Factor IX moiety-polymer conjugates having a releasable linkage

1. A compound having the following structure:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group;

Y 1 is O or S;

Y 2 is O or S; and

(F9) is a residue of an amine-containing Factor IX moiety.

2. The compound of claim 1 , wherein the amine-containing Factor IX moiety is recombinant Factor IX.

3. The compound of claim 2 , wherein the recombinant Factor IX is human recombinant Factor IX.

4. The compound of claim 1 , wherein the first water-soluble polymer is a poly(alkylene oxide) and the second water-soluble polymer is a poly(alkylene oxide).

5. The compound of claim 1 , wherein the first water-soluble polymer has a weight-average molecular weight of between 10,000 Daltons to 85,000 Daltons and the second water-soluble polymer has a weight-average molecular weight of between 10,000 Daltons to 85,000 Daltons.

6. The compound of claim 1 , having a structure selected from the group consisting of:

wherein, for each structure and in each instance, (n) is independently an integer from 4 to 1500, and (F9) is a residue of an amine-containing Factor IX moiety.

7. The compound of claim 1 , having the following structure:

wherein, (F9) is a residue of an amine-containing Factor IX moiety and (n), in each instance, is independently from 4 to 1500.

8. The compound of claim 1 , having the following structure:

wherein, (F9) is a residue of an amine-containing Factor IX moiety and (n), in each instance, is independently from 4 to 1500.

9. The compound of claim 7 , wherein the Factor IX moiety is human recombinant Factor IX.

10. A method comprising contacting a polymeric reagent with a Factor IX moiety comprising an amino group under conditions suitable to form a covalent attachment between the polymeric reagent and the Factor IX moiety amino group, wherein the polymeric reagent has the following structure:

wherein:

POLY 1 is a first water-soluble polymer;

POLY 2 is a second water-soluble polymer;

X 1 is a first spacer moiety;

X 2 is a second spacer moiety;

H α is an ionizable hydrogen atom;

R 1 is H or an organic radical;

R 2 is H or an organic radical;

(a) is either zero or one;

(b) is either zero or one;

R e1 , when present, is a first electron altering group;

R e2 , when present, is a second electron altering group; and

(FG) is a functional group capable of reacting with the amino group of the Factor IX moiety to form a releasable linkage.

11. The method of claim 10 , wherein the releasable linkage is a carbamate linkage.

12. The method of claim 10 , wherein the polymeric reagent has a structure selected from the group consisting of:

wherein, for each structure and in each instance, (n) is independently an integer from 4 to 1500.

13. The method of claim 12 , wherein Factor IX moiety is human recombinant Factor IX.

14. The compound of claim 8 , wherein the Factor IX moiety is human recombinant Factor IX.

15. A composition comprising a compound of any one of claims 1 though 9 or claim 14 and a pharmaceutically acceptable excipient.