developed in an animal system into human.
Despite these challenges, MPB83-99 (ENPVVHEFKNIVTPRTP) (SEQ ID NO: 213) was made into an APL and placed into limited human trials by replacing the bold and underlined amino acid residues "E", "N", "E" and "K," resulting in a single peptide sequence consisting of AKPVVHLFANIVTPRTP (SEQ ID NO: 214), Kim et al. Clinical Immunology, 2002, 104:105-114. The authors describe the long term immune reactivity against the peptide, but the treatment has been deemed clinically ineffective by evaluation using MRI. Thus an APL, once identified, can be used as a therapeutic agent; however, its effectiveness may be limited in terms of clinical efficacy.
It has been observed for some time that in the course of development of multiple sclerosis, the reactive epitope does not stay constant. That is, the self recognition associated with the development of MS is a developmental process characterized by autoreactive diversity, plasticity, and instability, wherein the target epitope changes over time, typically from one epitope on a myelin proteolipid protein to one overlapping the amino acid residues but shifting by one or few amino acids to either side of the original epitope. The consequence of this phenomenon is that if an immunotherapeutic drug was targeted at the original epitope, over time, it becomes ineffective, not because of resistance to the mechanism of the drug, but simply because the target is no longer valid. J. Clin. Invest., 1997, 99:1682-1690.
A method conceived to make an investigational concept like a mixture of peptides into a drug is peptide dendrimer structures. Peptide dendrimers solve certain manufacturing issue of soluble peptide mixtures, in part by the promise of delivering to a patient a consistent ratio and quantity of each of the peptides in the mixture. This approach is schematically represented in FIG. 1C.
Dendrimers are diverse. They can range in size from 2 kDa to greater than 100 kDa. The design of dendrimers intends to mimic two traits of naturally occurring biological structures: a globular structure and polyvalency. As described in two comprehensive reviews (P. Niederhafier et al., J Peptide Sci. 11:757-788; K. Sadler and J. P. Tam, Rev. Mol. Biotechnol., 2002, 90:195-229), they are complex compounds that contain highly branched components organized in a radial or wedge-like fashion, and are intended to have an extensive three-dimensional structure. They have three distinct structural features: a central core surface functionalities and branching units that link the two. Peptide dendrimers are designed as vehicles for delivery of: RNA and DNA as gene expression therapeutics, biosensor systems as diagnostics, inhibitors of autoimmune diseases or cancer metastasis. The strategy behind each of these applications is to use the globular, polyvalent structure to amplify the ligand:substrate interaction (D. Zanini and R. Roy, J. Org. Chem., 1998, 63:3468-3491; J. Haensler and F. C. Szoka, Bioconjug Chem., 1993, 4:372-379).
Dendrimers have been made using amino, hydroxyl, carboxy, poly(propylenimine), silicone and polyamino amine cores (G. M. Dykes et al., J. Chem. Technol. Biotechnol., 2001, 76:903-918, P. Sadler and J. Jezek, Rev. Mol. Biotechnol., 2002, 80:195-229, and J. P. Tam, Methods Org. Chemistry, 2004, Vol E22d 129-168. Peptide dendrimers can be divided into three types: grafted peptide dendrimers, branching polyamino acids and multiple antigen peptides (MAPs).
The branching strategies in MAPs vary widely. The majority of first generation branches have used lysine. Second generation solid phase synthesis of MAPs has seen an interest in proline. The interest is said to come from both the properties of its secondary amine which decreases the reactivity during production, as well as its role in many cellular functions.
Simple MAPs have been synthesized using solid phase chemistry, with this type of synthesis strategy called divergent. Synthesis methods have been described which involves a two-step iterative reaction sequence producing concentric shells of dendritic beta-alanine units covalently linked in the second step to various functional groups (Kojima et al., Bioconjugate Chem., 2000, 11:910-17). These types of MAPs, which are synthesized using the divergent strategy, by necessity have simple branching schemes with few distinct members, as the purification and characterization are untenable with more complex MAPs. The end-product needs to be purified away from deletion compounds having similar characteristics to the end-product. Purifications have been described using gel filtration chromatography, reverse phase high-performance liquid chromatography (HPLC), or electromigration methods.
For complex MAPs, for example, those having a multiplicity of branching moieties, convergent synthesis is the preferred synthesis strategy. Convergent synthesis can be performed using either fragment condensation or ligation of the pre-purified fragments. There are many types of ligations: natural (true peptide bond created), thiol, hydrazone, or other. MAPs prepared using convergent synthesis strategies are easier to purify, as the end-product will look distinctly different from the reaction byproducts. HPLC was first used to purify convergent MAPs (J. C. Spetzler et al., Int. J. Pept. Protein Res., 1995, 45:78-85).
However, a high cost of manufacturing and the subsequent analytical development precludes this technology from being further currently developed commercially.
All of the above strategies, while recognizing the advantage of variations in the therapeutic peptide compositions, derive from the concept that there is one or more defined peptide sequence evoking a defined immunological response. These strategies have attempted to multiply and diversify modulatory peptides via the introduction of defined, single changes performed one at a time.
An entirely different approach which has evolved alongside the defined sequence peptide immunotherapy approach is the use of limited amino acid diversity, random epitope polymers. Random sequence polymers (RSP) can be described as a random order mixture of amino acid copolymers comprising two or more amino acid residues in various ratios, forming copolymers by random sequence bonding, preferably through peptide bonds, of these amino acid residues, which mixture is useful for invoking or attenuating certain immunological reactions when administered to a mammal. Because of the extensive diversity of the sequence mixture, a large number of therapeutically effective peptide sequences are likely included in the mixture. In addition, because of the additional peptides which may at any given time not be therapeutically effective, but may emerge as effective as the epitope shifting and spreading occurs, the therapeutic composition may remain effective over a time of dosing regimen. This approach is schematically represented in FIG. 1D.
Starting in 1959 (P. H. Maurer et al., J. Immunol., 1959, 83:193-7) to 1988, (J. L. Grun, and P. H. Maurer, Immunogenetics, 1988, 28(1): 61-3) Maurer and colleagues investigated the immune responses to poly glutamic acid and other random sequence polymers such as those consisting of tyrosine, glutamate and alanine (YEA), phenylalanine, glutamate and alanine (FEA), and phenylalanine, glutamate and lysine (FEK). Teitelbaum et al., Eur. J. Immunol., 1971, 1:242-8 was the initial report of work on random copolymer consisting of tyrosine, glutamate, alanine and lysine, that eventually culminated in an FDA approved therapy for multiple sclerosis using COP-1, described below. In 1978, Germain and Benacerraf, J. Exp. Medicine 148:1324-37, investigated suppressor T cell responses to YEA in what was to become Benacerrafs 1980 Nobel winning work on the role of MHC in the immune system and its relevance to alloreactivity (http://nobelprize.org/nobel_prizes/medicine/laureates/1980/benacerraf-lecture.html).
Copolymer-1 (also known as Copaxone, glatiramer acetate, COP-1, or YEAK (SEQ ID NO: 217) random copolymer), is used for the treatment of multiple sclerosis. Random copolymers are described in International PCT Publication Nos. WO 00/05250, WO 00/05249; WO 0/59143, WO 0027417, WO 96/32119, WO/2005/085323, in U.S. Patent Publication Nos. 2004/003888, 2002/005546, 2003/0004099, 2003/0064915 and 2002/0037848, in U.S. Pat. Nos. 6,514,938, 5,800,808 and 5,858,964.

Methods for designing and synthesizing directed sequence polymer compositions via the directed expansion of epitope permeability


A magazine is provided for rifles and smooth barrel shoulder guns of the single shot type that use pellets as projectiles, that further have loading mechanisms which include a bolt, and that use as propellant either compressed air (pre-charged or provided by a pump), or carbon dioxide cartridges. The magazine of this invention will permit the operation of these guns as repeaters. The magazine stores pellets in reservoir ducts built into a body. The pellets are fed one at a time into a chute duct for rifle loading. The motion of the pellets within the magazine is propelled by gravity. A guide, which is part of the magazine, helps the operation of filling the magazine with pellets. This guide has a gate which prevents filling the magazine with pellets turned around backwards. The preferred embodiment of the invention may be attached and removed from the rifles by means of built-in clamps, or may be built onto a rifle especially designed to feature it. Another embodiment of the invention provides a magazine which may be pre-filled with pellets before installing it on guns of the type mentioned, permitting the use of magazines of this type as clips.

Rifles or smooth barrel shoulder guns utilizing compressed air (pre-charged or pump pneumatic) or compressed carbon dioxide cartridges to propel projectiles have been in existence for many years. The specification of the invention relates only to the part of these rifles or smooth barrel shoulder guns that further have a bolt-action as part of the loading mechanism; the specification of the invention henceforth often refers to any of such restricted class of guns simply as "rifle" or "rifles", and the references to "rifles" include smooth barrel shoulder guns. Some of these rifles use spherical, steel projectiles (BB's), others utilize lead pellets with specific shapes to optimize performance, others still are designed to utilize either type. Some rifles have mechanisms for loading projectiles of the BB type, so that these rifles may operate as bolt-action repeater rifles only when using BB's. The mechanical systems for storing and feeding BB's to load these projectiles into repeater rifles only work due to two facts: first, the orientation of the spherical projectile is unimportant, and second, the projectiles are magnetic so that they are not lost during loading. The front to back orientation with which lead pellets are loaded into these gas rifles is critical because of the asymmetrical shape these pellets have for optimum performance. Furthermore, the special shape these pellets have causes them to be easily susceptible to deformation, since they have very thin walls in some places, and they are very soft, being made of lead. A system that would guide such pellets into the breech of a gas rifle must do so without deforming them. The existing devices that provide rifle operation in the repeater mode are of two general classes: one class requires very complex and expensive mechanisms to avoid pellet deformation and jamming during loading; the other class is exemplified by a magazine that merely stores and aligns the pellets before loading, requiring manual advance of a pellet chamber by the user. The magazines of this latter class further require care while filling them with pellets so that pellets are not inserted backwards.
An object of the invention is to provide a magazine which will make it possible to operate as repeaters single shot, bolt-action, compressed air (pre-charged or pump pneumatic) or carbon dioxide cartridge pellet rifles.
Another object of the invention is to provide a magazine which operates by gravity for bolt-action, single shot compressed air (pre-charged or pump pneumatic) or carbon dioxide cartridge pellet rifles.
Another object of the invention is to provide a magazine which can be filled with a plurality of pellets after being attached to a bolt-action, single shot compressed air (precharged or pump pneumatic) or carbon dioxide cartridge pellet rifle.
Another object of the invention is to provide a magazine which can be permanently built into a bolt-action, single shot compressed air (pre-charged or pump pneumatic) or carbon dioxide cartridge pellet rifle.
Another object of the invention is to provide a magazine that can be pre-filled with a plurality of pellets and that will work as a clip for attachment to bolt-action, single shot compressed air (pre-charged or pump pneumatic) or carbon dioxide cartridge pellet rifles.
Another object of the invention is to provide a magazine which has a guide to make it easy to fill the magazine with pellets for bolt-action, single shot compressed air (precharged or pump pneumatic) or carbon dioxide cartridge pellet rifles.
Another object of the invention is to provide a magazine which prevents loading pellets backwards into rifles of the bolt-action, single shot compressed air (pre-charged or pump pneumatic) or carbon dioxide cartridge type.

Magazine for compressed gas single-shot bolt-action pellet shoulder guns


Methods, apparatus, systems and articles of manufacture are disclosed that enable out-of-order pipelined execution of static mapping of a workload to one or more computational building blocks of an accelerator. An example apparatus includes an interface to load a first number of credits into memory; a comparator to compare the first number of credits to a threshold number of credits associated with memory availability in a buffer; and a dispatcher to, when the first number of credits meets the threshold number of credits, select a workload node of the workload to be executed at a first one of the one or more computational building blocks.

Computer hardware manufacturers develop hardware components for use in various components of a computer platform. For example, computer hardware manufacturers develop motherboards, chipsets for motherboards, central processing units (CPUs), hard disk drives (HDDs), solid state drives (SSDs), and other computer components. Additionally, computer hardware manufacturers develop processing elements, known as accelerators, to accelerate the processing of a workload. For example, an accelerator can be a CPU, a graphics processing units (GPU), a vision processing units (VPU), and/or a field programmable gate arrays (FPGA).
The figures are not to scale. In general, the same reference numbers will be used throughout the drawing(s) and accompanying written description to refer to the same or like parts. Connection references (e.g., attached, coupled, connected, and joined) are to be construed broadly and may include intermediate members between a collection of elements and relative movement between elements unless otherwise indicated. As such, connection references do not necessarily infer that two elements are directly connected and in fixed relation to each other.
Descriptors "first," "second," "third," etc. are used herein when identifying multiple elements or components which may be referred to separately. Unless otherwise specified or understood based on their context of use, such descriptors are not intended to impute any meaning of priority, physical order or arrangement in a list, or ordering in time but are merely used as labels for referring to multiple elements or components separately for ease of understanding the disclosed examples. In some examples, the descriptor "first" may be used to refer to an element in the detailed description, while the same element may be referred to in a claim with a different descriptor such as "second" or "third." In such instances, it should be understood that such descriptors are used merely for ease of referencing multiple elements or components.

Methods and apparatus to enable out-of-order pipelined execution of static mapping of a workload


Particular embodiments of the present invention relate generally to semiconductor lasers and wavelength conversion devices and, more particularly, to wavelength conversion devices and methods of fabrication thereof that reduce back reflections of light from the wavelength conversion device to the laser. According to one embodiment of the present invention, a wavelength conversion device comprising a nonlinear optical material is poled with domains comprising randomly varying domain widths defined by an ideal poling period ΛI plus or minus a disruption value. According to another embodiment, the wavelength conversion device comprises a plurality of sequentially positioned ideal poling domains and one or more non-ideal poling domains. The ideal poling domains comprise a domain width of the ideal poling period ΛI while the non-ideal poling domains comprise a domain width of the ideal poling period ΛI plus or minus a discontinuity value.

The present invention relates generally to wavelength conversion devices and fabrication methods for the same. More particularly, some embodiments of the present invention relate wavelength conversion devices and methods of fabrication thereof that utilize poling period manipulation to reduce Bragg resonance and corresponding back reflections of light while maintaining an effective conversion efficiency of the wavelength conversion device.

Wavelength conversion devices and fabrication methods for the same


An improved mixed down synthesizer scheme 10 having a first phase locked loop 12 and a second phase locked loop 14 provides a first frequency and a second frequency respectively. The first phase locked loop 12 has at least a first programmably tunable filter 30 and a mixer 28. The second phase locked loop 14 has an output received by the mixer 28 in the first phase locked loop 12. A controlling means (18 and 20) controls the first and second frequencies and tunes the first programmably tunable filter 30. The first and the second phase locked loops 12 and 14 are programmed to maintain a constant frequency ratio between the first and second frequencies in order to maintain a minimum frequency offset from the mixed-in spurious products.

The tuning bandwidth of a conventional single loop analog synthesizer often has a narrow tuning bandwidth (below 20% bandwidth), due to limitations in the tuning range of the varactor diode. More particularly applicable to low band and mid band ranges, if a high resonator Q is desired for good sideband noise performance, then a large and bulky resonating coil is usually required. The typical techniques used to diminish these problems involves the use of the divide down synthesis method or the mix down synthesis method.
Use of the divide down synthesis method generally reduces the size of the coil when a higher frequency voltage controlled oscillator (VCO) is used, but fails to provide an adequate tuning range due to the limits of the divider ratio. The conventional mix down method eliminates the problems with coil size and limits in tuning range, but adds the additional problem of inherent in-band spurious response signals due to Able-Baker mixing products. The Able-Baker spurious response signals cannot be filtered out due to their proximity to the desired signal over a wide frequency band. Therefore, a need for a mix down synthesizer method that reduces the in-band spurious response signal problems is required.

Multiloop synthesizer with optimal spurious performance


A device stores forwarding information associated with fragments of a first data unit, stores information common to the fragments of the first data unit, receives fragments of a second data unit, and forwards the fragments of the second data unit based on the forwarding information of the first data unit and the information common to the first data unit.

Numerous network data unit handling schemes have been developed to improve the performance of capturing and forwarding data. For example, a forwarding device, such as a router or a switch, may be designed to minimize latency, jitter, and/or storage requirements. However, if a data unit is fragmented (e.g., due to a maximum transmission unit requirement) and transmitted through a network, a first fragment may contain forwarding information that may not be contained in other fragments of the same data unit. As a result, a forwarding device may wait before forwarding fragments of a first data unit until a first fragment of the first data unit is received. In this regard, a forwarding device may perform sub-optimally.

This patent is subject to a terminal disclaimer.


A method and a system for implementing interconversion between a ring back tone and a ringing tone are disclosed. The method for converting the ring back tone into the ringing tone includes: configuring ring back tone information for a user according to a ring back tone configuration request; obtaining relevant data of corresponding ringtone information according to the ring back tone information configured, and sending the relevant data to a user terminal. The method for converting the ringing tone into the ring back tone includes: generating a ring back tone configuration request according to ringing tone configuration information, where a user terminal configures the ringing tone with the ringing tone configuration information; and configuring the ring back tone corresponding to the ringing tone to be a ring back tone information of the user terminal according to the ringing tone configuration information in the ring back tone configuration request.

Ring back tone is an audio played for a calling party before a called party picks up the telephone and answers the call initiated by the calling party. The coloring ring back tone service developed presently becomes more and more popular due to its strongly customizable service. In the coloring ring back tone service, various audio files may be played for the calling party in accordance with the configuration of the user, and further, different ring back tones may be configured for different calling parties. For example, a group ring back tone or a default ring back tone may be configured. As for the group ring back tone, an audio file is configured for a contact group in the address book by the user, the sound of the audio file is the ring back tone for the group. As a contact user of the contact group initiates a call to the user, the contact user who is a calling party will hear the sound of this audio file. As for the default ring back tone, there is no special ring back tone configured for the contact users in the address book by the user. Therefore, when such a contact user initiates a call to the user, the default ring back tone configured by the user may be heard by the contact user. The coincidence relation between the calling party and the audio file configured by the user is stored in a ring back tone platform. When a calling party initiates a call, the ring back tone platform plays the corresponding audio file for the calling party in accordance with the stored coincidence relation between the calling party and the audio file.
Ringing tone is an audio played for the called party by the user terminal of the called party when the user is called. The user may configure different ringing tones for different calling parties via the user terminal, such as a group ringing tone and a default ringing tone. As for the group ringing tone, it means that an audio file is configured for a contact group in the address book by the user, the sound of the audio file is the ringing tone for the group. When a contact user of the contact group initiates a call to the user, the called party will hear the sound of the corresponding audio file. As for the default ringing tone, it means that no special ringing tone is configured for the contact users in the address book by the user. Therefore, when such a contact user initiates a call to the user, the default ringing tone configured by the user may be heard by the called party.
Presently, there exist three ring back tone schemes, i.e. intelligent network scheme, calling party end office scheme and called party end office scheme. An example of the present schemes includes following steps:
Step A: a calling party initiates a call to a service switching point (SSP), the SSP triggers an intelligent service in accordance with a ring back tone service tag in the call, and reports the tag to a service control point (SCP), the SCP obtains the ring back tone number and sends the number to the SSP.
Step B: the SSP initiates a call to the called party and the ring back tone platform respectively in accordance with the ring back tone number obtained.
Step C: a voice channel via the SSP is determined under the control of the SSP, where the voice channel connects the called party and the calling party, and a voice channel via the SSP is established and activated under the control of the SSP, where the voice channel connects the ring back tone platform and the calling party.
Step D: the ring back tone platform plays a coloring ring back tone for the calling party via the voice channel between the ring back tone platform and the calling party.
Step E: the called party picks up the telephone, so as to activate the voice channel between the calling party and the called party, and the calling party and the called party communicate with each other through the voice channel. Meanwhile, the SSP terminates the connection with the ring back tone platform and releases the resources of the ring back tone platform.
FIG. 1 is a schematic diagram showing the architecture of a system for downloading and configuring the ringing tone in the prior art. As shown in FIG. 1, the system includes: a ringing tone download server, a push proxy gateway (PPG), a wireless application protocol (WAP) gateway and a mobile terminal. The ringing tone download server is adapted to provide the PPG with information of the ringing tone selected by the user, and provide the mobile terminal with the ringing tone via the WAP gateway in accordance with a ringing tone downloading request from the mobile terminal. The PPG is adapted to constitute a Push message in accordance with the ringing tone information from the ringing tone download server, and send the Push message including ringing tone download information to the mobile terminal. The mobile terminal is adapted to connect with the WAP gateway in accordance with the Push message from the PPG, send a ringing tone downloading request to the ringing tone download server via the WAP gateway, and download the ringing tone provided by the ringing tone download server via the WAP gateway. Since the information exchange between the mobile terminal and the WAP gateway is implemented based on WAP, and the information exchange between the WAP gateway and the ringing tone download server is implemented based on the hyper text transfer protocol (HTTP), the WAP gateway is adapted to implement the protocol conversion for the information that is exchanged between the mobile terminal and the ringing tone download server. Further, the mobile terminal is adapted to configure the received ringing tone as the ringing tone for a corresponding contact user in the address book in accordance with the operation of the user. The PPG is mainly adapted to implement the active push of the information, receive the push request of the WAP information from the ringing tone download server, and provide the mobile terminal with the WAP information.
Further, the information exchange between the ringing tone download server and the PPG is implemented based on the Push Access Protocol (PAP), and the information exchange between the PPC and the mobile terminal is implemented based on the Push Over-The-Air protocol (P-OTA).
The user may log on the ringing tone download server via PC or mobile terminal and select the ringing tone to be downloaded. When the user logs on the ringing tone download server via PC, the PC logs on the ringing tone download server through Internet, and the user may select the ringing tone to be downloaded through the interaction between the PC and the ringing tone download server. When the user logs on the ringing tone download server via the mobile terminal, the mobile terminal logs on the ringing tone download server through the WAP gateway, and the user may select the ringing tone to be downloaded through the interaction between the mobile terminal and the ringing tone download server.
FIG. 2 is a diagram showing the flow chart for downloading and configuring the ringing tone in the prior art. As shown in FIG. 2, the process of downloading and configuring the ringing tone includes the following steps:
Step 201-Step 202: a user logs on the ringing tone download server via PC or mobile terminal, and selects the ringing tone to be downloaded through the interaction between the ringing tone download server and the PC or the mobile terminal.
Step 203: when the ringing tone to be downloaded is selected by the user, the ringing tone download server provides the PPG with information of the ringing tone selected by the user.
Step 204: when the PPG receives the ringing tone information, it constitutes a Push message according to the ringing tone information, and then sends the Push message including the download information of the ringing tone to the mobile terminal. In the subsequent steps, the mobile terminal is considered, and PC is not considered.
Step 205-Step 206: the mobile terminal receives the Push message, connects to the WAP gateway in accordance with the Push message, and sends a ringing tone downloading request to the WAP gateway. When the WAP gateway receives the ringing tone downloading request, it sends the ringing tone downloading request to the ringing tone download server, and requests to download the corresponding ringing tone.
Step 207: after receiving the ringing tone downloading request, the ringing tone download server provides the WAP gateway with the ringing tone selected by the user.
Step 208: after receiving the ringing tone, the WAP gateway provides the mobile terminal with the ringing tone selected by the user.
Step 209: after receiving the ringing tone, the mobile terminal sends a reception acknowledgement to the WAP gateway, for notifying the WAP gateway that the ringing tone is successfully received.
Step 210: after receiving the reception acknowledgement, the WAP gateway sends the ringing tone sending result to the ringing tone download server, for notifying the ringing tone download server to complete the present ringing tone download.
Step 211: when receiving the ringing tone, the mobile terminal may configure the ringing tone to be the ringing tone for the corresponding contact user in the address book according to the operation of the user.
There is no evident temporal sequence when executing Step 209-Step 210 and Step 211. Step 209-Step 210 and Step 211 may be executed at the same time; or it is possible to execute Step 209-Step 210 first, and then execute Step 211; or it is also possible to execute Step 211 first, and then execute Step 209-Step 210.
FIG. 3 is a schematic diagram showing the system for configuring the ring back tone in the prior art. As shown in FIG. 3, the system includes: peripheral equipment, a WEB server and a ring back tone platform. The peripheral equipment is adapted to log on the ring back tone platform via the WEB server, and request the ring back tone platform to configure the ring back tone. The ring back tone platform is adapted to configure the ring back tone of the user terminal in accordance with the ring back tone configuring request, and store the coincidence relation between the ring back tone configured and the calling party. The WEB server is adapted to implement the protocol conversion for the information exchanged between the peripheral equipment and the ring back tone platform. The information exchange between the peripheral equipment and the WEB server is implemented based on HTTP, and the information exchange between the WEB server and the ring back tone platform is implemented based on the Simple Object Access Protocol (SOAP). The peripheral equipment may be a PC.
FIG. 4 is a diagram showing the flow chart of configuring the ring back tone in the prior art. As shown in FIG. 4, the process of configuring the ring back tone includes the following steps:
Step 401: the peripheral equipment requests to log on the ring back tone platform, the ring back tone platform performs authentication on the peripheral equipment. When the authentication is passed, the peripheral equipment logs on the ring back tone platform.
Step 402-Step 403: the peripheral equipment sends a ring back tone configuring request to the WEB server, requests to configure the ring back tone. When the ring back tone configuring request is received, the WEB server sends the ring back tone configuring request to the ring back tone platform.
Step 404: when the ring back tone configuring request is received, the ring back tone platform configures the ring back tone for the user terminal in accordance with the ring back tone configuring request, and stores the coincidence relation between the calling party and the ring back tone configured.
Step 405-Step 406: when the configuration of the ring back tone is finished, the ring back tone platform returns the ring back tone configuring result to the WEB server, so as to notify the peripheral equipment that the ring back tone is successfully configured. When the ring back tone configuring result is received, the WEB server sends the ring back tone configuring result to the peripheral equipment.
During the research, it is found by the inventor that interconversion between the ringing tone and the ring back tone cannot be implemented in the prior art.
Since the ringing tone and the ring back tone cannot be interconverted into each other in the prior art, it cannot be ensured that the ringing tone and the ring back tone of the same sound may be stored on the terminal and the network side. Even if the ringing tone and the ring back tone of the same sound are stored on the terminal and the network side, because the configuration of the ringing tone and the ring back tone is separated and no correlation exists between them, the configuration has to be initiated and performed respectively, when a user wants to configure the same ringing tone and ring back tone for a contact user or contact group. Therefore, the configuration of the ringing tone and the ring back tone has to be initiated respectively by the user, the operation is fussy, and much inconvenience is brought about with the user, and is not good for the development and application of the ring back tone service and the ringing tone download service.

Method and system for implementing interconversion between ring back tone and ringing tone


There is disclosed a method of simulating the output of a medical imaging device, the medical imaging device being operable to image an anatomical structure, and the method including: accessing model data representing a model of the anatomical structure; accessing selection data representing a selected region of the anatomical structure to be imaged; and processing the selection data and the model data to generate output data representing a simulation of the output of the medical imaging device when imaging the selected region.

Medical imaging devices provide an important diagnostic tool for many medical applications. One example of a medical imaging device is an ultrasound scanner. Ultrasound scans are carried out by transmitting high frequency ultrasonic sound into a human body and received and processing reflections of the transmitted sound in order to create an image of an organ or other structure in the body.
For diagnostic purposes, a medical professional performs an ultrasound scan using a hand-held probe (or more commonly referred to as a transducer) that is placed directly on and moved over the surface of the body. Essentially, the transducer transmits sound waves into the body and receives echoing waves that reflect from internal organs, fluids and tissues. The reflected waves are converted to corresponding electrical pulses that are transmitted to an electronic analyser, and displayed by a computer, which in turn creates a real-time image on a monitor.
Cardiac ultrasound, or echocardiogram, uses standard ultrasound technique to image two-dimensional slices of the heart. An echocardiogram allows a medical professional to analyse the heart beating and to visualise the structures of the heart in order to monitor the state of the heart and to diagnose cardiovascular diseases.
There are two main types of echocardiogram, namely, a transthoracic echocardiogram (TTE), and a transoesophageal echocardiogram (known as TEE or TOE).
TTE is a standard non-invasive procedure and is performed by placing the transducer on the chest wall, aiming an ultrasound beam through the chest and to the heart. Similarly, the transducer records the sound wave echoes as they reflect off internal structures of the patient's chest. In this procedure, the lungs and ribs may obscure the view, and a small amount of intravenous dye may be applied to improve the images.
Although TTE is considered a highly accurate procedure, the accuracy can be reduced because of obesity, chronic obstructive pulmonary disease, or chest-wall deformities. In these circumstances, TOE is recommended. In a TOE procedure, a flexible tube containing a transducer is guided down the patient's throat and into the lower part of the oesophagus. This procedure can allow a clearer two-dimensional echocardiogram of the heart.
As echocardiography becomes a widely used diagnostic tool, training and accreditation in echocardiography has also become vitally important. Training in echocardiography includes instruction in the basic aspects of ultrasound, performing echocardiographic examination to integrate understanding of three-dimensional cardiac anatomy, interpreting two-dimensional (2D) screen images and learning to build a mental model of the heart from multiple 2D images.
Thus, it is desirable to provide a realistic training device for training medical professionals in the use of echocardiography equipment and in the interpretation of resulting 2D ultrasound images.
A similar need can also arise in relation to other types of medical imaging device, such as magnetic resonance imaging (MRI) scanners, X-ray devices, and so on.


A method of improving a session in which a remote terminal is linked to a mobile device, the method comprising determining a performance profile for each of said remote terminal and said mobile device, said performance profiles including a set of parameters which determine performance of a session when said remote terminal is linked to a mobile device to receive and display an image of data currently displayed on said mobile device; estimating performance of a session between the remote terminal and the mobile device whilst there is no live connection; identifying a change to a parameter from said set of parameters; changing said identified parameter; re-evaluating said estimate based on the changed parameter; including said identified parameter change in said appropriate performance profile if performance is improved; reiterating, if necessary, said estimating, identifying, changing, re-evaluating and adopting steps until termination; and storing said changed performance profiles for said mobile device and said remote terminal.

It is known to use a remote computer terminal to view and control mobile phones using a Virtual Network Computing (VNC) application running both on the remote computer terminal (VNC viewer) and the mobile phone (VNC server). The contents of the display of the mobile device are duplicated on the remote computer terminal. The remote computer terminal has an interface mechanism which allows the user to send user input events, such as pressing a physical key on the device or touching a touch screen input, to the mobile device being controlled. As will be appreciated, the form of data link and the nature of the remote computer terminal can vary, depending on the situation being used.
The remote computer terminal may be for a support engineer using the remote control facility to provide device support to a customer using a mobile phone. If a customer of a company experiences a problem with a mobile phone, such as being unable to send picture messages, the support engineer can diagnose and fix the problem by viewing or interacting with the phone by using the remote terminal. Alternatively, the support engineer may use the remote terminal to install or update software or other settings on a user's mobile phone. In this situation the data link would typically be via a form of radio communication, such as Wifi, GPRS or HSDPA and the remote terminal may be a long distance, e.g. hundreds of miles away from the mobile phone.
Alternatively, the remote terminal may be located close to the mobile phone for example in the automotive industry. The remote terminal may be a headunit embedded as a large display mounted on the dashboard of the car. The familiar interface of the user's phone is shown on the display and the user can use this interface to play music or perform map based navigation. Typically, there will be additional safety mechanisms to prevent the user from using the remote terminal to control distracting applications, such as computer games, while driving. In this situation the data link would typically be via a physically wired connection, such as USB, or a short range radio communication system, such as Wifi or Bluetooth.
Particularly, but not exclusively, in the automotive setting, the mobile device and remote terminal (i.e. headunit) are typically resource-constrained devices, which can have wide-ranging hardware specifications. Furthermore, as well as supporting a VNC session, both the mobile device and headunit may run one or more third party applications, which also compete for the resources of the device. These applications may also utilise the interface between the mobile device and headunit, affecting the bandwidth that is available to support the VNC session.
A VNC session requires the configuration of a number of parameters. Many of these parameters require negotiation between the VNC server and VNC viewer, and some parameters can be mandated by either side. One key factor in the performance of a VNC session is the configuration parameters used by that session. Properties such as pixel format, encoding and encryption can all be varied through configuration parameters. Some of these parameters must take on mandated values for a particular scenario, but others can be tuned to optimise performance.
During a VNC session, a VNC viewer requests that pixel data be provided in a particular format and encoding type. A pixel format defines how a pixel should be described. It specifies the number of bits to use to describe the pixel and how the red, green and blue component information is encoded. The greater the number of bits used to describe a pixel, the more distinct shades of colour that can be communicated through the VNC session. However, increasing the number of bits also increases the amount of data that must be transferred from the VNC server to the VNC viewer to describe a framebuffer update.
An encoding type specifies how pixel data should be sent by the VNC server. An encoding type can facilitate the compression of pixel data, reducing the number of bytes being sent over the wire. For example, pixel data can be encoded using JPEG encoding, a compressed image format. However, whilst compressing pixel data reduces the number of bytes required describing a framebuffer update, this also requires extra CPU resources on both sides of the VNC session to encode and decode the data.
One solution for dynamically adjusting the parameters is shown in FIG. 1 and described in more detail below. In FIG. 1, the pixel format and encoding type are adjusted according to a performance metric, namely Line Speed Estimate (LSE).
The present applicant has recognised that the set of VNC session parameters that allows the best performance to be attained is highly dependent on the properties of the server and viewer platform hardware, the speed of the interface connecting the viewer and server and the influences presented by third party applications. In this light, the present applicant has recognised that an improved method and system for remote controlling mobile phones is required.

Method and system for remote controlling and viewing mobile phones