1. A method of registering sales associates to assist customers in online sales transactions, the method comprising:
receiving, by a computer in a network of computers, sales associate information from a plurality of sales associates;
receiving, by the computer, session information from a website about a customer’s session on the website, the session information comprising the products the customer is viewing on the website;
analyzing, by the computer, the session information received;
identifying, by the computer, the customer as a potential target for permissive assistance, based at least in part on the analysis of the session information received;
matching, by the computer, the customer with at least one of the plurality of sales associates based on weighted parameters comprising the session information and information about the plurality of sales associates, wherein matching comprises:
determining a rule set to apply in order to match the customer with at least one of the plurality of sales associates, said rule set comprising two or more rules, respective rules having a relative weight associated therewith; and
generating a matching score for each of the plurality of sales associates based at least in part on a relative ranking of the sales associate with respect to each rule of the determined rule set multiplied by the relative weight associated with the corresponding rule;
dynamically changing the determined rule set based at least in part on a combination of sales successes and market conditions; and
notifying, by the computer, at least the sales associate with the highest matching score that the sales associate is an acceptable candidate.
2. The method of claim 1, further comprising:
requesting credit and background information on the sales associate from a third party; and
receiving credit and background information on the sales associate from a third party.
3. The method of claim 1, further comprising:
receiving a schedule of availability from the sales associate.
4. The method of claim 1, further comprising:
receiving method of contact preferences from the sales associate.
5. A method of registering sales associates to assist customers in online sales transactions, the method comprising:
receiving, by a computer in a network of computers, a registration request from respective sales associates of a plurality of sales associates;
receiving, by the computer, sales associate information from the plurality of sales associates;
receiving, by the computer, enterprise sales associate information comprising product accreditations from one or more enterprises employing the plurality of sales associates;
analyzing, by the computer, sales associate information, enterprise sales associate information, and testing results to determine if each of the plurality of sales associates is an acceptable candidate to assist a customer;
notifying, by the computer, respective sales associates of the plurality of sales associates that the sales associate is an acceptable candidate;
receiving, by the computer, session information from a website about a customer’s session on the website, the session information comprising the products the customer is viewing on the website;
analyzing, by the computer, the session information received;
identifying, by the computer, the customer as a potential target for permissive assistance, based at least in part on the analysis of the session information received; and
matching, by the computer, the customer with at least one of the plurality of sales associates based on weighted parameters comprising the session information and the corresponding sales associate’s accreditation information, wherein matching comprises:
determining a rule set to apply in order to match the customer with at least one of the plurality of sales associates, said rule set comprising two or more rules, respective rules having a relative weight associated therewith; and
generating a matching score for each of the plurality of sales associates based at least in part on a relative ranking of the sales associate with respect to each rule of the determined rule set multiplied by the relative weight associated with the corresponding rule; and
dynamically changing the determined rule set based at least in part on a combination of sales successes and market conditions.
6. The method of claim 5, further comprising:
ranking the sales associate based on sales associate information and enterprise sales associate information; and
matching the sales associate with the customer browsing on the enterprise’s website.
7. The method of claim 5, further comprising;
testing the sales associate to determine product accreditations.
8. A method of accrediting sales associates to assist customers in online sales transactions, the method comprising:
receiving, by a computer in a network of computers, an accreditation request from each of a plurality of sales associates;
delivering, by the computer, appropriate testing materials to respective sales associates of the plurality of sales associates;
receiving, by the computer, the completed testing materials from respective sales associates of the plurality of sales associates;
analyzing, by the computer, the completed testing materials from respective sales associates;
updating, by the computer, a record for respective sales associates to indicate a new level of accreditation;
receiving, by the computer, session information from a website about a customer’s session on the website, the session information comprising the products the customer is viewing on the website;
analyzing, by the computer, the session information received;
identifying, by the computer, the customer as a potential target for permissive assistance, based at least in part on the analysis of the session information received; and
matching, by the computer, the customer with at least one of the plurality of sales associates based on weighted parameters comprising the session information and the corresponding sales associate’s accreditation information, said matching comprising:
determining a rule set to apply in order to match the customer with at least one of the plurality of sales associates, said rule set comprising two or more rules, respective rules having a relative weight associated therewith; and
generating a matching score for each of the plurality of sales associates based at least in part on a relative ranking of the sales associate with respect to each rule of the determined rule set multiplied by the relative weight associated with the corresponding rule; and
dynamically changing the determined rule set based at least in part on a combination of sales successes and market conditions.
9. A method of registering sales associates to assist customers in online sales transactions, the method comprising:
receiving, by a computer in a network of computers, sales associate information from a plurality of sales associates;
receiving, by the computer, session information from a website about a customer’s session on the website, the session information comprising the products the customer is viewing on the website;
analyzing, by the computer, the session information received;
identifying, by the computer, the customer as a potential target for permissive assistance, based at least in part on the analysis of the session information received;
requesting and receiving, by the computer, credit and background information on respective sales associates of the plurality of sales associates from a third party; and
matching, by the computer, the customer with at least one of the plurality of sales associates based on weighted parameters comprising the session information and the corresponding sales associate’s credit and background information, said matching comprising:
determining a rule set to apply in order to match the customer with at least one of the plurality of sales associates, said rule set comprising two or more rules, respective rules having a relative weight associated therewith; and
generating a matching score for each of the plurality of sales associates based at least in part on a relative ranking of the sales associate with respect to each rule of the determined rule set multiplied by the relative weight associated with the corresponding rule; and
dynamically changing the determined rule set based at least in part on a combination of sales successes and market conditions.
10. A method of registering sales associates to assist customers in online sales transactions, the method comprising:
receiving, by a computer in a network of computers, a registration request from respective sales associates of a plurality of sales associates;
receiving, by the computer, sales associate information from the plurality of sales associates;
receiving, by the computer, enterprise sales associate information comprising product accreditations from one or more enterprises employing the plurality of sales associates;
receiving, by the computer, session information from a website about a customer’s session on the website, the session information comprising the products the customer is viewing on the website;
analyzing, by the computer, the session information received;
identifying, by the computer, the customer as a potential target for permissive assistance, based at least in part on the analysis of the session information received;
ranking, by the computer, the plurality of sales associates based on sales associate information and enterprise sales associate information; and
matching, by the computer, the customer with at least one of the plurality of sales associates based on weighted parameters comprising the sales associate information, enterprise sales associate information, and session information, said matching comprising:
determining a rule set to apply in order to match the customer with at least one of the plurality of sales associates, said rule set comprising two or more rules, respective rules having a relative weight associated therewith; and
generating a matching score for each of the plurality of sales associates based at least in part on a relative ranking of the sales associate with respect to each rule of the determined rule set multiplied by the relative weight associated with the corresponding rule; and
dynamically changing the determined rule set based at least in part on a combination of sales successes and market conditions.
The claims below are in addition to those above.
All refrences to claim(s) which appear below refer to the numbering after this setence.
1. A solid complex comprising:
an insulin compound conjugate comprising an insulin compound conjugated to a modifying moiety, wherein the modifying moiety comprises from 2 to 10 PEG subunits (OCH2\u2014CH2) forming a PEG component coupled to a lipophilic component, where the lipophilic component is selected from the group consisting of alkyls, fatty acids and linear or branched lipids, and either the PEG component or the lipophilic component is coupled to the insulin compound at the B29 amino acid residue; and
a cation, wherein the cation is a divalent cation selected from the group consisting of Zn++, Mn++, Ca++, Fe++, Ni++, Cu++, Co++ and Mg++; where the insulin compound conjugate is complexed with the cation, and wherein the solid complex is a crystalline solid or a rod shaped crystal.
2. The complex of claim 1 where the insulin compound conjugate comprises an insulin compound analog.
3. The complex of claim 2 where the insulin compound analog is human insulin with Lys28 and Pro29.
4. The complex of claim 2 where the insulin compound analog is a native proinsulin compound.
5. The complex of claim 2 where the insulin compound analog is an artificial proinsulin compound.
6. The complex of claim 2 where the insulin compound analog is a miniproinsulin compound comprising a C-peptide having 5 or less amino acids.
7. The complex of claim 2 where the insulin compound analog is a native proinsulin compound having a leader peptide which is cleavable or non-cleavable.
8. The complex of claim 2 where the insulin compound analog is an artificial proinsulin compound having a leader peptide which is cleavable or non-cleavable.
9. The complex of claim 2 where the insulin compound analog is a miniproinsulin compound comprising:
a C-peptide having 5 or less amino acids;
a leader peptide which is cleavable or non-cleavable.
10. The complex of claim 2 where the insulin compound analog is a pre-proinsulin compound comprising proinsulin compound and a leader peptide or a carrier protein joined at the C-terminus or N-terminus of the proinsulin compound.
11. The complex of claim 2 where the insulin compound analog is a single chain insulin compound precursor comprising insulin compound A-chain-B-chain, where the A chain andor B chain may be truncated at the point of attachment to the other by 1, 2 or 3 amino acids.
12. The complex of claim 2 where the insulin compound analog is an insulin compound comprising a leader peptide or a carrier protein.
13. A solid complex comprising:
an insulin compound conjugate comprising an insulin compound conjugated to a modifying moiety, wherein the modifying moiety comprises (OCH2\u2014CH2) PEG subunits forming a PEG component coupled to a lipophilic component, where the lipophilic component is selected from the group consisting of alkyls, fatty acids and linear or branched lipids, and either the PEG component or the lipophilic component is coupled to the insulin compound at the B29 amino acid residue; and
a cation, wherein the cation is a divalent cation selected from the group consisting of Zn++, Mn++, Ca++, Fe++, Ni++, Cu++, Co++ and Mg++;
where the insulin compound conjugate is complexed with the cation,
where the modifying moiety is selected to render the insulin compound conjugate more water soluble than a corresponding unconjugated insulin compound, and wherein the solid complex is a crystalline solid or a rod shaped crystal.
14. The complex of claim 13 where the modifying moiety is selected to render the insulin compound conjugate more amphiphilic than a corresponding unconjugated insulin compound.
15. The complex of claim 13 where the modifying moiety is selected to render the insulin compound conjugate at least 1.05, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, 10, 10.5, 11, 11.5, 12, 12.5, 13, 13.5, 14, 14.5, or 15 times more soluble than a corresponding unconjugated insulin compound in an aqueous solution at a pH of about 7.4.
16. The complex of claim 13 where the modifying moiety is selected to render an insulin compound conjugate having a solubility that exceeds about 1 gL, 2 gL, 3 gL, 4 gL, 5 gL, 10 gL, 15 gL, 20 gL, 25 gL, 50 gL, 75 gL, 100 gL, 125 gL, or 150 gL at a pH ranging from about 4 to about 8.
17. The complex of claim 1 where the water solubility of the insulin compound conjugate is decreased by the addition of zinc.
18. The complex of claim 1 where the relative lipophilicity of the insulin compound conjugate relative to the corresponding parent insulin compound is 1 or less than 1.
19. The complex of claim 18, wherein:
(a) krel=(tconjugate\u2212t0)(thuman\u2212t0);
(b) relative lipophilicity is measured on an LiChroSorb RP18 (5 \u03bcm, 250\xd74 mm) high performance liquid chromatography column by isocratic elution at 40\xb0 C.
(c) the following mixtures are used as eluents:
(i) 0.1M sodium phosphate buffer at pH 7.3 containing 10% acetonitrile, and
(ii) 50% acetonitrile in water;
(d) void time (t0) is identified by injecting 0.1 mM sodium nitrate;
(e) retention time for human insulin is adjusted to at least 2t0 by varying the ratio between the mixtures of (c)(i) and (c)(ii).
20. The complex of claim 1 where the modifying moiety is coupled to one or more amino groups on the insulin compound.
21. The complex of claim 1 where a modifying moiety is coupled at the carboxy terminus of the A-chain andor a modifying moiety is coupled at the carboxy terminus of the B-chain of the insulin compound.
22. The complex of claim 1 where a modifying moiety is coupled at the N-terminus of a leader peptide which is coupled to the B-chain of the insulin compound.
23. The complex of claim 1 where the cation comprises Zn++.
24. The complex of claim 1 where the cation is greater than about 90, 95, 99, or 99.9% Zn++.
25. The complex of claim 1 where molar ratio of insulin compound conjugate to cation is between about 1:1 and about 1:100, about 1:2 and about 1:12, or about 1:2 and about 1:7.
26. The complex of claim 13 where resistance of the complexed insulin compound conjugate to chymotrypsin degradation is greater than the chymotrypsin degradation of a corresponding uncomplexed insulin compound conjugate.
27. The complex of claim 13 where resistance of the complexed insulin compound conjugate to chymotrypsin degradation is greater than the chymotrypsin degradation of a corresponding complexed but unconjugated insulin compound.
28. The complex of claim 1 where the insulin compound conjugate consists of human insulin coupled at B29 to a modifying moiety having a structure:
29. The complex of claim 13 where the modifying moiety has a formula:
where m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
30. The complex of claim 13 where the modifying moiety has a formula:
where PAG is a PAG moiety having m subunits and m is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 and n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20.
31. The complex of claim 1 where the modifying moiety has a structure:
32. The complex of claim 1 where the modifying moiety has a structure:
33. The complex of claim 1 where the modifying moiety has a structure:
34. The complex of claim 1 where the modifying moiety has a structure:
35. The complex of claim 1 where the modifying moiety has a structure:
36. The complex of claim 1 where the modifying moiety has a structure:
37. The complex of claim 1 where the modifying moiety has a structure:
38. The complex of claim 1 where the modifying moiety has a structure:
39. The complex of claim 1 where the modifying moiety has a structure:
40. The complex of claim 1 where the modifying moiety has a structure:
41. The complex of claim 1 where the modifying moiety has a structure:
42. The complex of claim 1 where the modifying moiety has a structure:
43. The complex of claim 1 where the modifying moiety has a structure:
44. The complex of claim 1 where the modifying moiety has a structure:
45. The complex of claim 1 where the modifying moiety has a structure:
46. A complex mixture comprising the complex of claim 1.
47. A solid mixture comprising the complex of claim 1.
48. A hybrid complex comprising the complex of claim 1.
49. A co-crystal comprising the complex of claim 1.
50. A composition comprising the complex of claim 1 wherein the composition is provided as a lyophilized powder.
51. The complex of claim 13 in a mixture having a pharmaceutically acceptable level of purity.
52. A composition comprising:
a first complex according to the complex of claim 1; and
a second complex selected from a group consisting of a conjugated insulin compound or unconjugated insulin compound.
53. The composition of claim 52 where the first complex and second complex is provided as a solid.
54. The composition of claim 52 where:
the second complex is provided as an amorphous solid.
55. The composition of claim 52 where the complex of where the first complex and second complex is provided as a crystalline solid.
56. The composition of claim 52 further comprising a third complex comprising:
an insulin compound conjugate comprising an insulin compound coupled to a third modifying moiety, and
a cation component, where the insulin compound conjugate is complexed with the cation.
57. The composition of claim 52 where the first complex and second complex comprise different insulin compounds.
58. The composition of claim 52 where:
the first complex and second complex comprise different insulin compound conjugates, and
one of the complexes comprises a lipophilic insulin compound conjugate and the other of the complexes comprises a hydrophilic insulin compound conjugate.
59. The composition of claim 52 where:
the first complex and second complex comprise different insulin compound conjugates, and
one of the complexes has a circulation half-life of from about 1 to about 4 hours; and
the other of the complexes has a circulation half-life that is greater than the circulation half-life of the first complex.
60. The composition of claim 52 where:
the first complex and second complex comprise different insulin compound conjugates, and
one of the complexes has a rapid-acting profile; and
the other of the complexes has a medium-to-long acting profile.
61. The composition of claim 52 where:
the first complex and second complex comprise different insulin compound conjugates, and
one of the complexes has profile suitable for basal insulin compound control; and
the other of the complexes has a profile suitable for post-prandial glucose control.
62. The composition of claim 52 where the composition is a crystal exhibiting one or more of the following characteristics: substantially homogenous dissolution, a single in vivo dissolution curve, andor a single peak pharmacodynamic profile.
63. The composition of claim 52 where the composition is a co-crystal of HIM2 and insulin compound.
64. The composition of claim 52 where the composition is a co-crystal of HIM2 and IN105.
65. The composition of claim 52 where the composition is a co-crystal of IN105 and insulin compound.
66. The composition of claim 52 where the composition is a co-crystal which has a PKPD profile suitable for post-prandial glucose control.
67. The composition of claim 52 where the composition is a co-crystal which has a PKPD profile suitable for overnight basal insulin compound control.
68. A composition comprising the complex of claim 1 in the form of a crystalline solid having irregular morphology.
69. A composition comprising the complex of claim 1 in the form of a crystalline solid having an average diameter ranging from about 0.5 to about 40 \u03bcm.
70. A composition comprising the complex of claim 1 and one or more additional pharmaceutically acceptable components.
71. The complex of claim 13 where in a dried state, the solid comprises:
greater than about 96% ww insulin compound conjugate, and
from about 0.05 to about 4% ww Zn++.
72. The complex of claim 13 where in a dried state, the solid comprises:
greater than about 91% ww insulin compound conjugate,
from about 0.3 to about 4% ww Zn++, and further comprises
from about 0.2 to about 5% ww phenol.
73. The complex of claim 13 where in a dried state, the solid comprises:
from about 0.1 to about 2% ww Zn++, and further comprises
from about 0.08 to about 1% ww phenol.
74. The complex of claim 13 where the solid is greater than about 90, 95, or 99% crystalline.
75. A pharmaceutical composition comprising the complex of claim 1 and a pharmaceutically acceptable carrier.
76. The pharmaceutical composition of claim 75 further comprising a stabilizing agent.
77. The pharmaceutical composition of claim 76 where the stabilizing agent is a phenolic compound.
78. The pharmaceutical composition of claim 76 where the stabilizing agent is selected from the group consisting of phenol, m-cresol and paraben.
79. A method of treating diabetes comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a complex of claim 1.
80. The method of claim 79 where the composition is administered orally.
81. The complex of claim 1, wherein the complex is an R-type complex, an NPH-type complex, a T-type complex, an R-type Zn complex, or T-type Zn complex.
82. The complex of claim 81, wherein the R-type Zn complex or T-type Zn complex further comprises protamine.