GLP-1 compositions and uses thereof

Information

  • Patent Grant
  • 11752198
  • Patent Number
    11,752,198
  • Date Filed
    Tuesday, December 8, 2020
    3 years ago
  • Date Issued
    Tuesday, September 12, 2023
    9 months ago
Abstract
The present invention relates to pharmaceutical compositions of the GLP-1 peptide semaglutide comprising no more than 0.01% (w/w) phenol, their preparation, kits comprising such compositions as well as uses thereof.
Description

The present invention relates to the field of pharmaceutical compositions comprising the GLP-1 peptide semaglutide.


BACKGROUND

GLP-1 peptides are known to be prone to develop lack of stability in liquid solutions, for example lack of physical stability. Thus, liquid pharmaceutical compositions comprising GLP-1 peptides with even better stability are desired. Such improved stability may be physical stability and/or chemical stability.


SUMMARY

In some embodiments the invention relates to liquid pharmaceutical compositions comprising semaglutide and no more than 0.01% (w/w) phenol. In some embodiments the invention relates to kits comprising the pharmaceutical composition as defined herein. In some embodiments the invention relates to the pharmaceutical composition as defined herein for use in medicine.


DESCRIPTION

The present invention relates to liquid pharmaceutical compositions comprising the GLP-1 peptide semaglutide and no more than 0.01% (w/w) phenol. Surprisingly, the present inventors found that such compositions have improved chemical and/or physical stability. In some embodiments the composition comprises no phenol. In some embodiments the composition comprises 0.01-10 mg/ml semaglutide. In some embodiments the composition has a pH in the range of 6.0-10.0, such as pH 7.0-7.8.


In some embodiments the composition of the invention is a liquid pharmaceutical composition comprising semaglutide and no more than 0.01% (w/w) phenol, wherein said composition

    • a. is for parenteral administration;
    • b. is an aqueous solution comprising at least 60% w/w water; or
    • c. further comprises one or more pharmaceutically acceptable excipients selected from the group consisting of a buffer or an isotonic agent.


In some embodiments the composition of the invention is a liquid pharmaceutical composition comprising semaglutide, no more than 0.01% (w/w) phenol, and optionally one or more pharmaceutically acceptable excipients, wherein the formulation is for parenteral administration, such as subcutaneous administration.


In some embodiments the composition of the invention is a liquid pharmaceutical composition comprising semaglutide, no more than 0.01% (w/w) phenol, at least 60% w/w water, and optionally one or more pharmaceutically acceptable excipients.


In some embodiments the term “stability” as used herein refers to stability of semaglutide in a liquid pharmaceutical composition. In some embodiments stability is chemical stability of the GLP-1 peptide (e.g. determined by HPLC, such as Assay (I) herein), and optionally physical stability of the GLP-1 peptide (e.g. determined by Thioflavine T assay, such as Assay (II) herein).


In some embodiments the term “chemical stability” in relation to semaglutide as used herein refers to the covalent bonds of the semaglutide compound being substantially intact. In some embodiments chemical stability of a GLP-1 peptide is determined by HPLC, such as Assay (I) herein. In some embodiments a composition possess chemical stability if its covalent bonds are intact in at least 80% (w/v) of said GLP-1 peptides after storage for 3 months at 25° C. In some embodiments chemical stability of semaglutide is determined by Assay (IV) herein.


In some embodiments the term “physical stability” in relation to semaglutide as used herein refers to semaglutide forming substantially no aggregates, e.g. in the form of fibril formation. In some embodiments physical stability is determined by Thioflavine T assay, such as Assay (II) herein.


In some embodiments the composition of the present invention is a stable pharmaceutical composition. The term “stable pharmaceutical composition” when used herein refers to a pharmaceutical composition, e.g. a solution or suspension, comprising GLP-1 peptide, and which composition following storage comprises at least 80% (w/v) of said GLP-1 peptide (e.g. after quiescent storage for 3 months at 25° C.). Storage conditions for stability testing may be 2-8° C., such as 5° C., or at least 2.5 years at 5° C. Alternatively, storage conditions for stability testing may be at least 4 weeks, such as 6 weeks or 3 months, optionally at 30° C. The conditions of storage for this stable pharmaceutical composition may be at 5° C. for 1 or 2 years. The conditions of storage for this stable pharmaceutical composition may be at 5° C. for 3 years. Alternatively, the conditions of this storage may be at 25° C. for 24 hours or 1 week. In yet another alternative, the conditions of this storage may be room temperature for two months, such as up to two months.


In some embodiments, chemical stability of the GLP-1 peptide requires at least 80% (w/v), such as at least 90% (w/v) or at least 95% (w/v), of said GLP-1 peptide remaining with its covalent bonds intact at the end of the storage period. In some embodiments chemical stability of the GLP-1 peptide requires at least 95% (w/v), such as at least 97% (w/v) or at least 99% (w/v), of said GLP-1 peptide remaining with its covalent bonds intact at the end of the storage period.


The composition of the invention comprises no more than 0.01% (w/w) phenol. In some embodiments the composition comprises substantially no phenol.


Pharmaceutical Compositions


The terms “pharmaceutical composition” and “composition” are used interchangeably herein and refer to pharmaceutical compositions suitable for administration to a subject in need thereof.


In some embodiments the composition comprises 0.01-100 mg/ml semaglutide. In some embodiments the composition comprises 0.1-50 mg/ml, such as 0.5-25 mg/ml or 1-15 mg/ml, semaglutide. In some embodiments the composition comprises 0.1-10 mg/ml, such as 0.5-5 mg/ml or 1-2 mg/ml, semaglutide. In some embodiments the composition comprises 0.01-10 mg/ml, such as 0.01-5 mg/ml, semaglutide. In some embodiments the composition comprises no more than 9 mg/ml, such as no more than 8 mg/ml or no more than 7 mg/ml, semaglutide. In some embodiments the composition comprises no more than 6 mg/ml, such as no more than 5 mg/ml or no more than 4 mg/ml, semaglutide. In some embodiments the composition comprises no more than 3 mg/ml, such as no more than 2 mg/ml or no more than 1 mg/ml, semaglutide. In some embodiments the composition comprises at least 0.01 mg/ml, such as at least 0.02 mg/ml or at least 0.05 mg/ml, semaglutide. In some embodiments the composition comprises 1.34 mg/ml semaglutide.


In some embodiments the composition of the invention has a pH in the range of 3-10, such as pH 6-10 or 6-9. In some embodiments the composition of the invention has a pH in the range of pH 6.5-8.5, such as pH 7.0-7.8.


In some embodiments the composition of the invention comprises one or more pharmaceutically acceptable excipients.


In some embodiments the composition of the invention comprises an isotonic agent, such as propylene glycol. In some embodiments the isotonic agent is propylene glycol or sodium chloride.


In some embodiments the composition of the invention comprises a buffer, such as phosphate buffer, TRIS, citrate, or no buffer. In some embodiments the phosphate buffer is a sodium phosphate buffer, such as disodium hydrogen phosphate.


In some embodiments the composition of the invention comprises no preservative.


The composition of the invention is in the form of a liquid pharmaceutical composition. In some embodiments the liquid pharmaceutical composition is a solution or a suspension. In some embodiments the composition of the invention is in the form of a solution, such as an aqueous solution. In some embodiments the term “aqueous solution” as used herein refers to a solution comprising at least 60% w/w water. In some embodiments the aqueous solution comprises 60-99% w/w water. In some embodiments the aqueous solution comprises at least 75% w/w water, such as at least 80% w/w water or at least 85% w/w water. In some embodiments the aqueous solution comprises at least 90% w/w water, such as at least 92% w/w water or at least 94% w/w water.


Semaglutide


The GLP-1 peptide semaglutide may be prepared as described in WO2006/097537, Example 4. Semaglutide is also known as N6.26-{18-[N-(17-carboxyheptadecanoyl)-L-γ-glutamyl]-10-oxo-3,6,12,15-tetraoxa-9,18-diazaoctadecanoyl}-[8-(2-amino-2-propanoic acid),34-L-arginine]human glucagon-like peptide 1(7-37), see WHO Drug Information Vol. 24, No. 1, 2010. In some embodiments semaglutide may be present in the composition in its fully or partly ionised form; for example one or more carboxylic acid groups (—COOH) may be deprotonated into the carboxylate group (—COO) and/or one or more amino groups (—NH2) may be protonated into the —NH3+ group. In some embodiments semaglutide is added to the composition in the form of a salt.


Administration and Kits


The composition of the invention is for parenteral administration. In some embodiments the composition is for subcutaneous administration.


In some embodiments the composition of the invention is for administration once weekly. In some embodiments the composition of the invention is for administration once daily, once every second or once every third day.


In some embodiments the invention relates to a kit comprising the pharmaceutical composition as defined herein and instructions for use. In some embodiments the instructions for use comprise the package insert of a drug.


In some embodiments the invention relates to a kit comprising the pharmaceutical composition as defined herein and an injection device. In some embodiments the injection device is selected from the group consisting of a durable pen and a prefilled pen. Examples of durable pens are NovoPen® 4 or NovoPen® 5 (both from Novo Nordisk A/S, Denmark). An example of a prefilled pen is FlexPen® (Novo Nordisk A/S, Denmark).


Indications


In some embodiments the compositions of the invention are for use in medicine. In some embodiments the composition of the invention may be used for the following medical treatments:

    • (i) prevention and/or treatment of all forms of diabetes, such as hyperglycaemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin dependent diabetes, MODY (maturity onset diabetes of the young), gestational diabetes, and/or for reduction of HbA1c;
    • (ii) delaying or preventing diabetic disease progression, such as progression in type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin requiring type 2 diabetes, and/or delaying the progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes;
    • (iii) prevention and/or treatment of eating disorders, such as obesity, e.g. by decreasing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa, and/or obesity induced by administration of an antipsychotic or a steroid; reduction of gastric motility; and/or delaying gastric emptying.


In some embodiments the indication is (i). In some embodiments the indication is (ii). In a still further particular aspect the indication is (iii). In some embodiments the indication is type 2 diabetes and/or obesity.


In some embodiments the method or use comprises prevention, treatment, reduction and/or induction in one or more diseases or conditions defined herein. In some embodiments the indication is (i) and (iii). In some embodiments the indication is (ii) and (iii). In some embodiments the invention comprises administration of an effective amount of a GLP-1 peptide. In some embodiments the invention relates to administration of an effective amount of a GLP-1 peptide.


Generally, all subjects suffering from obesity are also considered to be suffering from overweight. In some embodiments the invention relates to a method for treatment or prevention of obesity. In some embodiments the invention relates to use of the composition for treatment or prevention of obesity. In some embodiments the subject suffering from obesity is human, such as an adult human or a paediatric human (including infants, children, and adolescents). Body mass index (BMI) is a measure of body fat based on height and weight. The formula for calculation is BMI=weight in kilograms/height in meters2. A human subject suffering from obesity may have a BMI of ≥30; this subject may also be referred to as obese. In some embodiments the human subject suffering from obesity may have a BMI of ≥35 or a BMI in the range of ≥30 to <40. In some embodiments the obesity is severe obesity or morbid obesity, wherein the human subject may have a BMI of ≥40.


In some embodiments the invention relates to a method for treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity. In some embodiments the invention relates to use of the composition for treatment or prevention of overweight, optionally in the presence of at least one weight-related comorbidity. In some embodiments the subject suffering from overweight is human, such as an adult human or a paediatric human (including infants, children, and adolescents). In some embodiments a human subject suffering from overweight may have a BMI of ≥25, such as a BMI of ≥27. In some embodiments a human subject suffering from overweight has a BMI in the range of 25 to <30 or in the range of 27 to <30. In some embodiments the weight-related comorbidity is selected from the group consisting of hypertension, diabetes (such as type 2 diabetes), dyslipidaemia, high cholesterol, and obstructive sleep apnoea.


In some embodiments the invention relates to a method for reduction of body weight. In some embodiments the invention relates to use of the composition for reduction of body weight. A human to be subjected to reduction of body weight according to the present invention may have a BMI of such as a BMI of ≥27 or a BMI of ≥30. In some embodiments the human to be subjected to reduction of body weight according to the present invention may have a BMI of ≥35 or a BMI of ≥40. The term “reduction of body weight” may include treatment or prevention of obesity and/or overweight.


In some embodiments, as used herein, specific values given in relation to numbers or intervals may be understood as the specific value or as about the specific value (e.g. plus or minus 10 percent of the specific value).


Embodiments of the Invention


The following are non-limiting embodiments of the invention:

    • 1. A liquid pharmaceutical composition comprising semaglutide and no more than 0.01% (w/w) phenol.
    • 2. A liquid pharmaceutical composition comprising semaglutide and substantially no phenol.
    • 3. The composition according to claim 1 or 2, wherein said composition does not comprise phenol.
    • 4. The composition according to any one of the preceding claims, wherein said composition is an aqueous solution comprising at least 60% w/w water, such as at least 70% w/w water or at least 80% w/w water.
    • 5. The composition according to any one of the preceding claims, wherein the concentration of semaglutide is 0.5-10 mg/ml of said composition.
    • 6. The composition according to any one of the preceding claims, wherein said semaglutide is in the form of a pharmaceutically acceptable salt.
    • 7. The composition according to any one of the preceding claims, wherein said composition comprises one or more pharmaceutically acceptable excipients.
    • 8. The composition according to any one of the preceding claims, wherein said composition comprises one or more agents for adjusting pH, such as HCl, NaOH, or acetate.
    • 9. The composition according to any one of the preceding claims, wherein said composition comprises a buffer and/or an isotonic agent.
    • 10. The composition according to any one of the preceding claims, wherein said buffer is present in a concentration of 0.01-50 mM of said composition.
    • 11. The composition according to any one of the preceding claims, wherein said buffer is a phosphate buffer.
    • 12. The composition according to any one of the preceding claims, wherein said phosphate buffer is selected from the group consisting of sodium dihydrogen phosphate, disodium hydrogen phosphate, and sodium phosphate.
    • 13. The composition according to any one of the preceding claims, wherein said isotonic agent is present in a concentration from 8 mg/ml to 50 mg/ml, such as 14 mg/ml to 30 mg/ml, of said composition.
    • 14. The composition according to any one of the preceding claims, wherein said isotonic is propylene glycol.
    • 15. The composition according to any one of the preceding claims, wherein said composition comprises no preservative.
    • 16. The composition according to any one of the preceding claims, wherein said composition has a pH in the range of 6.0-10.0.
    • 17. The composition according to any one of the preceding claims, wherein said composition is for parenteral administration.
    • 18. The composition according to any one of the preceding claims, wherein said composition is for subcutaneous administration.
    • 19. A kit comprising the pharmaceutical composition as defined in any one of the preceding claims and instructions for use.
    • 20. A kit comprising the pharmaceutical composition as defined in any one of the preceding claims and an injection device for administration of said composition to a subject, wherein said injection device is selected from the group consisting of a durable pen and a prefilled pen.
    • 21. A pharmaceutical composition as defined in any one of the preceding claims for use in medicine.
    • 22. The pharmaceutical composition for use as defined in any one of the preceding claims for use in the treatment of diabetes or obesity.
    • 23. A method for the prevention or treatment of diabetes or obesity, wherein the pharmaceutical composition as defined in any one of the preceding claims is administered to a subject in need thereof.







EXAMPLES

General Methods and Characterisation


Preparation of Semaglutide Compositions:


Unless otherwise noted, compositions of semaglutide were prepared by dissolving buffer (e.g. disodiumhydrogenphosphate dihydrate), isotonic agent (e.g. propylene glycol) and optionally preservative (phenol) in water. Semaglutide was dissolved therein, pH was adjusted to 7.4 using sodium hydroxide and/or hydrochloric acid, and the composition was finally sterilised by filtration through a 0.22 μm sterile filter.


Preparation of Liraglutide Compositions:


Unless otherwise noted, compositions of liraglutide were prepared from Solution 1 and Solution 2: Solution 1 was prepared by dissolving buffer (disodiumhydrogenphosphate dihydrate), isotonic agent (mannitol), and optionally preservative (phenol) in water. Solution 2 was prepared by dissolving liraglutide while stirring slowly. Solution 1 and Solution 2 were mixed, pH was adjusted to 8.15 using sodium hydroxide and/or hydrochloric acid, and the composition was finally sterilised by filtration through a 0.22 μm sterile filter.


Assay (I): Determination of High Molecular Weight Proteins (HMWP) Content of Semaglutide Compositions


Determination of HMWP content was performed using size exclusion chromatography (SE-HPLC) using a Waters Insulin HMWP column with a mobile phase of sodium chloride, sodium phosphate, phosphoric acid and isopropanol, isocratic elution and detection at 280 nm. Content of HMWP is given in % as the combined area of chromatographic peaks eluting earlier than the semaglutide monomer peak (i.e. HMWP peaks), relative to the total area of HMWP and semaglutide monomer peaks.


Assay (II): Physical Stability of Semaglutide Compositions Assessed Via ThT


The purpose of this assay is to assess the physical stability of a GLP-1 peptide in aqueous solution.


Low physical stability of a peptide or protein may lead to amyloid fibril formation. Fibrils are structurally well-ordered, filamentous macromolecular structures formed by aggregation of soluble proteins and dominated by beta-sheet structure. Mature fibrils are insoluble and are resistant to degradation. For the sake of drug product quality and patient safety, it is desirable to minimize and control fibrillation events in pharmaceutical compositions of therapeutic peptides and proteins. Protein aggregation, including fibrillation, can be assessed by visual inspection of a sample. Fibrillation can be assessed by the use of Thioflavine T (ThT), a small molecule indicator probe with a high specificity for fibrils. ThT has a distinct fluorescence signature when binding to fibrils compared to ThT in solution [Naiki et al. (1989) Anal. Biochem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284].


Formation of a partially folded intermediate of the peptide is suggested as a general initiating mechanism for fibrillation. A small amount of these intermediates nucleates to form a template onto which further intermediates may assembly and the fibrillation proceeds. The lag-time corresponds to the interval in which a critical amount of nuclei is generated and the apparent rate constant is the rate with which the fibril itself is formed. The lag-time described in a ThT assay performed on a plate reader is therefore considered indicative of the fibrillation tendency of a peptide composition in solution.


Before performing the assay, ThT was added to the samples from a stock solution in H2O to a final concentration of 20 μM in samples. Sample aliquots of 200 μl of the composition comprising the GLP-1 peptide were placed in a 96 well microtiter plate (optical 0.4 mL black Thermo Scientific Nunc) with a glass bead (2.8-3.2 mm, Whitehouse Scientific) placed in each well. Usually, eight replica of each sample were placed on the plate. The plate was sealed with sealing tape (Thermo Scientific Nunc).


Incubation at given temperature, shaking and measurement of the ThT fluorescence emission were performed in a BMG FLUOStar Omega or a BMG FLUOStar Optima. The plate was incubated at 40° C. with double orbital shaking at 300 rpm with an amplitude of 2 mm. Fluorescence measurement was performed using excitation through a 450 nm filter and measurement of emission through a 480 nm filter. The plate was measured every 20 minutes for a desired period of time. Between each measurement, the plate was shaken and heated as described.


The threshold value was determined as the highest ThT fluorescence (in relative fluorescence units (RFU)) measured on the plate at time 1 h 13 min, plus 100 RFU. The threshold value was then used to calculate the lag time using the “time to threshold” method in the BMG FLUOstar software.


Assay (III): Determination of Purity of Liraglutide


Determination of purity was performed using high performance liquid chromatography (HPLC) using a Waters XTerra™ MS C18 column with a gradient elution of two mobile phases, where one mobile phase was an aqueous ammonium phosphate buffer (pH 8)/acetonitrile mixture and the other mobile phase was acetonitrile in water. Detection was performed at 215 nm.


Assay (IV): Determination of Sum of Impurities of Semaglutide


Determination of purity of semaglutide is performed using reversed phase high performance liquid chromatography (RP-HPLC) using a Kinetex C18 column with an isocratic elution followed by a gradient elution of two mobile phases, where one mobile phase was an aqueous phosphate buffer/acetonitrile mixture and the other mobile phase was an aqueous acetonitrile/isopropanol mixture. Detection was performed at 210 nm. Purity of semaglutide is given as sum of impurities in % as the combined area of all chromatographic peaks relative to semaglutide monomer peaks.


Example 1
Semaglutide

Compositions comprising semaglutide were tested in this experiment. The tested compositions contained semaglutide (as specified in Table 1), propylene glycol (14 mg/ml), disodiumhydrogenphosphate dihydrate (1.42 mg/ml), and optionally phenol (5.5 mg/ml) (as specified in Table 1), at pH 7.4 in an aqueous solution. These compositions were prepared as described herein in the section General Methods of Preparation. Chemical stability as expressed by HMWP was determined by Assay (I) described herein at start of the experiment and after storage at 25° C., 30° C. or at 37° C. Physical stability as expressed by Thioflavin T (ThT) assay was determined by Assay (II) described herein.


The results are given in Tables 2 and 3. Surprisingly, these results show that physical and chemical stability of semaglutide were improved in compositions without phenol relative to those with phenol. Results shown in Table 3 are an average of 8 samples tested.









TABLE 1







Compositions tested in Example 1








Composition no.
Description











1
Semaglutide 1 mg/ml, with phenol


2
Semaglutide 1 mg/ml, without phenol


3
Semaglutide 1.34 mg/ml, with phenol


4
Semaglutide 1.34 mg/ml, without phenol


5
Semaglutide 0.5 mg/ml, without phenol


6
Semaglutide 0.5 mg/ml, with phenol


7
Semaglutide 1.0 mg/ml, without phenol


8
Semaglutide 1.0 mg/ml, with phenol


9
Semaglutide 2.0 mg/ml, without phenol


10
Semaglutide 2.0 mg/ml, with phenol
















TABLE 2







Chemical stability of semaglutide compositions, as expressed


by content of high molecular weight proteins (HMWP), following


storage at different temperatures. A lower HMWP concentration


corresponds to a better chemical stability.









HMWP (%)











Composition

25° C.
30° C.
37° C.


no.
0 months
6 months
3 months
3 months














1
0.1
2.0
1.9
4.1


2 (no phenol)
0.1
0.3
0.3
0.5


3
0.1
1.9
1.8
3.9


4 (no phenol)
0.1
0.3
0.4
0.6
















TABLE 3







Physical stability of semaglutide compositions as


expressed by Thioflavin T (ThT) assay. A longer lag


time corresponds to a better physical stability.










Composition no.
Lag time (hours)














5 (no phenol)
>117



6
19



7 (no phenol)
>117



8
35



9 (no phenol)
>117



10 
35










Example 2 (Reference)
Liraglutide

The results of Example 1 are also surprising in view of the fact that the GLP-1 compound liraglutide—contrary to semaglutide—is less chemically stable in a composition without phenol. These results are shown in Table 5.


The results in Table 5 were obtained as follows: Compositions comprising liraglutide were tested. The tested compositions contained liraglutide (as specified in Table 4), mannitol (36.9 mg/ml), disodium hydrogen phosphate (1.42 mg/ml), and optionally phenol (as specified in Table 4), at pH 7.4 in an aqueous solution. These compositions were prepared as described herein in the section General Methods of Preparation. Chemical stability as expressed by purity was determined by Assay (Ill) described herein at start of the experiment and after storage at 25° C. or at 37° C.









TABLE 4







Compositions tested in Example 2








Composition no.
Description





11
Liraglutide (3 mg/ml), without phenol (pH 7.4)


12
Liraglutide (3 mg/ml), phenol (0.04 mg/ml) (pH 7.4)


13
Liraglutide (3 mg/ml), phenol (0.16 mg/ml) (pH 7.4)


14
Liraglutide (3 mg/ml), phenol (0.8 mg/ml) (pH 7.4)


15
Liraglutide (3 mg/ml), phenol (2.5 mg/ml) (pH 7.4)
















TABLE 5







Chemical stability, as expressed by purity, of compositions comprising


liraglutide following storage at different temperatures. A higher


purity corresponds to a better chemical stability.








Composition
Purity (%)










no.
0 months
3 months at 25° C.
3 months at 37° C.













11 (no phenol)
98
88
72


12
98
93
80


13
98
94
81


14
97
95
83


15
98
95
84









Example 3
Semaglutide—Additional Experiments

Compositions comprising semaglutide were tested in this experiment. The tested compositions contained semaglutide, isotonic agent (propylene glycol (14 mg/ml) or sodium chloride (6.3 mg/ml)), optionally buffer (disodiumhydrogenphosphate dihydrate (1.42 mg/ml) or trisodiumcitrate dihydrate (2.35 mg/ml)), and optionally phenol (5.5 mg/ml or 0.1 mg/ml), at pH 7.0, 7.4 or 7.8 in an aqueous solution; details of each composition tested is shown in Table 6. The compositions were prepared as described herein in the section General Methods of Preparation. Chemical stability as expressed by HMWP was determined by Assay (I) and as expressed by sum of impurities was determined by Assay (IV) described herein at start of the experiment and after storage at 30° C. Physical stability as expressed by Thioflavin T (ThT) assay was determined by Assay (II) described herein.


The results are given in Table 7 and 8. In line with the results of Example 1, these results show that physical stability and chemical stability of semaglutide were improved in compositions without or with low phenol concentration relative to those with phenol at 5.5 mg/ml. The results show that physical stability and chemical stability of semaglutide were also improved in compositions without phenol comprising either the buffer trisodiumcitrate dihydrate or no buffer or isotonic agent sodium chloride, relative to those with phenol. Chemical and physical stability were improved for compositions with 0.1 mg/ml phenol relative to compositions with 5.5 mg/ml phenol and similar to compositions with no phenol. This was demonstrated for compositions with pH 7.0-7.8 and semaglutide concentration 0.1-10 mg/ml.









TABLE 6







Compositions tested in Example 3









Content of composition












Comp.
Semaglutide
Phenol

Isotonic



No.
(mg/ml)
(mg/ml)
Buffer
agent
pH















1
0.5
0
Phos*
PG**
7.0


2
0.5
0.1
Phos
PG
7.0


3
0.5
5.5
Phos
PG
7.0


4
0.5
0
Phos
PG
7.4


5
0.5
0.1
Phos
PG
7.4


6
0.5
5.5
Phos
PG
7.4


7
0.5
0
Phos
PG
7.8


8
0.5
0.1
Phos
PG
7.8


9
0.5
5.5
Phos
PG
7.8


10
10
0
Phos
PG
7.0


11
10
0.1
Phos
PG
7.0


12
10
5.5
Phos
PG
7.0


13
10
0
Phos
PG
7.4


14
10
0.1
Phos
PG
7.4


15
10
5.5
Phos
PG
7.4


16
10
0
Phos
PG
7.8


17
10
0.1
Phos
PG
7.8


18
10
5.5
Phos
PG
7.8


19
0.1
0
Phos
PG
7.4


20
0.1
5.5
Phos
PG
7.4


21
0.5
0
Phos
Citrate***
7.4


22
0.5
5.5
Phos
Citrate
7.4


23
0.5
0
Phos
None#
7.4


24
0.5
5.5
Phos
None
7.4


25
0.5
0
NaCl##
PG
7.4


26
0.5
5.5
NaCl
PG
7.4





*Phos: Disodiumhydrogenphosphate dihydrate, 1.42 mg/ml.


**PG: Propylene glycol, 14 mg/ml.


***Citrate: Trisodiumcitrate dihydrate, 2.35 mg/ml.



#None: No pharmaceutical excipeints added in the form of a buffer.




##NaCl: Sodium chloride, 6.3 mg/ml.














TABLE 7







Chemical stability of semaglutide compositions, as expressed by content


of high molecular weight proteins (HMWP) and sum of impurities, following


storage at 30° C. temperature. A lower HMWP concentration and sum


of impurities concentration corresponds to a better chemical stability.









Chemical Stability










HMWP (%)
Sum of impurities (%)













Composition
DS
Phenol

30° C.

30° C.


No.
(mg/ml)
(mg/ml)
0 months
3 months
0 months
3 months
















 1 (pH 7.0)
0.5
0
0.1
0.3
3.1
7.0


 2 (pH 7.0)
0.5
0.1
0.1
0.3
3.2
7.2


 3 (pH 7.0)
0.5
5.5
0.1
1.4
3.2
7.8


 4 (pH 7.4)
0.5
0
0.1
0.3
3.1
6.7


 5 (pH 7.4)
0.5
0.1
0.1
0.3
3.2
6.6


 6 (pH 7.4)
0.5
5.5
0.1
2.4
3.2
8.4


 7 (pH 7.8)
0.5
0
0.1
0.2
3.1
6.5


 8 (pH 7.8)
0.5
0.1
0.1
0.3
3.2
6.6


 9 (pH 7.8)
0.5
5.5
0.1
4.8
3.1
10.6


10 (pH 7.0)
10
0
0.1
1.4
3.1
8.4


11 (pH 7.0)
10
0.1
0.1
0.7
3.1
7.7


12 (pH 7.0)
10
5.5
0.1
N/A1
3.0
N/A1


13 (pH 7.4)
10
0
0.1
0.9
3.1
7.8


14 (pH 7.4)
10
0.1
0.1
0.7
3.1
6.9


15 (pH 7.4)
10
5.5
0.1
0.8
3.0
6.9


16 (pH 7.8)
10
0
0.1
0.9
3.0
6.6


17 (pH 7.8)
10
0.1
0.1
0.6
3.1
6.8


18 (pH 7.8)
10
5.5
0.1
1.0
3.1
6.9


19 (low DS)
0.1
0
0.1
0.2
3.5
7.7


20 (low DS)
0.1
5.5
0.1
4.7
3.7
11.4


21 (citrate)
0.5
0
0.1
0.2
3.1
6.2


22 (citrate)
0.5
5.5
0.1
2.2
3.2
7.7


23 (no buffer)
0.5
0
0.1
0.2
3.2
6.9


24 (no buffer)
0.5
5.5
0.1
2.3
3.2
9.3


25 (NaCl)
0.5
0
0.1
0.3
3.1
6.4


26 (NaCl)
0.5
5.5
0.1
3.4
3.2
8.9





DS: Semaglutide.



1Not physically stable >1 month at 30° C.














TABLE 8







Physical stability of semaglutide compositions as


expressed by Thioflavin T (ThT) assay. A longer lag


time corresponds to a better physical stability.












Composition
Semaglutide
Phenol
Lag time



No.
(mg/ml)
(mg/ml)
(hours)















1
(pH 7.0)
0.5
0
42


2
(pH 7.0)
0.5
0.1
63


3
(pH 7.0)
0.5
5.5
5


4
(pH 7.4)
0.5
0
>117


5
(pH 7.4)
0.5
0.1
>117


6
(pH 7.4)
0.5
5.5
87


7
(pH 7.8)
0.5
0
>117


8
(pH 7.8)
0.5
0.1
>117


9
(pH 7.8)
0.5
5.5
>117


10
(pH 7.0)
10
0
117


11
(pH 7.0)
10
0.1
>117


12
(pH 7.0)
10
5.5
25


13
(pH 7.4)
10
0
>117


14
(pH 7.4)
10
0.1
>117


15
(pH 7.4)
10
5.5
>117


16
(pH 7.8)
10
0
>117


17
(pH 7.8)
10
0.1
>117


18
(pH 7.8)
10
5.5
>117


19
(low DS)
0.1
0
>117


20
(low DS)
0.1
5.5
>117


21
(citrate)
0.5
0
>117


22
(citrate)
0.5
5.5
>117


23
(no buffer)
0.5
0
>117


24
(no buffer)
0.5
5.5
4


25
(NaCl)
0.5
0
>117


26
(NaCl)
0.5
5.5
8










Results are an average of 8 samples tested. DS: Semaglutide.


While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention.

Claims
  • 1. A liquid pharmaceutical composition comprising: semaglutide;wherein said composition does not contain phenol;is for parenteral administration;is an aqueous solution comprising at least 60% (w/w) water; orfurther comprises one or more pharmaceutically acceptable excipients selected from the group consisting of a buffer or an isotonic agent; andwherein the semaglutide is in the range of 0.01 mg/ml-10.0 mg/ml; andwherein the pH of the composition is in between 7.0 and 7.8;wherein the liquid pharmaceutical composition exhibits improved chemical and/or physical stability as compared to a liquid pharmaceutical composition that contains phenol.
  • 2. The liquid pharmaceutical composition according to claim 1, wherein the concentration of semaglutide is selected from 0.5-10 mg/ml or 0.01-5 mg/ml of said composition.
  • 3. The liquid pharmaceutical composition according to claim 1, wherein said composition comprises no added pharmaceutical preservative.
  • 4. The liquid pharmaceutical composition according to claim 1, wherein said parenteral administration is subcutaneous administration.
  • 5. A kit comprising the liquid pharmaceutical composition according to claim 1 and instructions for use.
  • 6. A kit comprising the liquid pharmaceutical composition according to claim 1 and an injection device for administration of said composition to a subject, wherein said injection device is selected from the group consisting of a durable pen and a prefilled pen.
  • 7. A method of treating diabetes comprising administering to a subject in need of such method a therapeutically effective amount of the pharmaceutical composition according to claim 1.
  • 8. A method of treating obesity comprising administering to a subject in need of such method a therapeutically effective amount of the pharmaceutical composition according to claim 1.
  • 9. The liquid pharmaceutical composition according to claim 1, wherein said composition has a pH in the range of 7.0-7.4.
Priority Claims (1)
Number Date Country Kind
17187676 Aug 2017 EP regional
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 16/774,666, filed Jan. 28, 2020, which is a continuation of International Application PCT/EP2018/072835 (WO/2019/038412), filed Aug. 24, 2018, which claims priority to European Patent Application 17187676.6, filed Aug. 24, 2017; the contents of which are incorporated herein by reference.

US Referenced Citations (290)
Number Name Date Kind
2444570 Lawrence et al. Aug 1946 A
2828742 Ashkenaz Apr 1958 A
3318289 Marynissen May 1967 A
3758683 Jackson Sep 1973 A
4282316 Modrovich Aug 1981 A
4425346 Horlington Jan 1984 A
4468346 Paul et al. Aug 1984 A
4470317 Sabloewski et al. Sep 1984 A
4483849 Carter et al. Nov 1984 A
4498904 Turner et al. Feb 1985 A
4568335 Updike et al. Feb 1986 A
4585439 Michel Apr 1986 A
4592745 Rex et al. Jun 1986 A
4629455 Kanno Dec 1986 A
4833379 Kaibel et al. May 1989 A
4865591 Sams Sep 1989 A
4883472 Michel Nov 1989 A
4917685 Viswanathan et al. Apr 1990 A
4919596 Slate et al. Apr 1990 A
4936833 Sams Jun 1990 A
4973318 Holm et al. Nov 1990 A
4994033 Shockey et al. Feb 1991 A
5017190 Simon et al. May 1991 A
5092842 Bechtold et al. Mar 1992 A
5112317 Michel May 1992 A
5114406 Gabriel et al. May 1992 A
5118666 Habener Jun 1992 A
5120712 Habener Jun 1992 A
5169759 Faust et al. Dec 1992 A
5169771 Christner et al. Dec 1992 A
5206216 Yoshida Apr 1993 A
5206219 Desai Apr 1993 A
5207752 Sorenson et al. May 1993 A
5216011 Paborji et al. Jun 1993 A
5216437 Yamamoto et al. Jun 1993 A
5226895 Harris Jul 1993 A
5232459 Hjertman Aug 1993 A
5232706 Palomo Coll Aug 1993 A
5246417 Haak et al. Sep 1993 A
5257987 Athayde et al. Nov 1993 A
5271527 Haber et al. Dec 1993 A
5272135 Takruri Dec 1993 A
5279585 Balkwill Jan 1994 A
5279586 Balkwill Jan 1994 A
5281198 Haber et al. Jan 1994 A
5284480 Porter et al. Feb 1994 A
5304152 Sams Apr 1994 A
5308340 Harris May 1994 A
5314412 Rex May 1994 A
5318540 Athayde et al. Jun 1994 A
5320609 Haber et al. Jun 1994 A
5331954 Rex et al. Jul 1994 A
5370629 Michel et al. Dec 1994 A
5378233 Haber et al. Jan 1995 A
5380297 Wadman et al. Jan 1995 A
5383166 Gallay Jan 1995 A
5383865 Michel Jan 1995 A
5440976 Giuliano et al. Aug 1995 A
5445606 Haak et al. Aug 1995 A
5447150 Bacon Sep 1995 A
5455331 Pearce Oct 1995 A
5461031 De Felippis Oct 1995 A
5478316 Bitdinger et al. Dec 1995 A
5478324 Meyer Dec 1995 A
5480387 Gabriel et al. Jan 1996 A
5492534 Athayde et al. Feb 1996 A
5505704 Pawelka et al. Apr 1996 A
5512549 Chen et al. Apr 1996 A
5514097 Knauer May 1996 A
5545147 Harris Aug 1996 A
5545618 Buckley et al. Aug 1996 A
5546932 Galli Aug 1996 A
5549574 Townsend Aug 1996 A
5549575 Giambattista et al. Aug 1996 A
5571719 Christensen et al. Nov 1996 A
5574008 Johnson et al. Nov 1996 A
5584815 Pawelka et al. Dec 1996 A
5591136 Gabriel Jan 1997 A
5599314 Neill Feb 1997 A
5611783 Mikkelsen Mar 1997 A
5614492 Habener Mar 1997 A
5626566 Petersen et al. May 1997 A
5645052 Kersey Jul 1997 A
5652216 Kornfelt et al. Jul 1997 A
5674204 Chanoch Oct 1997 A
5679111 Hjertman et al. Oct 1997 A
5681285 Ford et al. Oct 1997 A
5685864 Shanley et al. Nov 1997 A
5686411 Gaeta et al. Nov 1997 A
5688251 Chanoch Nov 1997 A
5693027 Hansen et al. Dec 1997 A
5693520 Branner et al. Dec 1997 A
5693608 Bechgaard et al. Dec 1997 A
5705483 Galloway et al. Jan 1998 A
5709662 Olive et al. Jan 1998 A
5716990 Bagshawe et al. Feb 1998 A
5725508 Chanoch et al. Mar 1998 A
5741688 Oxenbøll et al. Apr 1998 A
5743889 Sams Apr 1998 A
5750140 Weibel et al. May 1998 A
5755692 Manicom May 1998 A
5823998 Yamagata Oct 1998 A
5827232 Chanoch et al. Oct 1998 A
5843036 Olive et al. Dec 1998 A
5849700 Sørensen et al. Dec 1998 A
5882718 Pommer et al. Mar 1999 A
5898028 Jensen et al. Apr 1999 A
5908830 Smith et al. Jun 1999 A
5921966 Bendek et al. Jul 1999 A
5928201 Poulsen et al. Jul 1999 A
5932547 Stevenson et al. Aug 1999 A
5938642 Burroughs et al. Aug 1999 A
5947934 Hansen et al. Sep 1999 A
5951530 Steengaard et al. Sep 1999 A
5954689 Poulsen Sep 1999 A
5961496 Nielsen et al. Oct 1999 A
5962407 Kelly Oct 1999 A
5972873 Nielsen et al. Oct 1999 A
5980491 Hansen Nov 1999 A
5981489 Stevenson et al. Nov 1999 A
5984900 Mikkelsen Nov 1999 A
5985629 Aaslyng et al. Nov 1999 A
5989169 Svendsen et al. Nov 1999 A
6003736 Ljunggren Dec 1999 A
6004297 Steenfeldt-Jensen et al. Dec 1999 A
6010485 Buch-Rasmussen et al. Jan 2000 A
6033376 Rockley Mar 2000 A
6033377 Rasmussen et al. Mar 2000 A
6048336 Gabriel Apr 2000 A
6059616 Bluemmel et al. May 2000 A
6066619 Stevenson et al. May 2000 A
6074372 Hansen Jun 2000 A
6083197 Umbaugh Jul 2000 A
6086567 Kirchhofer et al. Jul 2000 A
6096010 Walters et al. Aug 2000 A
6110149 Klitgaard et al. Aug 2000 A
6129080 Pitcher et al. Oct 2000 A
6133229 Gibson et al. Oct 2000 A
6136784 L'Italien et al. Oct 2000 A
6146361 DiBiasi et al. Nov 2000 A
6184201 Drucker et al. Feb 2001 B1
6193698 Kirchhofer et al. Feb 2001 B1
6207684 Aberg Mar 2001 B1
6221046 Burroughs et al. Apr 2001 B1
6221053 Walters et al. Apr 2001 B1
6231540 Smedegaard May 2001 B1
6235004 Steenfeldt-Jensen et al. May 2001 B1
6245572 Wall Jun 2001 B1
6248090 Jensen et al. Jun 2001 B1
6248095 Giambattista et al. Jun 2001 B1
6258062 Thielen et al. Jul 2001 B1
6268343 Knudsen et al. Jul 2001 B1
6269340 Ford et al. Jul 2001 B1
6274553 Furuya et al. Aug 2001 B1
6277097 Mikkelsen et al. Aug 2001 B1
6277098 Klitmose et al. Aug 2001 B1
6281225 Hearst et al. Aug 2001 B1
6283941 Schoenfeld et al. Sep 2001 B1
6284727 Kim et al. Sep 2001 B1
6287283 Ljunggreen et al. Sep 2001 B1
6302869 Klitgaard Oct 2001 B1
6303661 Demuth et al. Oct 2001 B1
6312413 Jensen et al. Nov 2001 B1
6340357 Poulsen et al. Jan 2002 B1
6375975 Modi Apr 2002 B1
6379339 Klitgaard et al. Apr 2002 B1
6380357 Hermeling et al. Apr 2002 B2
6384016 Kaarsholm May 2002 B1
6440460 Gurny et al. Aug 2002 B1
6440930 Rinella, Jr. Aug 2002 B1
6444788 Staby Sep 2002 B1
6458924 Knudsen et al. Oct 2002 B2
6489292 Havelund et al. Dec 2002 B1
6514230 Munk et al. Feb 2003 B1
6547763 Steenfeldt-Jensen et al. Apr 2003 B2
6547764 Larsen et al. Apr 2003 B2
6551992 DeFelippis et al. Apr 2003 B1
6562006 Hjertman et al. May 2003 B1
6562011 Buch-Rasmussen et al. May 2003 B1
6569126 Poulsen et al. May 2003 B1
6569832 Knudsen et al. May 2003 B1
6573237 Rinella, Jr. Jun 2003 B2
6582404 Klitgaard et al. Jun 2003 B1
6586399 Drucker Jul 2003 B1
6605067 Larsen Aug 2003 B1
6613019 Munk Sep 2003 B2
6660716 Yakubu-Madus et al. Dec 2003 B1
6663602 Moller Dec 2003 B2
6692472 Hansen et al. Feb 2004 B2
6708846 Fuchs et al. Mar 2004 B1
6716198 Larsen Apr 2004 B2
6726661 Munk et al. Apr 2004 B2
6759291 Divakaruni et al. Jul 2004 B2
6770288 Duirs Aug 2004 B2
6796970 Klitmose et al. Sep 2004 B1
6844321 Arentsen Jan 2005 B2
6893415 Madsen et al. May 2005 B2
6899698 Sams May 2005 B2
6899699 Enggaard May 2005 B2
6945961 Miller et al. Sep 2005 B2
7008399 Larsen et al. Mar 2006 B2
7022674 DeFelippis et al. Apr 2006 B2
7049284 Drucker May 2006 B2
7056886 Isaacs Jun 2006 B2
7090662 Wimpenny et al. Aug 2006 B2
7094221 Veasey et al. Aug 2006 B2
7104972 Moller et al. Sep 2006 B2
7112187 Karlsson Sep 2006 B2
7112567 Bridon et al. Sep 2006 B2
7133329 Skyggebjerg et al. Nov 2006 B2
7175055 Hansen et al. Feb 2007 B2
7202213 Mogensen et al. Apr 2007 B2
7226990 Knudsen et al. Jun 2007 B2
7235627 Knudson et al. Jun 2007 B2
7238663 DeFelippis et al. Jul 2007 B2
7241278 Moller Jul 2007 B2
7273921 Dunweber et al. Sep 2007 B2
7595293 Engelund et al. Sep 2009 B2
7632806 Juul-Mortensen et al. Dec 2009 B2
7833531 O'Neil et al. Nov 2010 B2
8071103 O'Neil et al. Dec 2011 B2
8114833 Pedersen et al. Feb 2012 B2
8129343 Lau et al. Mar 2012 B2
8158583 Knudsen et al. Apr 2012 B2
RE43834 Steenfeldt-Jensen et al. Nov 2012 E
8541470 Davis Sep 2013 B2
8846618 Flink et al. Sep 2014 B2
9133276 Cleemann et al. Sep 2015 B2
9217022 Alfaro-Lopez et al. Dec 2015 B2
9265723 Sprogoe et al. Feb 2016 B2
9457066 Rau et al. Oct 2016 B2
9764003 Jensen Sep 2017 B2
10888605 Moeller et al. Jan 2021 B2
20010014666 Hermeling et al. Aug 2001 A1
20010027180 Isaacs Oct 2001 A1
20020007154 Hansen et al. Jan 2002 A1
20020052578 Moller May 2002 A1
20020061838 Holmquist et al. May 2002 A1
20020077852 Ford et al. Jun 2002 A1
20020120235 Enggaard Aug 2002 A1
20020151467 Leung Oct 2002 A1
20030039679 Duirs Feb 2003 A1
20030045838 Woodard et al. Mar 2003 A1
20030060412 Prouty et al. Mar 2003 A1
20030069182 Rinella Apr 2003 A1
20030092606 L'Italien et al. May 2003 A1
20030092612 Lyons May 2003 A1
20030119734 Flink et al. Jun 2003 A1
20030158101 Drucker Aug 2003 A1
20030172924 Staniforth et al. Sep 2003 A1
20030207802 DeFelippis et al. Nov 2003 A1
20030211047 Dugger Nov 2003 A1
20030220243 Glaesner et al. Nov 2003 A1
20030220255 Knudsen et al. Nov 2003 A1
20040059299 Moller Mar 2004 A1
20040156835 Imoto et al. Aug 2004 A1
20040186431 Graf et al. Sep 2004 A1
20040210199 Atterbury et al. Oct 2004 A1
20040236282 Braithwaite Nov 2004 A1
20040248782 Bridon et al. Dec 2004 A1
20040249348 Wimpenny et al. Dec 2004 A1
20040260247 Veasey et al. Dec 2004 A1
20040267207 Veasey et al. Dec 2004 A1
20050004529 Veasey et al. Jan 2005 A1
20050009742 Bertilsson et al. Jan 2005 A1
20050019400 Deveney et al. Jan 2005 A1
20050033244 Veasey et al. Feb 2005 A1
20050055011 Enggaard Mar 2005 A1
20050143303 Quay et al. Jun 2005 A1
20050148497 Khan Jul 2005 A1
20050205083 Staniforth et al. Sep 2005 A1
20050268915 Wassenaar et al. Dec 2005 A1
20060084605 Engelund et al. Apr 2006 A1
20060178304 Juul-Mortensen et al. Aug 2006 A1
20060286129 Sarubbi Dec 2006 A1
20060287221 Knudsen et al. Dec 2006 A1
20070093761 Veasey et al. Apr 2007 A1
20080125361 Ludvigsen et al. May 2008 A1
20090011976 Ludvigsen et al. Jan 2009 A1
20090156478 Lau Jun 2009 A1
20100311643 Bevec et al. Dec 2010 A1
20120208755 Leung Aug 2012 A1
20120225810 Pedersen et al. Sep 2012 A1
20130190230 Casadesus Smith et al. Jul 2013 A1
20150011462 Reedtz-Runge et al. Jan 2015 A1
20160235855 Xiong et al. Aug 2016 A1
20190231876 Pedersen et al. Aug 2019 A1
20190388502 Corvari et al. Dec 2019 A1
20200316204 Pedersen et al. Oct 2020 A1
20210252111 Engelund et al. Aug 2021 A1
Foreign Referenced Citations (289)
Number Date Country
611385 Jun 1991 AU
2223531 Dec 1996 CA
2306024 Apr 1999 CA
2359375 Jul 2000 CA
2527743 Dec 2004 CA
2021001430 Nov 2021 CL
1199339 Nov 1998 CN
1250370 Apr 2000 CN
1257510 Jun 2000 CN
1376166 Oct 2002 CN
101663022 Mar 2010 CN
102579350 Jul 2012 CN
105777872 Jul 2016 CN
3546150 Jan 1987 DE
3609555 Sep 1987 DE
3900926 Aug 1989 DE
42 08 677 Sep 1993 DE
PA 200101010 Jun 2001 DK
1412384 Apr 2008 DK
0037043 Nov 1984 EP
295075 Dec 1988 EP
0299527 Jan 1989 EP
327910 Aug 1989 EP
359070 Mar 1990 EP
0431679 Nov 1990 EP
0438767 Dec 1990 EP
450905 Oct 1991 EP
0452281 Oct 1991 EP
0496141 Jul 1992 EP
498737 Aug 1992 EP
879610 Aug 1992 EP
608343 Apr 1993 EP
0552996 Jul 1993 EP
0554996 Aug 1993 EP
594349 Apr 1994 EP
699687 Aug 1995 EP
0673482 Sep 1995 EP
699686 Mar 1996 EP
702970 Mar 1996 EP
0708179 Apr 1996 EP
747390 Dec 1996 EP
0923159 Jun 1999 EP
0923950 Jun 1999 EP
0926159 Jun 1999 EP
0937471 Aug 1999 EP
937476 Aug 1999 EP
1003581 Aug 1999 EP
0978565 Feb 2000 EP
1025125 Aug 2000 EP
1329462 Oct 2001 EP
1424077 May 2002 EP
1250167 Oct 2002 EP
1344533 Sep 2003 EP
1396499 Mar 2004 EP
1412384 Apr 2004 EP
722492 Mar 2005 EP
1570876 Sep 2005 EP
1601396 Dec 2005 EP
1687019 Aug 2006 EP
0944648 Mar 2007 EP
2394656 Dec 2011 EP
3295952 Mar 2018 EP
2583291 Dec 1986 FR
2767479 Feb 1999 FR
735443 Aug 1955 GB
995065 Jun 1965 GB
1232899 May 1971 GB
2141799 Jan 1985 GB
213691 Sep 1997 HU
215007 Aug 1998 HU
215366 Dec 1998 HU
215634 Jan 1999 HU
1222331 Sep 1990 IT
H05337179 Dec 1993 JP
H06296691 Oct 1994 JP
10101696 Apr 1998 JP
2000-510813 Aug 2000 JP
2001-525371 Dec 2001 JP
2002501790 Jan 2002 JP
2002-504908 Feb 2002 JP
2002-508332 Mar 2002 JP
2002-524514 Aug 2002 JP
2002532557 Oct 2002 JP
2003519195 Jun 2003 JP
2003519195 Jun 2003 JP
3503129 Mar 2004 JP
2004-518756 Jun 2004 JP
2015522573 Aug 2015 JP
200101010 Jun 2001 PA
2111019 May 1997 RU
2180218 Mar 2002 RU
267945 Jan 1996 TW
8706941 Nov 1987 WO
8907463 Aug 1989 WO
9000200 Jan 1990 WO
9009202 Aug 1990 WO
9010020 Sep 1990 WO
9011296 Oct 1990 WO
9110460 Jul 1991 WO
9111457 Aug 1991 WO
9114467 Oct 1991 WO
9217482 Oct 1992 WO
9219260 Nov 1992 WO
9307922 Apr 1993 WO
9318785 Sep 1993 WO
9319175 Sep 1993 WO
9323010 Nov 1993 WO
199325579 Dec 1993 WO
9415120 Jul 1994 WO
9419034 Sep 1994 WO
9522560 Feb 1995 WO
9507931 Mar 1995 WO
9505848 Mar 1995 WO
9510605 Apr 1995 WO
9513825 May 1995 WO
9531214 Nov 1995 WO
9620005 Jul 1996 WO
9624369 Aug 1996 WO
9629342 Sep 1996 WO
9629344 Sep 1996 WO
9626754 Sep 1996 WO
9638190 Dec 1996 WO
9638469 Dec 1996 WO
9736626 Oct 1997 WO
9800152 Jan 1998 WO
98005351 Feb 1998 WO
9808531 Mar 1998 WO
9808873 Mar 1998 WO
9808871 Mar 1998 WO
9810813 Mar 1998 WO
9819698 May 1998 WO
9824767 Jun 1998 WO
9831386 Jul 1998 WO
98030231 Jul 1998 WO
9843658 Oct 1998 WO
9850059 Nov 1998 WO
9855144 Dec 1998 WO
9857688 Dec 1998 WO
9856406 Dec 1998 WO
9856436 Dec 1998 WO
9916417 Apr 1999 WO
9916487 Apr 1999 WO
9921888 May 1999 WO
9921889 May 1999 WO
9929336 Jun 1999 WO
9929337 Jun 1999 WO
9930731 Jun 1999 WO
9934764 Jul 1999 WO
9934822 Jul 1999 WO
9940788 Aug 1999 WO
9940928 Aug 1999 WO
9938554 Aug 1999 WO
9943341 Sep 1999 WO
9943705 Sep 1999 WO
9943706 Sep 1999 WO
9943708 Sep 1999 WO
9947160 Sep 1999 WO
9943707 Sep 1999 WO
0015224 Mar 2000 WO
0037098 Jun 2000 WO
0041546 Jul 2000 WO
0041546 Jul 2000 WO
0055119 Sep 2000 WO
0062847 Oct 2000 WO
0069413 Nov 2000 WO
200073331 Dec 2000 WO
0104156 Jan 2001 WO
0100223 Jan 2001 WO
0101774 Jan 2001 WO
0102369 Jan 2001 WO
0110484 Feb 2001 WO
0119434 Mar 2001 WO
01021198 Mar 2001 WO
0143762 Jun 2001 WO
0149314 Jul 2001 WO
0151071 Jul 2001 WO
0152937 Jul 2001 WO
0155213 Aug 2001 WO
0177141 Oct 2001 WO
0198331 Dec 2001 WO
02067989 Jan 2002 WO
02046227 Jun 2002 WO
0247715 Jun 2002 WO
0247716 Jun 2002 WO
0248183 Jun 2002 WO
02069994 Sep 2002 WO
2002098445 Dec 2002 WO
03002136 Jan 2003 WO
2003002136 Jan 2003 WO
03013589 Feb 2003 WO
03020201 Mar 2003 WO
03033671 Apr 2003 WO
03035099 May 2003 WO
03072195 Sep 2003 WO
03084563 Oct 2003 WO
03101395 Dec 2003 WO
2004004781 Jan 2004 WO
2004029076 Apr 2004 WO
04037168 May 2004 WO
04056313 Jul 2004 WO
2004078226 Sep 2004 WO
2004105781 Dec 2004 WO
2005000222 Jan 2005 WO
05027978 Mar 2005 WO
2005018721 Mar 2005 WO
2005021026 Mar 2005 WO
2005046716 May 2005 WO
2005042488 May 2005 WO
2005044294 May 2005 WO
2005058252 Jun 2005 WO
2005049061 Jun 2005 WO
2005081711 Sep 2005 WO
05120492 Dec 2005 WO
2005113008 Dec 2005 WO
06000567 Jan 2006 WO
2006025882 Mar 2006 WO
2006052608 May 2006 WO
2006055603 May 2006 WO
2006072065 Jul 2006 WO
2006076921 Jul 2006 WO
2006083254 Aug 2006 WO
2006097537 Sep 2006 WO
2006096461 Sep 2006 WO
2006099561 Sep 2006 WO
2007014051 Feb 2007 WO
2007022518 Feb 2007 WO
2007075720 Jul 2007 WO
2007094893 Aug 2007 WO
2007120899 Oct 2007 WO
2008019115 Feb 2008 WO
08133908 Nov 2008 WO
09030771 Mar 2009 WO
2009051992 Apr 2009 WO
2009064298 May 2009 WO
2009075859 Jun 2009 WO
2010046357 Apr 2010 WO
2010107874 Sep 2010 WO
2010139793 Dec 2010 WO
11050008 Apr 2011 WO
11073328 Jun 2011 WO
2011069629 Jun 2011 WO
2011117415 Sep 2011 WO
2011104378 Sep 2011 WO
2011109784 Sep 2011 WO
2011109787 Sep 2011 WO
2012062803 May 2012 WO
2012098187 Jul 2012 WO
2012104655 Aug 2012 WO
2012107476 Aug 2012 WO
2012112626 Aug 2012 WO
2012140117 Oct 2012 WO
2012151248 Nov 2012 WO
2012168430 Dec 2012 WO
2012168432 Dec 2012 WO
2013009539 Jan 2013 WO
2013037690 Mar 2013 WO
2013072406 May 2013 WO
13083826 Jun 2013 WO
13127779 Sep 2013 WO
2013151663 Oct 2013 WO
2013151668 Oct 2013 WO
2013151729 Oct 2013 WO
2013156594 Oct 2013 WO
2013167454 Nov 2013 WO
2013167455 Nov 2013 WO
2013177565 Nov 2013 WO
2013190384 Dec 2013 WO
2014005858 Jan 2014 WO
2014060472 Apr 2014 WO
14144842 Sep 2014 WO
2014177683 Nov 2014 WO
2014182950 Nov 2014 WO
2014202780 Dec 2014 WO
2015000942 Jan 2015 WO
2015009616 Jan 2015 WO
2015155151 Oct 2015 WO
15200324 Dec 2015 WO
2016001862 Jan 2016 WO
2016038521 Mar 2016 WO
2017009236 Jan 2017 WO
2017149070 Sep 2017 WO
2017186896 Nov 2017 WO
18096460 May 2018 WO
18115901 Jun 2018 WO
2018115901 Jun 2018 WO
18139991 Aug 2018 WO
2019038412 Feb 2019 WO
2019122109 Jun 2019 WO
2020004368 Jan 2020 WO
Non-Patent Literature Citations (345)
Entry
BASF: “BASF Chemical Emergency Medical Guidelines,” Jan. 1, 2016, Retrieved from the Internet: URL: https://www.basf.com/documents/corp/en/sustainability/employees-and-society/employees/occupational-medicine/medical-guidelines/Phenol_B_BASF_medGuidelines_E104.pdf, retrieved on Nov. 20, 2017.
Lau et al., Journal of Medicinal Chemistry, 2015, vol. 58, No. 18, pp. 7370-7380.
Marbury et al., “Pharmacokinetics and Tolerability of a Single Dose of Semaglutide, a Once-Weekly Human GLP-1 Analogue, in Subjects With and Without Renal Impairment,” Diabetologia, 2014, vol. 57, Supplement: 1, pages S358-S359.
The report excerpts including some chromatograms from patent ZL200480034152.8, granted Feb. 25, 2015.
Pharmacopoeia of China 2000 Edition, Chemical Industry Press, vol. 2, pp. 378-381, Apr. 2001.
Pharmacopoeia of China 2000 Edition, Chemical Industry Press, vol. 2, p. 94, Jan. 2000.
Pharmaceutics, Edition 4, People's Health Publishing House, pp. 198-199 and 240, Jul. 2002.
Pharmaceutical Excipients, Edition 1, Luo Mingsheng etaL, Sichuan Education Publishing House, Jan. 1995, pp. 18-19, 46-48, 63-68 and 300-302.
Powell MF, Sanders LM, Rogerson A, Si V. Pharmaceutical Research, vol. 8, No. 10, 1991 entitled “Parenteral peptide formulations: chemical and physical properties of native luteinizing hormone-releasing hormone (LHRH) and hydrophobic analogues in aqueous solution” pp. 1258-1263.
Excerpts from the file wrapper of corresponding EP application i.e. EP1687019, dated Oct. 21, 2013.
Letter dated Jul. 8, 2011 submitted in response to the First Examination Report during prosecution of the impugned Patent application.
E-Registerof Indian Patent 257402, filed Nov. 18, 2004.
INPADOC patent family 6683 Jun. 11, 2014.
Relevant pages of prosecution history of Counterpart EP Patent Application EP11157594, filed Mar. 10, 2011.
Relevant pages of prosecution history of Counterpart EP Patent Application EP04797453, filed May 19, 2006.
Bibliographic details and the relevant pages of the prosecution history of the counterpart U.S. Appl. No. 13/362,745, filed Jan. 31, 2012.
Affidavit by Dr. Ravindra Agarwal and curriculum vitae dated Feb. 27, 2015.
Affidavit of John F Carpenter and Exhibit, dated Dec. 16, 2014.
Becton, Dickinson and Company Tokoroyo. “Injection Brush Needle.” 2015. URL: https://www.bd.com/tw/diabetes/main.aspx?cat=6211&id=6612. Accessed Oct. 30, 2015.
Anand and Anand “Reply Statement and Evidence under section 25(2) of the Patents (Amendment) Act, 2005 and Rule 58 of the Patents (Amendment) Rules 2006” for Novo Nordisk Jan. 6, 2014.
Anand and Anand “Reply Statement and Evidence under section 25(2) of the Patents (Amendment) Act, 2005 and Rule 58 of the Patents (Amendment) Rules 2006” for Novo Nordisk Dec. 30, 2014.
Ken-Chi Izutsu et al. “Effect of Mannitol Crystallinity on the Stabilization of Enzymes During Freeze Drying.” Chem. Pharm. Bull. 1994 vol. 42(1) p. 5-8.
Henry Constantino et al. “Effect of Mannitol Crystallization on the Stability and Aersol Performance of a Spray Dried Pharmaceutical Protein, Recombinant Humanized Anti-IgE Monoclonal Antibody.” Journal of Pharma. Sci. 1998 vol. 87 (11) pp. 1406-1411.
Raghu K. Cavatur et al. “Crystallization Behaviour of Mannitol in Frozen Aqueous Solutions” Pharmaceutical Research. 2002 vol. 19(6) pp. 894-900.
Somnah Singh et al. “Effects of Polyols on the Conformational Stability and Biological Activity of a Model Protein Lysozyme.” AAPS PharmSciTech 2003 vol. 4(3) article 42 pp. 1-9.
Luwei Zhao et al. “Stabilization of Eptifibatide by Cosolvents.” International Journal of Pharmaceutics. 2001 vol. 218 pp. 43-56.
Affidavit of Mr. R. Sukumar. Dec. 22, 2015.
R. Sukumar. “Reply to the Declaration of Ms. Dorte Kot Engelund, by way of Affidavit of Mr. R. Sukumar.” Dec. 22, 2015.
Affidavit of Omar Sherief Mohammad submitted in USV Opposition dated Jul. 7, 2015.
Federal Register/vol. 67, No. 236/Dec. 9, 2002, pp. 72965-72967.
Case Law of the Boards of Appeal, I.D.9.16., Small improvement in commercially used process, p. 1 URL: https://www.epo.org/law-practice/legal-texts/html/caselaw/2013/e/clr_i_d_9_16.html Last Updated Jan. 10, 2013; Accessed Mar. 31, 2016.
Robyn Rice, Home Care Nursing Practice, Third Edition, Mosby, Inc. 2001, pp. 270-271.
Robyn Rice, Home Care Nursing Practice, Fourth Edition, Mosby, Inc. 2006, p. 273.
Guan Ronglan, Challenging Traditional Insulin Injection Practices, Foreign Medical Sciences (Nursing Foreign Medical Science), 1999, vol. 18 No. 8, pp. 367-368.
Mary MacKinnon RGN, Providing Diabetes Care in General Practice, Third Edition, London : Class Publishing, 1998, p. 111.
American Diabetes Association Complete Guide to Diabetes, American Diabetes Association, 1996, pp. 105-106, 413-414.
Karen Bellenir, Diabetes Sourcebook, Omnigraphics, Inc., 1995, pp. 271-272.
Brunner and Suddarth's textbook of medical-surgical nursing, Seventh Edition, edited by Suzanne C. Smeltzer, Lippincott Company, 1992, pp. 1122-1123.
Cheng Qiao-yun, Discussion on the Safe Times of Repeated Uses of the Syringe Special for Insulin Injection at Home, Journal of Nursing (China), Nov. 2006, vol. 13 No. 11, pp. 87-89.
Fleming et al.,Challenging Traditional Insulin Injection Practices, American Journal of Nursing, Feb. 1999, vol. 99(2), pp. 72-74.
Cooperative Multimodal Communication, edited by Harry Bunt, Springer, 2001, p. 17.
Cao Hongxia, Caring Guideline for application of Novolin by diabetes patient, Family Nurse, Feb. 2008, vol. 6 No 2A, pp. 344-345.
United States Pharmacopeia and National Formulary (USPNF), United States Pharmacopeial Convention, 2003, pp. 2679-2682.
Adelhorst, et al., “Structure-activity Studies of Glucagon-like Peptide-1,” J. Bio. Chem. 269(9):6275-6278 (1994).
Akers, “Excipient-Drug Interactions in Parenteral Formulations,” J. Pharm. Sci. 91:2283-2300 (2002).
Avis and Levchuk, “Parenteral Preparations,” Chapter 87 in Remington's Pharmaceutical Sciences, 19th ed., vol. 2, pp. 1524-1548 (1995).
Bojesen and Bojesen, “Albumin Binding of Long-chain Fatty Acids: Thermodyanmics and Kinetics,” J. Phys. Chem. 100(45): 17981-17985 (1996).
Conlon, “Proglucagon-derived peptides: nomenclature, biosynthetic relationships and physiological roles,” Diabetologis 31:563-566 (1988).
Cistola, et al., “Carbon 13 NMR Studies of Saturated Fatty Acids Bound to Bovine Serum Albumin,” J. Biological Chem. 262(23): 10980-10985 (1987).
Clodfelter et al., “Effects of non-covalent self-association on the subcutaneous absorption of a therapeutic peptide,” Pharmaceutical Res. 15(2):254-262 (1998).
Deacon, et al., “Both Subcutaneously and Intravenously Administered Glucagon-Like Peptide I Are Rapidly Degraded From the NH2-Terminus in Type II Diabetic Patients and in Healthy Subjects,” Diabetes 44:1126-1131 (1995).
Doenicke, et al., “Solvent for etomidate may cause pain and adverse effects,” Br. J. Anaesth. 83(3):464-466 (1999).
Doenicke, et al., “Osmolalties of Propylene Glycol-Containing Drug Formulations for Parenteral Use. Should Propylene Glycol Be Used as a Solvent?” Anesth. Analg. 75:431-435, 431 (1992).
Gennaro, Remington Pharmacy 2003, 20th Edition, No. 1 Chapter 38, pp. 815-837.
Bailey et al. The Kinetics of Enzyme-Catalysed Reactions Biochemical Engineering Fundamentals, 2nd Ed., pp. 129-148(1986).
Blundell, T.L., Handbook of Experimental Pharmacology, Chapter 3, “The Conformation of Glucagon”, Springer Verlag, 1983, pp. 37-55.
Brittain, Harry G., Buffers, Buffering Agents, and Ionic Equilibria, Encyclopedia of Pharmaceutical Technology, p. 385, 2007.
Chou, J. Z. et al., Journal of Pharmaceutical Sciences, a Radioimmunoassay for LY315902, an Analog of Glucagon-Like Insulinotropic Pepride, and Its Application in the Study of Canine Pharmacokinetics, vol. 86(7), pp. 768-773 (1997).
D. Voet and J.G. Voet, “Abnormal Hemoglobins”, Biochem, 2nd Ed., pp. 235-241 (1995).
D.E. Smilek et al., “A Single Amino Acid Change in a Myelin Basic Protein Peptide Confers the Capacity to Prevent Rather Than Induce Experimental Autoimmune Encephalomyelitis”, Proc Natl Acad Sci USA, vol. 88, pp. 9633-9637, (1991).
Eli Lilly & Co., Humalog Lispro Injection, USP Product Information Dated Feb. 11, 2010.
Entry for Glycerin in Drugs.com (www.drugs.com/ppa/glycerin-glycerol.html), printed Aug. 4, 2009.
European Pharmacopoeia, 3rd Edition, 2.2.3, 1997, pp. 17-18, Council of Europe-Strasbourg.
European Pharmacopoeia, 2007, vol. 1, p. 730, Council of Europe-Strasbourg.
Frokjaer & Hovgaard, Pharmaceutical Formulation Development of Peptides and Proteins, Chapter 8, “Peptides and Proteins as Parenteral Solutions”, 2000, pp. 145-148 & 150-151.
Further Experimental Data, Part A, Physical Stability, Dated Jun. 22, 2009.
G.F. Stamper et al., “Accelerated Stability Testing of Proteins and Peptides: pH-Stability Profile of Insulinotropin Using Traditional Arrheneius and Non-Linear Fitting Analysis”, Drug Development and Industrial Pharmacy, 1995, vol. 21, No. 13, pp. 1503-1511.
30Nzales, Johnny C., Declaration of (Including Curriculum Vita) Dated Nov. 1, 2010.
H. Qi et al., “Stability and Stabilization of Insulinotropin in a Dextran Formulation”, PDA Journal of Pharmaceutical Science & Technology, vol. 49, No. 6, Nov.-Dec. 1995, pp. 289-293.
H.J.C. Berendsen, A Glimpse of the Holy Grail, Science, vol. 282, pp. 642-643 (1998).
Knudsen, L.B et al., Potent Derivatives of Glucogon-Like PEPTIDE-1, Journal of Medicinal Chemistry, 2000, vol. 43, pp. 1664-1669.
Kristensen, H.G., Almen Farmaci, 2000, pp. 273-274, 281.
Larsen, P.J. et al., “Systemic Administration of the Long Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats”, Diabetes, 2001, vol. 50, pp. 2530-2539.
Lund, Walter, Editor, The Pharmaceutical Codex, 12th Edition, Principles and Practice of Pharmaceutics, 1994, The Pharmaceutical Press, London, pp. 98-99.
Malendowicz, L.K. et al., “Preproglucagon derived peptides and thyrotropin (TSH) secretion in the rat: Robust and sustained lowering of blood TSH levels in extendin-4 injected animals”, International Journal of Molecular Medicine, vol. 10, pp. 327-331 (2002).
Mack Publishing Co., Remington's Pharmaceutical Sciences, 16th Edition,1980, Chapter 79, p. 1406.
Mack Publishing Co., Remington's Pharmaceutical Sciences, 18th Edition, 1990, Chapter 84 “Parental Preparations”, pp. 1545-1550.
Martin A. et al., Physical Pharmacy; Physical Chemical Principles in the Pharmaceutical Sciences, 1983, 3rd Edition, p. 222-225.
N. Good et al., “Hydrogen Ion Buffers for Biological Research”, Biochemistry, 1966, vol. 5, No. 2, pp. 467-477.
Rudinger, In: “Characteristics of the Amino Acids as Components of a Peptide Hormone Sequence”, Peptide Hormones, JA Parsons, Ed., pp. 1-7 (1976).
S.E. Bondos & A. Bicknell, Detection and prevention of protein aggregation before during and after purification, Analytical Biochemistry, 2003, 223-231, vol. 316, Academic Press.
Senderoff, R.I. et al., Consideration of Conformational Transitions and Racemization during Process Development of Recombinant Glucagon-like Peptide-1, Journal of Pharmaceutical Sciences, 1998, 183-189, vol. 87—No. 2, American Chemical Society & American Pharm. Assc.
Sigma Product Information on Gly-Gly Buffer Dated Mar. 16, 2010.
Sigma, “Designing Custom Peptides” http://www.sigma-genosys.com/peptide design.asp (accessed Dec. 16, 2004).
Singh, S. et al., “Effect of Polyols On the Conformational Stability and Biological Activity of a Model Protein Lysozyme”, AAPS Pharmscitech, vol. 4(3), pp. 334-342 (2003).
Skovgaard et al., “Using Evolutionary Information and Ancestral Sequences to Understand the Sequence-Function Relationship in GLP-1 Agonists,” J. Mol Bio., 2006, vol. 363, pp. 977-988.
Stenesh, J. “Foundation of Biochemistry—Biomolecules”, Biochemistry, 1998, pp. 67-69.
Tsoka et al., Selective Flocculation ands Precipitation for the Improvement of Virus-Like Particle Recovery From Yeast Homogenate, Biotechnol Prog. vol. 16(4), pp. 661-667 (2000).
United States Pharmacopoeia, 24th Edition, 1999, pp. 1977-1978.
Villanueva Penacarril, M.L., Potent Glycognic Effect of GLP-1(7-36) Amide in Rat Skeletal Muscle, Diabetologia, 1994, vol. 37, pp. 1163-1166.
Wang & Hansen, “Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers”, Journal of Parenteral Science & TECHNOLOGY, 1988, vol. 42, pp. 4-26.
Wang et. al., Aggregation of Therapeutic Proteins, 2010, p. 241.
Weinstein, Sharon, “Principles of Parenteral Fluid Administration”, Plumer's Principles & Practice of Intravenous, 2006, vol. 8 (8), pp. 124-128.
W.S. Messer, Vasopressin and Oxytocin,, Apr. 3, 2000, http://www.neurosci.pharm.utoldeo.edu/MBC3320/vasopressin.htm.
Duma et al., Pharmaceutical Dosage Forms: Parenteral Medications, 1991, vol. 1,2nd Edition, p. 20.
http://www.sigmaaldrich.com/life-science/metabolomics/enzyme-explorer/learning-center/assay-library/assays-by-enzyme-name-ii.html#%20G%, Enzymatic Assay of Glucose-6-Phosphate obtained from the SIGMA ALDRICH website, 1996.
Pridal et al., “Absorption of Glucagon-Like Peptide-1 Can Be Protracted by Zinc or Protamine”, International Journal of Pharmaceutics, 1996, vol. 136, pp. 53-59.
Ruzin, 1999, Plant Microtechnique and Microscopy, “Buffers”, Accessed On-Line on Dec. 24, 2013 at http://microscopy.berkeley.edu/resources/instruction/bufers.html, pp. 1-6.
Powell Micheal F.et al.Parenteral Peptide Formulations:Chemical and Physical properties of Native Luteinizing Hormone-Releasing Hormone (LHRH) and Hydrophobic Analogues in Aqueous Solution, Journal:Pharmaceutical Research, Year 1991, vol. 8. No 10 pp. 1258-1263.
“Parenteral Preparations” Remington, Joseph Price. Remington: The science and practice of pharmacy. Eds. Alfonso R Gennaro, vol. 1.Lippincott Williams & Wilkins, 20th edition, 2000, Chapter 41, pp. 780-785.
Rejection Decision of the Chinese application CN201210294716.8 as a divisional application of the present patent, dated Dec. 2, 2014.
Prosecution history excerpts for U.S. Pat. No. 8,114,833, Issued Feb. 14, 2012.
Remington's Pharmaceutical Sciences, 18th Edition, 1990, pp. 207-227, 228-246, 257-309, 495-528, 697-724, 725-745, 746-756, 757-773, 1286-1329, 1349-1364, 1435-1458, 1481-1498, 1513-1518, 1519-1544, 1545-1569, 1570-1580, 1596-1614.
Robinson et al., “Subcutaneous versus intravenous administration of heparin in the treatment of deep vein thrombosis; which do patients prefer? A randomized cross-over study,” Postgrad Med. J., 1993, vol. 69, pp. 115-116.
Roe et al., “Dose Accuracy Testing of the Humalog/Humulin Insulin Pen Device,” Diabetes Technology & Therapeutics, 2001, vol. 3, No. 4, pp. 623-629.
Schade et al.,“The Intravenous, Intraperitoneal, and Subcutaneous Routes of Insulin Delivery in Diabetic Man,” Diabetes, Dec. 1979, vol. 28, pp. 1069-1072.
Stranz et al., “A Review of pH and Osmolarity,” International Journal of Pharmaceutical Compounding, May/Jun. 2002, vol. 6, No. 3, pp. 216-220.
Sturis et al., “GLP-1 derivative liraglutide in rats with b-cell deficiencies: influence of metabolic state on b-cell mass dynamics,” British Journal of Pharmacology, 2003, vol. 140, pp. 123-132.
U.S. Pharmacopeia XXII, National Formulary XVII, 1990, pp. 1470-1623.
WIPO Patentscope PCT Bibliography Data for PCT/DK2004/000792 (WO2005049061), filed Nov. 18, 2004.
Zhou et al., “Peptide and protein drugs: I. Therapeutic applications, absorption and parenteral administration,” International Journal of Pharmaceutics, 1991, vol. 75, pp. 97-115.
Knudsen et al., “The discovery and development of liraglutide and semaglutide,” Frontiers in Endocrinology, Apr. 2019, vol. 10, Article 155, pp. 1-32.
Prickett et al., “Potentiation of Preservatives (Parabens) in Pharmaceutical Formulations by Low Concentrations of Propylene Glycol,” Journal of Pharmaceutical Sciences, Apr. 1961, vol. 50, No. 4, pp. 316-320.
Rowe et al., “Propylene Glycol,” Handbook of Pharmaceutical Excipients, London/Chicago: Pharmaceutical Press, 2003, Ed. 4, pp. 521-522.
Experimental Report on influence of speed of mixing on fibrillation tendency, dated Dec. 4, 2019, pp. 1-2.
Bates et al., “pH of Aqueous Mixtures of Potassium Dihydrogen Phosphate and Disodium Hydrogen Phosphate at 0° C. to 60° C.,” J. Research Nat'l Bureau Standards, Apr. 1945, vol. 34, pp. 373-394.
Covington, “Definition of pH Scales, Standard Reference Values, Measurement of pH and Related Terminology,” Pure & Appl. Chem., 1985, col. 57, No. 3, pp. 531-542.
French et al., “What is a Conservative Substitution?,” J. Molecular Evolution, 1983, vol. 19, pp. 171-175.
Kieffer et al., “Degradation of Glucose-Dependent Insulinotropic Polypeptide and Truncated Glucagon-Like Peptide 1 in vitro and in vivo by Dipeptidyl Peptidase IV,” Endocrinology, 1995, vol. 136, pp. 3585-3596.
Orskov et al., “Biological Effects and Metabolic Rates of Glucagonlike Peptide-1(7-36) Amide and Glucagonlike Peptide-1(7-37) in Healthy Subjects are Indistinguishable,” Diabetes, May 1993, vol. 42, pp. 658-661.
Shen et al., “Pharmacokinetics and Biodistribution of PAL-BBI, a Fatty Acid-Polypeptide Conjugate,” Proceedings of the Int'l Symposium on Controlled Release of Bioactive Materials, 1996, vol. 23, pp. 387-888.
Wei et al., “Tissue-Specific Expression of the Human Receptor for Glucagon-Like Peptide-I: Brain, Heart and Pancreatic Forms have the Same Deduced Amino Acid Sequences,” FEBS Letters, 1995, vol. 358, pp. 219-224.
Decision rejecting the opposition dated Feb. 11, 2020 filed in Opposition of EP1687019.
Bummer & Koppenol, “Chemical and Physical Considerations in Protein and Peptide Stability”, in Protein Formulation and Delivery, 2000, Chapter 2, pp. 5-69.
Catanzaro et al., “Propylene glycol dermatitis”, Jan. 1991, Journal of the American Academy of Dermatology, vol. 24, No. 1, pp. 90-95.
Chi et al. “Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation.” Pharmaceutical research, Sep. 2003, vol. 20, No. 9, pp. 1325-1336.
Cleland et al. “Formulation and delivery of proteins and peptides: design and development strategies.” (1994), Chapter 1, pp. 1-19.
Contaxis et al.“A study of the conformational properties of glucagon in the presence of glycols.” Canadian journal of biochemistry, 1972, vol. 52, No. 6, pp. 456-468.
Frokjaer et al. “Protein drug stability: a formulation challenge.” Nat Rev Drug Discov, Apr. 2005, vol. 4, No. 4, pp. 298-306.
Furia, Thomas., “CRC Handbook of Food Additives, 2nd Ed.” (1972), vol. I, Chapter 10.
Goolcharran et al. “Chemical pathways of peptide and protein degradation.” Pharmaceutical formulation and Jevelopment of peptides and proteins, 2000, Chapter 5, pp. 70-88.
Gutniak, Mark et al. “Antidiabetogenic Effect of Glucagon-like Peptide-1 (7-36)amide in Normal Subjects and Patients with Diabetes Mellitus” The New England Journal of Medicine May 1992. vol. 326(20) pp. 1316-1322. Oth.
Hashimoto M et al., Synthesis of palmitoyl derivatives of insulin and their biological activities, Pharmaceutical Research, Feb. 1989, vol. 6(2), 171-176, Others.
Humira® Package Insert (revised Jan. 2003) retrieved from https://www.accessdata.fda.gov/drugsatfda_docs/label/2002/adalabb123102lb.htm Accessed Nov. 12, 2020.
Japanese Pharmaceutical Excipients Directory (1996), at p. 437.
Jeffrey et al. “The Preparation of a Sterile Solution of Mannitol.” American Journal of Hospital Pharmacy, May 1963, vol. 20, No. 5, pp. 255-258.
Kaiser et al., “Secondary structures of proteins and peptides in amphiphilic environments (A Review)” 80 Proc. Natl. Acad. Sci. USA, Feb. 1983, vol. 80, No. 4, pp. 1137-1143.
Kenyon et al., “13C NMR Studies of the Binding of Medium-Chain Fatty Acids to Human Serum Albumin”, 35 J. Lipid Research, Mar. 1994, vol. 35, No. 3, pp. 458-467.
Kitsberg, “Not Quite Crystal Clear”, ANAESTHESIA, Mar. 2002, vol. 57, No. 3, pp. 284-313.
Losasso et al., “Doppler Detection of Intravenous Mannitol Crystals Mimics Venous Air Embolism”,, Anesth Analg, Nov. 1990, vol. 71, No. 5 , pp. 561-569.
Maniatis, T et al., Journal Title: Cold Spring Harbor Laborator,Title: Molecular Cloning a Laboratory Manual, 1982, pp. 324-328, AU Office Action.
Manning, M.C et al., Journal Title: Pharmaceutical Research,Stability of Protein Pharmaceuticals, 1989, vol. 6, No. 11,pp. 903-918.
Meier, et al., “Contrasting Effects of Lixisenatide and Liragluide on Postprandial Glycemic Control, Gastric Emptying, and Safety Parameters in Patients with Type 2 Diabetes on Optimized Insulin Glargine with Or Without Metformin: A Randomized, Open-Label Trial”, Diabetes Care, Jul. 2015, vol. 38, No. 7, pp. 1263-1273.
Mentlein, R et al., “Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagonlike peptide-1 (7-36) amide, peptide histidine methionine and is responsible for their degradation in human serum” 1993, European Journal of Biochemistry, vol. 214, pp. 829-835.
Nauck et al., JTitle: Normalization of Fasting Hyperglycaemia by Exogenous Glucagon-Like Peptide 1 (7-36 Amide) in Type 2 (Non-Insulin-Dependent) Diabetic Patients, 1993, vol. 36, pp. 741-744.
Niu et al., “FDA Perspective on Peptide Formulation and Stability Issues,” Nov. 1998, vol. 87, No. 11, J. Pharm. Sciences, pp. 1331-1334.
O'Grady et al. “Guidelines for the prevention of intravascular catheter-related infections. Centers for Disease Control and Prevention.” MMWR, Recommendations and Reports, Jul. 2002, vol. 5, No. RR-10, pp. 1-29.
Omnitrope® Highlights of Prescribing Information (dated Jun. 2009).
Padrick et al., “Islet Amyloid Polypeptide: Identification of Long-range Contact and Local Order on the Fibrillogenesis Pathway” J. Mol. Biol., Jun. 2001, vol. 308, No. 4, pp. 783-794.
Parks, “Interactions of the Carboxyl Group of Oleic Acid with Bovine Serum Albumin: A 13C NMR Study”, J. Biol. Chem , Issue of Aug. 10, 1983, vol. 258, No. 15, p. 9262-9269.
Payne, Robert W., and Mark Cornell Manning. “Peptide formulation: challenges and strategies.” Innov Pharm Technol, 2009, vol. 28, pp. 64-68.
Klement and Arndt, “Pain on IV Injection of Some Anaesthetic Agents Is Evoked by the Unphysiological Osmolality or pH of Their Formulations,” Br. J. Anaesth. 66:189-195 (1991).
Knudsen, et al., “GLP-1 derivatives as novel compounds for the treatment of type 2 diabetes: Selection of NN2211 for clinical development,” Drugs of the Future 26(7): 677-685 (Jul. 2001).
Kurtzhals, et al., “Albumin binding of insulins acylated with fatty acids: characterization of the ligand-protein interaction and correlation between binding affinity and timing of the insulin effect in vivo,” J. Biochem. 312: 725-731 (1995).
Lehninger, Biochemistry: The Molecular Basis of Cell Structure and Function, 2:72-76, 279-281 (1975).
Markussen, J. et al., “Soluble, Fatty Acid Acylated Insulins Bind to Albumin and Show Protracted Action in Pigs,” Diabetologia 39:281-288 (1996).
Peters, T., “Ligand Binding by Albumin,” All About Albumin,76-95, Academic Press, Inc. (1995).
Radebaugh and Ravin, “Preformulation,” Chapter 83 in Remington's Pharmaceutical Sciences, 19th ed. 2:1447-1462 (1995).
Ravin and Radebaugh, “Preformulation,” Chapter 75 in Remington's Pharmaceutical Sciences, 18th ed. 1435-1450 (1990).
Sigma-Aldrich, Glycylglycine Product Information Sheet, Accessed online at https://www.sigmaaldrich.com/content/dam/sigma-aldrich/docs/Sigma/Product_Information_Sheet/g1002pis.pdf (last accessed Dec. 14, 2017).
Strickley, “Solubilizing Excipients in Oral and Injectable Formulations,” Pharm. Research 21(2):201-230 (2004).
Stryer, “Protein Structure and Function,” Biochemistry 4th ed.: 17-44 (1995).
Sweetana and Akers, “Solubility Principles and Practices for Parenteral Drug Dosage Form Development,” PDA Journal of Pharmaceutical Science and Technology 50:330-342 (1996).
Thornton and Gorenstein, “Structure of Glucagon-like Peptide(7-36) Amide in a Dodecylphosphocholine Micelle as Determined by 2D NMR,” Biochem. 33:3532-3539 (1994).
Toney, et al., “Aspartimide Formation in the Joining Peptide Sequence of Porcine and Mouse Proopiomelanocortin,” J. Biol. Chem. 268(2):1024-1031 (1993).
Tonsgard, J. H. et al., “Binding of Straight-Chain Saturated Dicarboxylic Acids to Albumin,” J. Clin. Invest. 82:1567-1573 (1988).
Wang and Hanson, “Parenteral Formulations of Proteins and Peptides: Stability and Stabilizers,” Journal of Parenteral Science & Technology 42:S2-S36 (1988).
Whittingham, et al., “Crystal Structure of a Prolonged-Acting Insulin with Albumin-Binding Properties,” Biochemistry 36:2826-2831 (1997).
Remington's Pharmaceutical Sciences, 19th ed., vol. 2:843-1934 (1995).
Siegel, “Tonicity, Osmoticity, Osmolality and Osmolarity,” Chapter 79 in Remington's Pharmaceutical Sciences, 18th ed. :1481-1498 (1990).
Smyth and Evans, “Critical Analysis,” Chapter 28 in Remington's Pharmaceutical Sciences, 18th ed. :495-528 (1990).
Vadas, “Stability of Pharmaceutical Products,” Chapter 81 in Remington's Pharmaceutical Sciences, 18th ed. :1504-1512 (1990).
Turco, “Intravenous Admixtures,” Chapter 85 in Remington's Pharmaceutical Sciences, 18th ed. :1570-1580 (1990).
Zograf and Schott, “Disperse Systems,” Chapter 19 in Remington's Pharmaceutical Sciences, 18th ed. :257-309 (1990).
Reilly, “Pharmaceutical Necessities,” Chapter 80 in Remington's Pharmaceutical Sciences, 18th ed. :1380-1416 (1990).
Selected Pages from Remington's Pharmaceutical Sciences :761-762, 1406, 1467 (1980).
Sokoloski, “Solutions and Phase Equilibria,” Chapter 16 in Remington's Pharmaceutical Sciences, 18th ed. :207-227 (1990).
Swinyard and Lowenthol, “Pharmaceutical Necessities,” Chapter 66 in Remington's Pharmaceutical Sciences, 18th ed. :1286-1329 (1990).
Selected Pages from Remington's Pharmaceutical Sciences, 18th ed. :266-269, 1302-1303, 1444-1445, 1448-1449, 1484-1485, 1506-1509, 1550-1551 (1990).
Yalkowsky, et al., “In Vitro Method for Detecting Precipitation of Parenteral Formulations After Injection,” Journal of Pharmaceutical Sciences 72(9): 1014-1017 (1983).
M. J. Reader, “Influence of Isotonic Agents on the Stability of Thimerosal in Ophthalmic Formulations,” Journal of Pharmaceutical Sciences, 1984, vol. 73, pp. 840-841.
“Disodium Hydrogen Phosphate,” PubChem CID: 24203, available online at https://pubchem.ncbi.nim.nih.gov/compound/disodium_hydrogen_phosphate#section=top, 72 pages (accessed on Jan. 10, 2018).
“Disodium Hydrogen Phosphate Dihydrate,” Chemical Book, available online at http://www.chemicalbook.com/chemicalproductproperty_DE_CB4852564.htm, 3 pages (accessed online Jan. 8, 2018).
Akers et al., “Formulation Development of Protein Dosage Forms,” Development and Manufacture of Protein Pharmaceuticals, New York, Kluwer, 2003, pp. 47-127.
Gekko et al., “The stability of protein structure in aqueous propylene glycol: Amino acid solubility and preferential solvation of protein,” Biochimica et Biophysica Acta (BBA)—Protein Structure and Molecular Enzymology, 1984, vol. 786, No. 3, pp. 151-160.
Gekko, “Hydration-structure-function relationships of polysaccharides and proteins,” Food Hydrocolloids, 1989, vol. 3, No. 4, pp. 289-299.
Lee, “Biopharmaceutical Formulation,” Current Opinion in Biotechnology, 2000, vol. 11, No. 1, pp. 81-84.
Sweetana et al., Solubility Principles and Practices for Parenteral Drug Dosage Form Development, PDA J Pharm Sci and Tech, 1996, vol. 50, pp. 330-342.
Nema et al., “Excipients and their use in injectable products,” PDA Journal of Pharmaceutical Sciences and Technology, 1997, vol. 51, No. 4, pp. 166-171.
Doenicke et al., “Osmolalities of Propylene Glycol-Containing Drug Formulations for Parenteral Use, Should Proylene Glycol Be Used as a Solvent?,” Anesthesia & Analgesia, 1992, vol. 75, No. 3, pp. 431-435.
Powell et al., “Compendium of Excipients for Parenteral Formulations,” PDA J Pharm Sci and Tech, 1998, vol. 52, pp. 238-311.
Krakoff et al., “Use of a Parenteral Propylene Glycol-Containing Etomidate Preparation for the Long-Term Management of Ectopic Cushing's Syndrome,” The Journal of Clinical Endocrinology & Metabolism, 2001, vol. 86, No. 9, pp. 4104-4108.
Abstract of Ribel et al, “NN2211: a long-acting glucagon-like peptide-1 derivative with anti-diabetic effects in glucose-intolerant pigs,” Eur J Pharmacol., Sep. 13, 2002, vol. 451, No. 2, pp. 217-225.
Arakawa T et al., “The Effects of Protein Stabilizers on Aggregation Induced by Multiple-Stresses,” Yakugaku Zasshi, 2003, vol. 123, No. 11, pp. 957-961.
Danish Patent Application PA200301719, filed Nov. 20, 2003.
EPO Board of Appeal Decision T 0235/97-3.3.2, Jan. 10, 2002.
Epperson, “Mannitol Crystallization in Plastic Containers,” Am J Hosp Pharm., Nov. 1978, vol. 35, No. 11, p. 1337.
Lottspeich/Zotbas, Bioanalytik, 1998, p. 55.
Modern Pharmaceutics, Fourth Edition, 2002, p. 682.
O'Neil M J et al (eds): The Merck Index—An Encyclopedia of Chemicals, Drugs, and Biologicals. Merck & Co., Inc. Whitehouse Station, NJ, 13th edition 2001, pp. 799/1026/1299/1405/1545.
Pharmaceutical Press and American Pharmaceutical Association, “Handbook of Pharmaceutical Excipients”, 2003, pp. 521-522.
Rapoport, S. I. “Microinfarction: osmotic BBB opening or microcrystals in infusate?” Journal of neurosurgery, Apr. 1991, vol. 74, No. 685.
Robblee et al. “Hypoxemia after intraluminal oxygen line obstruction during cardiopulmonary bypass.” The Annals of thoracic surgery, 1989, vol. 48, No. 4, pp. 575-576.
Schellekens H. “Bioequivalence and the immunogenicity of biopharmaceuticals.” Jun. 2002, Nature reviews Drug discovery. vol. 1, No. 6, pp. 457-462.
Shanbhag et al., “Interaction of Human Serum Albumin with Fatty Acids Role of Anionic Group Studied by Affinity Partition”, Jan. 1979, Eur. J. Biochem. vol. 93, pp. 363-367.
Strauss et al., “A pan European epidemiologic study of insulin injection technique in patients with diabetes” Practical Diabetes Int'l, Apr. 2002, vol. 19, No. 3, pp. 71-76.
Strickley, “Parenteral Formulations of Small Molecules Therapeutics Marketed in the United States (1999)—Part I” Nov.-Dec. 1999, vol. 53, No. 6, PDA J. Pharm. Sci. & Tech. pp. 324-349.
Suzuki et al. “Sequelae of the osmotic blood-brain barrier opening in rats”, J. Neurosurg, Sep. 1988, vol. 39 , No. 3, pp. 421-428.
Thorens et al.“Glucagon-like peptide-l and the control of insulin secretion in the normal state and in NIDDM.” Diabetes, Sep. 1993, vol. 42, No. 9, pp. 1219-1225.
Tomiwa et al., “Reversible Osmotic Opening of the Blood-Brain Barrier”, Acta Pathol. Jpn, May 1982, vol. 32, No. 3, pp. 427-435.
U.S. Food & Drug Admin., New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2), Guidance for Industry, Dec. 2018, pp. 1-17, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/new-and-revised-draft-qas-biosimilar-development-and-bpci-act-revision-2.
U.S. Appl. No. 08/918,810, filed Aug. 26, 1997.
U.S. Appl. No. 11/786,095, filed Jun. 27, 2002.
U.S. Appl. No. 12/785,861, filed Jun. 27, 2002.
U.S. Appl. No. 09/038,432, filed Aug. 26, 1997.
U.S. Appl. No. 09/258,750, filed Aug. 26, 1997.
U.S. Appl. No. 10/185,923, filed Jun. 27, 2002.
U.S. Appl. No. 11/435,977, filed Nov. 18, 2004.
U.S. Appl. No. 60/082,802, filed Apr. 23, 1998.
U.S. Appl. No. 60/084,357, filed May 5, 1998.
U.S. Appl. No. 60/308,297, filed Jul. 27, 2001.
U.S. Appl. No. 60/308,325, filed Jul. 27, 2001.
U.S. Appl. No. 60/524,653, filed Nov. 24, 2003.
U.S. Appl. No. 60/035,904, filed Jan. 24, 1997.
U.S. Appl. No. 60/036,226, filed Jan. 24, 1997.
U.S. Appl. No. 60/036,255, filed Jan. 24, 1997.
U.S. Appl. No. 60/082,478, filed Apr. 21, 1998, Docket No. 5428.013US.
U.S. Appl. No. 60/082,480, filed Apr. 21, 1998, Attorney Docket No. 5488.013US.
Ven de Weert & Randolph, “Physical Instability of Peptides and Proteins”, in Pharmaceutical Formulation Development of Peptides and Proteins, 2nd Ed, 2013, pp. 107-116 & 119-126.
Wolffenbuttel et al., “New Treatments for Patients with Type 2 Diabetes Mellitus”, Postgrad Med J., Nov. 1996, vol. 72, No. 853, pp. 657-662.
Norditropin® Approved Labeling (revised May 2000).
Kibbe, Handbook of Pharmaceutical Excipients, 2000, 3rd Edition, American Pharmaceutical Association, Washington, DC, all pp. 220-222, 324-328, 442-444, 493-495, 496-497.
Handbook of Pharmaceutical Excipients (4th ed. 2003) pp. 257-259; 373-377; 521-523; 574-578.
Remington's Pharmaceutical Sciences (18th ed. 1990) Chs. 16-17, pp. 207-246; Ch. 19, pp. 257-309; Ch. 28, pp. 495-528; Chs. 35-38, pp. 697-773; Ch. 66, pp. 1286-1329; Ch. 69, pp. 1349-1364; Chs. 75-76, pp. 1435-1458; Ch. 79, pp. 1481-1498; Chs. 81-85, pp. 1504-1580; Ch. 87, pp. 1596-1614.
Remington's Pharmaceutical Sciences (19th ed. 1995) vol. II, pp. 843-1934.
UNC, Eshelman School of Pharmacy, The Pharmaceutics and Compounding Laboratory. “Sterile Compounding: Syringes and Needle,” 1996, available online at https://pharmlabs.unc.edu/labs/parenterals/syringes.htm, pp. 1-2, accessed Nov. 30, 2020.
John Wiley & Sons, Inc., Common Buffers, Media, and Stock Solutions, in: Current Protocols in Human Genetics, Aug. 2000, Appendix 2D, vol. 26, No. 1, pp. 1-13.
Reich et al., “Tonicity, Osmoticity, Osmolality and Osmolarity,” The Science and Pharmacy, 1995, vol. 1, No. 4, Chapter 36, pp. 613-627.
Hong Qi et al., “Stability and Stabilization of Insulinotropin in a Dextran Formulation,” PDA Journal of Pharmaceutical Science and Technology, Pharmaceutical Research and Development, Pfizer Central Research, Nov.-Dec. 1995, vol. 49, No. 6, pp. 289-293.
Yang et al.,“The diabetes drug semaglutide reduces infarct size, inflammation, and apoptosis, and normalizes neurogenesis in a rat model stroke”, Aug. 2019, Neuropharmacology,, vol. 158, No. 107748, pp. 1-14.
Doenicke et al. “Solvent for etomidate may cause pain and adverse effects.” British journal of anaesthesia. Sep. 1999, vol. 83, No. 3, pp. 464-466.
Fransson et al., “Local Tolerance of Subcuraneous Injections,” Journal of Pharm. Pharmacol., Oct. 1996, vol. 48, pp. 1012-1015.
Niedermirtl et al., “Etomidate and propylene glycol activate nociceptive TRP ion channels.” Molecular pain. Nov. 2018, vol. 14, p. 1-18.
Affidavit of Omar Sherief Mohammad submitted in Ranbaxy Opposition dated Jul. 7, 2015.
International Diabetes Federation. IDF diabetes atlas. 6th ed. http://www.idf.org/diabetesatlas. Published 2013. Accessed Feb. 12, 2014.
Hex N, et al., Estimating the current and future costs of type 1 and type 2 diabetes in the UK, including direct health costs and indirect societal and productivity costs. Diabetic Medicine. 2012, vol. 29 No 7, pp. 855-862.
Stratton IM et al., on behalf of the UK Prospective Diabetes Study Group. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ, 2000, vol. 321 No. 7528, pp. 405-412.
Villareal DT, et al., Weight loss therapy improves pancreatic endocrine function in obese older adults, Obesity, 2008, vol. 16, No. 6 pp. 1349-1354.
Bron M, et al.. Hypoglycemia, treatment discontinuation, and costs in patients with type 2 diabetes mellitus on oral antidiabetic drugs, Postgraduate Medicine, 2012, vol. 124, No. 1, pp. 124-132.
Zinman B, et al., Achieving a clinically relevant composite outcome of an HbA1C of less than 7% without weight gain on hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme, Diabetes, Obesity and Metabolisim, 2012, vol. 14, No. 1, pp. 77-82.
Garber A et al., for the LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52 week, phase III, double-blind, parallel-treatment trial. Lancet. 2009,vol. 373, No. 9662, pp. 473-481.
Valentine WJ, et al., Evaluating the long-term cost-effectiveness of liraglutide versus exenatide BID in patients with type 2 diabetes who fail to improve with oral antidiabetic agents, Clinical Therapeutics, 2011, vol. 33, No. 11, pp. 1698-1712.
International Diabetes Federation. IDF diabetes atlas. 5th ed. http://www.idf.org/sites/default/files/da5/5eDiabetesAtlas_2011.pdf. Published 2011. Accessed Dec. 20, 2013.
Blundell, T.L, Lefébvre P.J (Ed), “The Conformation of Glucagon”, 1983, vol. 66, pp. 37-55.
Senderoff, Journal of Pharmaceutical Sciences, “Consideration of Conformational Transitions and . . . ”, 1998, vol. 87, No. 2, pp. 183-189.
D. Voet and J.G. Voet, Biochem, 2nd Ed., pp. 235-241 (1995).
D.E. Smilek et al., Proc Natl Acad Sci USA, vol. 88, pp. 9633-9637, (1991).
Larsen, P.J. et al., Systemic Administration of the Logn Acting GLP -1, Diabetes, 2000 vol. 50, pp. 2530-2539.
Rudinger, In: Peptide Hormones, JA Parsons, Ed., pp. 1-7 (1976).
Sigma, http://www.sigma-genosys.com/peptide design.asp (accessed Dec. 16, 2004).
Singh, S. et al. AAPS Pharmscitech, vol. 4(3), pp. 334-342 (2003).
Duma et al., Pharmaceutical Dosage Forms: Parenteral Medications, vol. 1, 2nd Edition, p. 20, 1992.
Eli Lilly & Co., Humalog Lispro Injection, USP Product Information dated Nov. 2, 2010.
European Pharmacopoeia, 3rd Edition, 2.2.3, 1997, pp. 17-18, Council of Europe-Strasbourg, “Physical and Physiochemical Methods”.
Declaration of Johnny C. Gonzalez, (Including Curriculum Vita) dated Nov. 1, 2010.
Knudsen, L.B. et al., Journal of Medicinal Chemistry, 2000, vol. 43, pp. 1664-1669, “Potent Derivatives of Glucagon-like Peptide-1 with Pharmacokinetic Properties Suitable for Once Daily Administration”.
Kristensen, H.G., Almen Farmaci, 2000, pp. 273-274, 281, “Parenteral Administration”.
Lund, Walter, Editor, the Pharmaceutical Codex, 12th Edition, 1994, The Pharmaceutical Press, London, pp. 98-99, “Principles and Practice of Pharmaceutics”.
Wack Publishing Co., Remington's Pharmaceutical Sciences, 16th edition,1980, Pt. 79, p. 1406, “Undesirable Effects of Abnormal Osmoticity”.
Martin A. et al., Physical Pharmacy, 1983, 3rd Edition, p. 232, “Physical Chemical Principles in the Pharmaceutical Sciences”.
Sigma Product Information on Gly-Gly Buffer Mar. 16, 2010.
United States Pharmacopoeia, 24th Edition, 1999, pp. 1977-1978, “polarography—Physical Tests”.
Weinstein, Sharon, Plumer's Principles & Practice of Intravenous, 2006, vol. 8 (8), pp. 124-128, “Principles of Parenteral Fluid Administration”.
Greig et al. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentralions,Diabetologia, 1999, vol. 42 pp. 45-50.
Tolman R C ,The Effect of Droplet Size on Surface Tension , Journal of Chemical Physics. 1949 vol. 17, p. 333 . http://scitation.aip.org/content/aip/journal/jcp/17/3/10.1063/1.1747247.
Ashworth MRF, Analytical Methods For Glycerol, Purely Physical Methods, 1979, p. 63 (Academic Press).
Glycerine, A Key Cosmetic Ingredient, (Edited by Jungermann E et al. ,Alternatives to glycerine, Propylene Glycol, 1991, p. 409.
Alfonso R. Gennaro, Remington : The science and practice of Pharmacy, 19Th edition, 1995 (Mack Publishing Company).
Names, Synonyms, and Structures of Organic Compounds, A CRC reference handbook, (Edited by Lide R D. et al., ) vol. 1, Year 1995, pp. 27 and 491.
CRC handbook of chemistry and physics, 81st Edition, Edited by David R. Lide, Version 2000-2001.
Declaration Dorthe Kot Engelund (inventor) dated Jul. 1, 2015.
Iventor declaration—Dorthe Kot Engelund, Ranbaxy Laboratories Limited dated Aug. 20, 2015.
Inventor declaration—Dorthe Kot Engelund, USV Limited dated Aug. 20, 2015.
Ji et al. (2014) “Insulin Pen Injection Technique Survey in Patients with Type 2 Diabetes in Mainland China in 2010.” Current Medical Research and Opinion. vol. 30:6 pp. 1087-1093.
Gibson, Mark. (2009) “Choice of Excipients.” Pharmaceutical Preformulation and Formulation. 2nd Edition. p. 328.
Chen, Juilette. “The Debate About Needle Reuse” http://www.diabeteshealth.com/blog/the-debate-about-needle-reuse/ Accessed Jan. 9, 2015.
Jiajia Ji, Qingqing Lou (2014), Insulin Pen Injection Technique survey in patients with type 2 diabetes in Mainland China in 2010, Current Medical Research and Opinion. Feb. 2014; 30(6).
Bahar Vardar, Incidence of lipohypertrophy in diabetic patients and a study of influencing factors, Diabetes Research and Clinical Practice 77 (2007) 231-236.
Pharmaceutical Preformulation and Formulation, Second Edition, Mark Gibson, Informa Healthcare USA, Inc., p. 328, 2009.
Clear and colorful Figures 1-7 of the patent ZL200480034152.8, granted Feb. 25, 2015.
Rowe et al., “Handbook of Pharmaceutical Excipients”, 2006, Fifth Edition, pp. 514-516.
Meyer et al., “Antimicrobial preservative use in parenteral products: Past and present,” Jour Pharm Sci, Dec. 2007, vol. 96, No. 12, pp. 3155-3167.
Geier et al., “The relative toxicity of compounds used as preservatives in vaccines and biologies”, Med Sci Monit, May 2010, vol. 16, No. 5, pp. SR21-SR27.
Inpadoc patent family for WO2005049061 as downloaded from worldwide.espacenet.com, last updated Jun. 11, 2014.
Luo Mingsheng et al., “The Extra Pharmaceutical Necessities”, Sichuan Science and Technology, Mar. 31, 1993, p. 495.
Pharmaceuticals and Medical Devices Agency Japan: Victoza Subcutaneous Injection 18 mg—Report on the Deliberation Results. Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare—published: 2009.
Remington: The Science and Practice of Pharmacy, 19th edition, 1995, pp. 1402, 1406 and 1462.
Sebeka H K et al, “Comparative effects of stabilizing additives on the rates of heat inactivation of recombinant human interferon a-2b in solution,” Antivir Res., Jan. 2000, vol. 50, pp. 117-127.
Voet: Biochemie, 1994, p. 39.
Voigt: Lehrbuch der pharmazeutischen Technologie, 6. Auflage, 1987, pp. 281/282.
Yu D K et al., “Pharmacokinetics of Propylene Glycol in Humans During Multiple Dosing Regimens,” J Pharm Sci., Aug. 1985, vol. 74, No. 8, pp. 876-879.
Danish Patent Application No. PA200301689, filed Nov. 13, 2003.
Appendix A document filed with response of Jul. 20, 2017 in EP04797453.0.
Declaration of Malin Persson, dated Jan. 14, 2019.
Victoza User Guide, 2017.
Scott et al., “Warming Kettle for Storing Mannitol Injection,” American Journal of Hospital Pharmacy, 1980, vol. 37, pp. 16-22.
Rowe et al., “Mannitol,” Handbook of Pharmaceutical Excipients, Sixth Edition, Pharmaceutical Press, 2009, pp. 424-428.
Agerso et al., “The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men,” Diabetologia, 2002, vol. 45, pp. 195-202.
Wilken et al., “An Immunoassay for the GLP-1 Derivative NN2211,” Diabetologia, 2000, vol. 43, Suppl 1, p. 413.
Ludwig, et al., “The 3D structure of rat DPPIV/CD26 as obtained by cryo-TEM and single particle analysis,” Biochemical and Biophysical Research Communications, 2003, vol. 304, pp. 73-77.
Ribel et al., “Glucose lowering of the protracted GLP-1 derivative, NN2211, in the Betacell Reduced Minipig,” Diabetologia, 2000, vol. 43, Suppl 1, p. 560.
Speth et al., “Propylene Glycol Pharmacokinetics and Effects after Intravenous Infusion in Humans,” Therapeutic Drug Monitoring, 1987, vol. 9, No. 3, pp. 255-258.
Younes et al., “Re-evaluation of propane-1,2-diol (E 1520) as a food additive,” EFSA Journal, 2018, vol. 16, No. 4:5235, pp. 1-40.
Gaunt et al., “Long-term Toxicity of Propylene Glycol in Rats,” Fd Cosmet. Toxicol., 1972, vol. 10, pp. 151-162.
Declaration of Ms. Dorte Kot Engelund dated Dec. 4, 2019.
Excipient Toxicity and Safety, 1st Edition, CRC Press, 2000, pp. 15-16.
A Dictionary of Chemistry (excerpts), 1996 , pp. 80-81.
Akiyama et al., “Comparison of behavior in muscle fiber regeneration after upivacaine hydrochloride- and acid anhydride-induced myonecrosis,” Acta Neuropathol, 1992, vol. 83, pp. 584-589.
Alfred Martin, Physical Pharmacy, 4th Edition, 1993, pp. 125-142, 169-189, 212-250.
Asakura et al., “Occurrence of Coring in Insulin Vials and Possibility of Rubber Piece Contaimination by Self-Injection,” Yakugaku Zasshi, 2001, vol. 121, No. 6, pp. 459-463.
Banker et al., “Principles of Drug Absorption,” Modem Pharmaceutics, 3rd Edition, 1996, pp. 21-73, 75-119, 155-178, 179-211, 213-237, 239-298, 441-487.
Bontempo, Development of Biophamnaceutical Parenteral Dosage Forms, 1997, pp. 91-142.
Borchert et al., “Particulate Matter in Parenteral Products: A Review,” Journal of Patenteral Science and Technology, Oct. 1986, vol. 40, No. 5, pp. 212-241.
Bothe et al., “Peptide Oligomerization Memory Effects and Their Impact on the Physical Stability of the GLP-1 Agonist Liraglutide,” Mol. Pharmaceutics, 2019, vol. 16, pp. 2153-2161.
Burke et al., “The Adsorption of Proteins to Pharmaceutical Container Surfaces,” International Journal of pharmaceutics, 1992, vol. 86, pp. 89-93.
Chang et al., “NMR studies of the aggregation of glucagon-like peptide-1: formation of a symmetric helical dimer,”FEBS Letters, 2002, vol. 515, pp. 165-170.
Development and Manufacture of Protein Pharmaceuticals, 2002, Kluwer Academic/Plenum Publishers, pp. 47-127, 129-189.
Dubost et al., “Characterization of a Solid State Reaction Product from a Lyophilized Formulation of a Cyclic Heptapeptide. A Novel Example of an Excipient-Induced Oxidation,” Pharmaceutical Research, 1996, vol. 13, No. 12, pp. 1811-1814.
Edwards et al., “Peptides as Drugs,” Q J Med, 1999, vol. 92, pp. 1-4.
Expert Declaration of Laird Forrest, Ph.D. in Support of Petition for Inter Parties Review of U.S. Pat. No. 8,114,833, dated Dec. 29, 2019.
FDA Guidance for Industry, Drug Product—Chemistry, Manufacturing, and Controls, 2003, pp. 1-61.
Fox et al., “Ability to handle, and patient preference for, insulin delivery devices in visually impaired patients with type 2 diabetes,” Practical Diabetes Int, 2002, vol. 19, No. 4, pp. 104-107.
Fransson et al., “Local Tolerance of Subcuraneous Injections,” Journal of Pharm. Pharmacol., 1996, vol. 48, pp. 1012-1015.
Gatlin, “Formulation and Administration Techniques to Minimize Injection Pain and Tissue Damage Associated with arenteral Products,” Injectable Drug Development, 1999, pp. 401-421.
Gerweck et al., “Cellular pH Gradient in Tumor versus Normal Tissue: Potential Exploitation for the Treatment of Cancer,” Cancer Research, Mar. 1996, vol. 56, pp. 1194-1198.
Gnanalingham et al., “Accuracy and Reproducibility of Low Dose Insulin Administration Using Pen-Injectors and Syringes,” Arch Dis Child, 1998, vol. 79, pp. 59-62.
Griffin et al., “Polyhydric Alcohols,” CRC Handbook of Food Additives (Thomas E. Furia, 2nd Edition), 1972, Chapter 10, pp. 431-455.
Handbook of Pharmaceutical Excipients, Fourth Edition, 2003, pp. 257-259, 373-377, 521-523, 574-576, 577-578.
Jacobs, “Factors Influencing Drug Stability in Intravenous Infusions,” The Journal of Hospital Pharmacy, Dec. 1969, vol. 27, pp. 341-347.
Madshus, “Regluation of Intracellular pH in Eukaryotic Cells,” Biochem. J., 1988, vol. 250, pp. 1-8.
Napapom et al., “Assessment of the Myotoxicity of Pharmaceutical Buffers Using an In Vitro Muscle Model: Effect of pH, Capacity, Tonicity, and Buffer Type,” Pharmaceutical Development and Technology, 2000, vol. 5, No. 1, pp. 123-130.
Noel, “Statistical Quality Control in the Manufacture of Pharmaceuficals,” Quality Engineering, 1992, vol. 4, No. 4, pp. 649-657.
Note for Guidance Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (CPMP/ICH/367-96), May 2000, pp. 1-32.
PDA Journal of Pharmaceutical and Science Technology, “Points to Consider for Cleaning Validation,” Technical Report No. 29, Aug. 1998, vol. 52, No. 6, pp. 1-23.
Pharmacuetics—The Science of Dosage Form Design (Michael E. Aulton ed., 2nd Edition), 2002, pp. 113-138, 334-359, 544-553.
Related Publications (1)
Number Date Country
20210085755 A1 Mar 2021 US
Continuations (2)
Number Date Country
Parent 16774666 Jan 2020 US
Child 17115773 US
Parent PCT/EP2018/072835 Aug 2018 US
Child 16774666 US