US5643575A — Non-antigenic branched polymer conjugates

Claim 1

Independent Claim 84 words

A branched substantially non-antigenic polymer comprising the formula: (R).sub.n L-A wherein (R) is a water soluble, substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (A) is a functional group capable of bonding with a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules or a moiety capable of being functionalized to react with said nucleophile; and (L) is selected from the group consisting of ##STR16## wherein (α) is 1 to 5.

Claim 2

Dependent Claim 84 words

A branched substantially non-antigenic polymer comprising the formula: (R).sub.n L-A wherein (R) is a water soluble, substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (A) is a functional group capable of bonding with a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules or a moiety capable of being functionalized to react with said nucleophile; and (L) is selected from the group consisting of ##STR16## wherein (α) is 1 to 5.

Claim 3

Dependent Claim 14 words

The polymer of claim 1, wherein at least one (R) is a straight-chained polymer.

Claim 4

Dependent Claim 14 words

The polymer of claim 1, wherein at least one (R) is a poly(alkylene oxide).

Claim 5

Dependent Claim 14 words

The polymer of claim 3, wherein said poly(alkylene oxide) is an α-substituted poly(alkylene oxide).

Claim 6

Dependent Claim 30 words

The polymer of claim 3, wherein said poly(alkylene oxide) is selected from the group consisting of poly(ethylene glycol) homopolymers, alkyl-capped poly(ethylene oxides), and copolymers of block copolymers of poly(alkylene oxides).

Claim 7

Dependent Claim 19 words

The polymer of claim 5, wherein said poly(alkylene oxide) has a molecular weight between about 200 and about 20,000.

Claim 8

Dependent Claim 18 words

The polymer of claim 6, wherein said poly(alkylene oxide) has a molecular weight between 2,000 and about 10,000.

Claim 9

Dependent Claim 17 words

The polymer of claim 7, wherein said poly(ethylene glycol) homopolymer has a molecular weight of about 5,000.

Claim 10

Dependent Claim 13 words

The polymer of claim 2, wherein each (R) is a poly(ethylene glycol) homopolymer.

Claim 11

Dependent Claim 14 words

The polymer of claim 1, wherein at least one (R) is a branched polymer.

Claim 12

Dependent Claim 11 words

The activated branched polymer of claim 1, wherein (n) is two.

Claim 13

Dependent Claim 25 words

The polymer of claim 1, wherein (A) is a moiety selected from the group consisting of hydroxyl, amino, carboxyl, carbonyl, thiol and methylene hydrogen moieties.

Claim 14

Dependent Claim 16 words

The polymer of claim 1, wherein (A) is a succinimidyl or a p-nitrophenyl carbonate active ester.

Claim 15

Dependent Claim 12 words

The polymer of claim 1, wherein (A) further comprises a spacer moiety.

Claim 16

Dependent Claim 33 words

The polymer of claim 14, wherein said spacer moiety is selected from the group consisting of alkyls containing up to 18 carbon atoms, cycloalkyl groups containing up to 18 carbon atoms and polymers.

Claim 17

Dependent Claim 21 words

The polymer of claim 1, wherein at least one (R) further comprises a functional group capable of covalently bonding with nucleophiles.

Claim 18

Independent Claim 91 words

A method of forming a biologically active conjugate, comprising: contacting a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules with an activated branched non-antigenic polymer having a structure represented by: (R).sub.n L-A wherein: (R) is a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR17## wherein (α) is 1 to 5; and (A) is a functional group capable of forming a covalent bond with said biologically active nucleophile.

Claim 19

Independent Claim 91 words

A method of forming a biologically active conjugate, comprising: contacting a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules with an activated branched non-antigenic polymer having a structure represented by: (R).sub.n L-A wherein: (R) is a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR17## wherein (α) is 1 to 5; and (A) is a functional group capable of forming a covalent bond with said biologically active nucleophile.

Claim 20

Dependent Claim 88 words

A polymer conjugate comprising the formula: [(R).sub.n L-A.sup.1 ].sub.z -(nucleophile) wherein: (R) is a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR18## wherein (α) is 1 to 5; (nucleophile) is a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules; (A 1 ) represents a covalent linkage between (L) and the biologically active nucleophile; and (z) represents the number of polymers attached to the nucleophile.

Claim 21

Dependent Claim 88 words

A polymer conjugate comprising the formula: [(R).sub.n L-A.sup.1 ].sub.z -(nucleophile) wherein: (R) is a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR18## wherein (α) is 1 to 5; (nucleophile) is a biologically active nucleophile selected from the group consisting of proteins, peptides, polypeptides, enzymes and chemotherapeutic molecules; (A 1 ) represents a covalent linkage between (L) and the biologically active nucleophile; and (z) represents the number of polymers attached to the nucleophile.

Claim 22

Dependent Claim 14 words

The conjugate of claim 18, wherein at least one (R) is a poly(alkylene oxide).

Claim 23

Dependent Claim 14 words

The conjugate of claim 19, wherein said poly(alkylene oxide is an α-substituted poly(alkylene oxide).

Claim 24

Dependent Claim 30 words

The conjugate of claim 19, wherein said poly(alkylene oxide) is selected from the group consisting of poly(ethylene glycol) homopolymers, alkyl-capped poly(ethylene oxides), and copolymers of block copolymers of poly(alkylene oxides).

Claim 25

Dependent Claim 19 words

The conjugate of claim 21, wherein said poly(alkylene oxide) has a molecular weight between about 200 and about 20,000.

Claim 26

Dependent Claim 18 words

The conjugate of claim 22, wherein said poly(alkylene oxide) has a molecular weight between 2,000 and about 10,000.

Claim 27

Dependent Claim 17 words

The conjugate of claim 23, wherein said poly(ethylene glycol) homopolymer has a molecular weight of about 5,000.

Claim 28

Dependent Claim 13 words

The conjugate of claim 19, wherein each (R) is a poly(ethylene glycol) homopolymer.

Claim 29

Dependent Claim 14 words

The conjugate of claim 18, wherein at least one (R) is a branched polymer.

Claim 30

Dependent Claim 11 words

The conjugate of claim 18, wherein (L) is a non-planar moiety.

Claim 31

Dependent Claim 25 words

The conjugate of claim 18, wherein said protein is selected from the group consisting of antibodies, monoclonal antibodies, fragments of antibodies and single chain-binding antigens.

Claim 32

Dependent Claim 43 words

The conjugate of claim 18, wherein said nucleophile is a member of the group consisting of anti-neoplastics, anti-infectives, anti-anxiety agents, anti-gastrointestinal agents, central nervous system-activating agents, analgesics, fertility, contraceptive agents, anti-inflammatory agents, steroidal agents, anti-urecemic agents, cardiovascular agents, vasodilating agents and vasconstricting agents.

Claim 33

Dependent Claim 23 words

The conjugate of claim 29, wherein said antineoplastic agent is selected from the group consisting of taxol, taxanes, taxoid molecules, anthracyclines and methotrexates.

Claim 34

Dependent Claim 25 words

A method of treatment comprising administering to a mammal in need such treatment a therapeutically effective amount of the branched polymer conjugate of claim 20.

Claim 35

Independent Claim 97 words

A method of preparing a succinimidyl carbonate active ester of a branched non-antigenic polymer comprising the steps of: i) contacting a branched non-antigenic polymer having a structure represented by: (R).sub.n L-A wherein (R) independently comprises a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR19## wherein (α) is 1 to 5; and (A) is a functional group capable of forming a covalent bond with a nucleophile; with p-nitrophenyl chloroformate; and ii) reacting the p-nitrophenyl carbonate active ester of step i) with N-hydroxysuccinimide.

Claim 36

Independent Claim 97 words

A method of preparing a succinimidyl carbonate active ester of a branched non-antigenic polymer comprising the steps of: i) contacting a branched non-antigenic polymer having a structure represented by: (R).sub.n L-A wherein (R) independently comprises a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR19## wherein (α) is 1 to 5; and (A) is a functional group capable of forming a covalent bond with a nucleophile; with p-nitrophenyl chloroformate; and ii) reacting the p-nitrophenyl carbonate active ester of step i) with N-hydroxysuccinimide.

Claim 37

Dependent Claim 12 words

The method of claim 32, wherein (A) further comprises a spacer moiety.

Claim 38

Independent Claim 80 words

A method of preparing a succinimidyl carbonate active ester of a branched non-antigenic polymer comprising contacting a branched non-antigenic polymer having a structure represented by: (R).sub.n L-A wherein (R) independently comprises a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR20## wherein (α) is 1 to 5; and (A) is a functional group capable of forming a covalent bond with a nucleophile with bis-succinimidyl carbonate.

Claim 39

Independent Claim 80 words

A method of preparing a succinimidyl carbonate active ester of a branched non-antigenic polymer comprising contacting a branched non-antigenic polymer having a structure represented by: (R).sub.n L-A wherein (R) independently comprises a water-soluble substantially non-antigenic polymer containing a C 1 -C 4 terminal group; (n)=2 or 3; (L) is selected from the group consisting of: ##STR20## wherein (α) is 1 to 5; and (A) is a functional group capable of forming a covalent bond with a nucleophile with bis-succinimidyl carbonate.

Claim 40

Dependent Claim 12 words

The method of claim 34, wherein (A) further comprises a spacer moiety.

Claim 41

Dependent Claim 15 words

The polymer of claim 1, wherein said C 1 -C 4 terminal group is methoxy.

Claim 42

Dependent Claim 32 words

The polymer of claim 1 wherein (A) is selected from the group consisting of carbonyl imidazole, azlactones, cyclic imide thiones, isocyanates, isothiocyanates, primary amines, hydrazines, acyl hydrazines, carbazates, semicarbazates, thiocarbazates and phenylglyoxals.

Claim 43

Dependent Claim 55 words

The polymer of claim 1 comprising a structure selected from the group consisting of: ##STR21## wherein a is 1 to 5 and R 2 is a spacer moiety selected from the group consisting of: ##STR22## where (m) is an integer between 1 and 18 inclusive and (X) is H, OH, NH 2 , or COOH.

Claim 44

Dependent Claim 15 words

The polymer of claim 1 comprising a structure selected from the group consisting of: ##STR23##

Claim 45

Dependent Claim 30 words

The polymer of claim 1, wherein said (R) is linked to said (L) by a linkage selected from the group consisting of urethane, amide, ether, amine urea, thio and thiol.

Annuity Stage	Window Opens	Payment Deadline	Surcharge Period Until	Estimated Fee	Status
3.5 Years (Year 4)	2000-06-30	2000-12-30	2001-07-01	$2000.00	Window Closed / Lapsed
7.5 Years (Year 8)	2004-06-30	2004-12-30	2005-07-01	$3760.00	Window Closed / Lapsed
11.5 Years (Year 12)	2008-06-30	2008-12-30	2009-07-01	$7700.00	Window Closed / Lapsed

Non-antigenic branched polymer conjugates

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