# US 10,864,276 B2 · Activated polyoxazolines and conjugates and compositions comprising the same

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- Number: US 10,864,276 B2
- Document ID: US10864276B2
- Status: Granted
- Kind: B2
- Application number: 16/144,358
- Filed: 2018-09-27
- Published: 2019-03-07
- Granted: 2020-12-15
- Earliest claimed: 2007-02-28
- Assignees: Serina Therapeutics, Inc.
- Applicants: Serina Therapeutics, Inc.
- Inventors: J Milton Harris; Kunsang Yoon; Michael David Bentley; Zhihao Fang; Tacey Viegas; Francesco Maria Veronese; Anna Mero
- Web page: https://patentgrep.com/patent/US10864276B2

## CPC

- A61K 47/59: obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K 31/727: Heparin; Heparan
- A61K 31/728: Hyaluronic acid
- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/1719: {Muscle proteins, e.g. myosin or actin}
- A61K 38/1816: {Erythropoietin [EPO]}
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 38/27: Growth hormone [GH], i.e. somatotropin
- A61K 38/33: derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
- A61K 38/42: Haemoglobins; Myoglobins
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/47: from mammals
- C07K 14/505: Erythropoietin [EPO]
- C07K 14/535: Granulocyte CSF; Granulocyte-macrophage CSF
- C07K 14/62: Insulins
- C08G 69/48: Polymers modified by chemical after-treatment
- C12N 9/96: Stabilising an enzyme by forming an adduct or a composition; Forming enzyme conjugates
- C12Y 302/01017: Lysozyme (3.2.1.17)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C08G: MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The present disclosure provides POZ derivatives having a range of active functional groups allowing conjugation of POZ derivatives to a variety of target molecules under a wide range of reaction conditions to produce a hydrolytically stable target molecule-POZ conjugate. Furthermore, the present disclosure provides novel methods of synthesis for the disclosed POZ derivatives and hydrolytically stable target molecule-POZ conjugates created using the disclosed terminally activated monofunctional POZ derivatives. In one embodiment, the POZ derivative is a terminally activated monofunctional POZ derivative.

## Claims

### Claim 1

A terminally activated polyoxazoline (POZ) compound of the general structure R1-POZ-Pp-Qq-Ww-Uu-X,
wherein
POZ is [N(COR7)CH2CH2]n
X is an active functional group;
P is —O—;
q is 0;
p, u and w are each 1;
U is a linking group selected from the group consisting of: —(R16)o—, —(CR5R6)o—, —NH—R21—NHCO—R22—;
W is —NH—CO;
R7 is independently selected for each repeating unit of POZ from an unsubstituted or substituted alkyl, alkenyl or aralkyl group;
R1, R5-R6 and R21-R22 are each independently selected from hydrogen, unsubstituted or substituted alkyl, alkenyl or aralkyl group;
R16 is an unsubstituted alkyl, alkenyl or aralkyl group;
n is an integer from 3 to 1000; and
o is an integer from 1 to 10.

### Claim 2 (depends on 1)

The terminally activated POZ compound of claim 1, wherein the active functional group is protected.

### Claim 3 (depends on 1)

The terminally activated POZ compound of claim 1, wherein R7 is an unsubstituted or substituted alkyl, alkenyl having from 1 to 12 carbon atoms.

### Claim 4 (depends on 1)

The terminally activated POZ compound of claim 1, wherein R7 is methyl, ethyl or n-propyl.

### Claim 5 (depends on 1)

The terminally activated POZ compound of claim 1, wherein the active functional group is selected from the group consisting of: aldehyde, active carbonate (O—CO—Z), maleimide, sulfonate ester (OSO2—R23), hydrazide, epoxide, iodoacetamide, alkyne, azide, isocyanate, cyanate isothiocyanate, thiocyanate, nitrile, a carbonyldiimidazole derivative, vinylsulfone, carboxylic acid halide, active ester (—CO—Z) and carboxylic acid, wherein any of the foregoing may be substituted or unsubstituted, Z is an activating group and R23 is an unsubstituted or substituted alkyl, alkenyl, alkynyl, aralkyl or aryl group.

### Claim 6 (depends on 5)

The terminally activated POZ compound of claim 5, wherein the sulfonate ester is tresylate or mesylate.

### Claim 7 (depends on 5)

The terminally activated POZ compound of claim 5, wherein Z is N-succinimidyloxy, chlorine, bromine, sulfo-N-succinimidyloxy, p-nitrophenoxy, 1-imidazolyl, or 1-benzotriazolyloxy.

### Claim 8 (depends on 5)

The terminally activated POZ compound of claim 5, wherein the active functional group is a substituted or unsubstituted piperazinyl or a substituted piperidinyl group.

### Claim 9 (depends on 1)

The terminally activated POZ compound of claim 1, wherein the POZ polymer has a polydispersity value of less than or equal to 1.05.

### Claim 10 (depends on 1)

The terminally activated POZ of claim 1 linked to a target molecule.

### Claim 11 (depends on 1)

The terminally activated POZ compound of claim 1, wherein the active functional group forms a linkage with a target molecule and wherein all linkages between the target molecule and the POZ compound are hydrolytically stable in a biological system.

### Claim 12

A compound having a structure:
(a) CH3—[N(COCH2CH3)CH2CH2]n—OCONH—CH2CH2—NH2; or
(b) CH3—[N(COCH2CH3)CH2CH2]n—OCONH—CH2—CHO
wherein, n is an integer from 3 to 1000.