`
`
`
`Report on the Deliberation Results
`
`December 3, 2009
`Evaluation and Licensing Division, Pharmaceutical and Food Safety Bureau
`Ministry of Health, Labour and Welfare
`
`
` Victoza Subcutaneous Injection 18 mg
`
`
`
`[Brand name]
`[Non-proprietary name] Liraglutide (Genetical Recombination) (JAN*)
`[Applicant]
`
`
`
`
` Novo Nordisk Pharma Ltd.
`[Date of application]
` July 14, 2008
`
`[Results of deliberation]
`In the meeting held on November 27, 2009, the First Committee on New Drugs concluded that the
`product may be approved and that this result should be presented to the Pharmaceutical Affairs
`Department of the Pharmaceutical Affairs and Food Sanitation Council.
`
`The product is not classified as a biological product or a specified biological product, the
`re-examination period is 8 years, and the drug substance and the drug product are both classified as
`powerful drugs.
`
`
`*Japanese Accepted Name (modified INN)
`
`This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In
`the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA
`shall not be responsible for any consequence resulting from the use of this English version.
`
`
`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00001
`
`

`

`
`
`Review Report
`
`
`November 10, 2009
`Pharmaceuticals and Medical Devices Agency
`
`
`The results of a regulatory review conducted by the Pharmaceuticals and Medical Devices Agency on
`the following pharmaceutical product submitted for registration are as follows.
`
`[Brand name]
`
` Victoza Subcutaneous Injection 18 mg (changed from Victoza Injection 18
`mg)
`[Non-proprietary name] Liraglutide (Genetical Recombination)
`[Applicant]
` Novo Nordisk Pharma Ltd.
`[Date of application]
` July 14, 2008
`[Dosage form/Strength]
`
`A solution for injection in a pre-filled pen. Each pre-filled pen (3 mL) contains
`18.0 mg Liraglutide (Genetical Recombination).
`[Application classification] Prescription drug (1) Drug with a new active ingredient
`[Chemical structure]
`
`
`
`51
`
`Molecular formula: C172H265N43O
`Molecular weight: 3751.20
`Chemical name:
`Modified polypeptide of 31 amino acid residues with a covalent linkage at the
`γ-position of N-palmitoylglutamic acid to the ε-amino group of Lys. The polypeptide
`is produced in a recombinant cell by expression of DNA encoding amino acid
`residues at position 7-37 of human glucagon-like peptide-1 with substitution of Arg
`for Lys at position 34
`
`
`[Items warranting special mention] None
`[Reviewing office]
`Office of New Drug I
`
`This English version of the Japanese review report is intended to be a reference material to provide convenience for users. In
`the event of inconsistency between the Japanese original and this English translation, the former shall prevail. The PMDA
`shall not be responsible for any consequence resulting from the use of this English version.
`
`
`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00002
`
`

`

`
`
`
`
`Review Results
`
`
`November 10, 2009
`
`
`[Brand name]
`
`Victoza Subcutaneous Injection 18 mg (changed from Victoza Injection 18
`mg)
`[Non-proprietary name]
` Liraglutide (Genetical Recombination)
`[Applicant]
`
` Novo Nordisk Pharma Ltd.
`[Date of application]
`
` July 14, 2008
`[Items warranting special mention] None
`[Results of review]
`Based on the submitted data, it is concluded that the efficacy of the product in patients with type 2
`diabetes mellitus has been demonstrated and its safety is acceptable in view of its observed benefits.
`The occurrence of cardiovascular events, pancreatitis, tumors (e.g., thyroid tumors and neuroendocrine
`tumors), etc. need to be further investigated via post-marketing surveillance.
`
`As a result of its regulatory review, the Pharmaceuticals and Medical Devices Agency has concluded
`that the product may be approved for the following indication and dosage and administration.
`
`[Indication]
`Type 2 diabetes mellitus;
`Victoza should be used only in patients who have not sufficiently responded to either of the following
`treatments.
`(a) Diet and/or exercise therapy alone
`(b) Use of sulfonylureas in addition to diet and/or exercise therapy
`
`[Dosage and administration]
`The usual adult dosage is 0.9 mg of Liraglutide (Genetical Recombination) subcutaneously injected
`once daily in the morning or evening. Therapy should be initiated with once-daily doses of 0.3 mg and
`then the dose should be increased in 0.3 mg increments at intervals of at least 1 week. The dose may
`be adjusted according to the patient’s condition. The daily dose should not exceed 0.9 mg.
`
`
`
`
`
`3
`
`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00003
`
`

`

`
`
`Review Report (1)
`
`September 29, 2009
`
`
`I. Product Submitted for Registration
`[Brand name]
`Victoza Injection 18 mg
`[Non-proprietary name] Liraglutide (Genetical Recombination)
`[Applicant]
`Novo Nordisk Pharma Ltd.
`[Date of application]
`July 14, 2008
`[Dosage form/Strength] A solution for injection in a pre-filled pen. Each pre-filled pen (3 mL)
`contains 18.0 mg Liraglutide (Genetical Recombination).
`
`[Proposed indication]
`Type 2 diabetes mellitus;
`Victoza should be used only in patients who have not sufficiently responded to either of the
`following treatments.
`(a) Diet and/or exercise therapy alone
`(b) Use of oral antidiabetic drugs in addition to diet and/or exercise therapy
`[Proposed dosage and administration]
`The usual adult dosage is 0.9 mg of liraglutide subcutaneously injected once daily. Therapy
`should be initiated with once-daily doses of 0.3 mg and then the dose should be increased in 0.3
`mg
`increments. Dose increases should occur at intervals of at least 1 week. Victoza should be
`injected at the same time each day.
`[Items warranting special mention] None in particular
`
`
`II. Summary of the Submitted Data and Outline of Review
`A summary of the submitted data and an outline of the review by the Pharmaceuticals and Medical
`Devices Agency
` (PMDA) are as shown below.
`
`1. Origin or history of discovery and usage conditions in foreign countries etc.
`Victoza injection 18 mg is a solution for injection containing an analog of human glucagon-like
`peptide-1 (GLP-1) (non-proprietary name, Liraglutide [Genetical Recombination], hereinafter referred
`to as liraglutide) produced by Novo Nordisk (Denmark), as the active ingredient.
`
`GLP-1 is an incretin hormone secreted from L cells in the lower gastrointestinal tract (Nauck MA, et
`al., Diabetologia, 1993; 36: 741-744, Gutniak MK, et al., Diabetes Care, 1994; 17: 1039-1044) and is
`known to lower blood glucose by stimulating glucose-dependent insulin secretion (Holst JJ, Annu Rev
`
`
`
`4
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00004
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`

`
`
`Physiol, 1997; 59: 257-271). Since it has been suggested that GLP-1 secretion is impaired in patients
`with type 2 diabetes mellitus (Toft-Nielsen MB, et al., J Clin Endocrinol Metab, 2001; 86: 3717-3723),
`GLP-1 is considered a drug candidate suitable for treatment of type 2 diabetes mellitus. However, as
`GLP-1 has a very short elimination half-life (less than 1.5 minutes after intravenous administration)
`due to rapid degradation by endogenous dipeptidyl peptidase-4 (DPP-4), it is not suitable as a
`therapeutic drug.
`
`Liraglutide is an intentionally modified GLP-1 molecule with 24-hour durations of blood levels and
`pharmacologic action and once-daily liraglutide is expected to improve or normalize glycemic control
`without increasing the risk of hypoglycemia by improving glucose-dependent insulin secretion etc.
`These effects are expected to be useful for treatment of Japanese patients with type 2 diabetes mellitus
`especially in view of their decreased insulin secretion (Kiyono H, et al., Japanese Journal of Clinical
`Medicine 1994; 52: 2686-2692, Fukushima M, et al., Diabetes Res Clin Pract, 2004; 66S: S37-S43,
`Fukushima M, et al., Metabolism, 2004; 53: 831-835).
`
`In Japan, a clinical trial was initiated in 2002 and as the usefulness of liraglutide in patients with type 2
`diabetes mellitus has now been demonstrated, a marketing application has been filed.
`
`Overseas, regulatory applications were submitted in the US and the EU for liraglutide in May 2008
`and approval was granted in the EU in June 2009.
`
`2. Data relating to quality
`2.A Summary of the submitted data
`; molecular weight, 3751.20) produced using
`Liraglutide is a modified polypeptide (C172H265N43O51
`recombinant DNA technology in yeast (Saccharomyces cerevisiae) with the expression plasmid
`pKV308 introduced, and is a fragment of GLP-1 sequence position 7-37 with substitution of the
`naturally occurring lysine amino acid residue in position 34 by arginine and with addition of a
`***************************** palmitic acid to the ε-amino group of lysine in position 26. The
`applicant has filed a new drug application for “Victoza Injection 18 mg,” a 3 ml clear colorless
`aqueous solution for injection containing 6 mg/ml of liraglutide as the active ingredient, filled in a
`cartridge assembled into a pen-injector, i.e., a liraglutide pen.
`
`2.A.(1) Drug substance
`2.A.(1).1) Manufacturing process
`(a) Establishment of cell banking system
`The expression vector pKV308 was constructed with the DNA encoding liraglutide precursor and a
`variant of the DNA for ***************** leader sequence from S. cerevisiae inserted into E. coli-S.
`
`
`
`5
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00005
`
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`

`
`
`cerevisiae shuttle vector. The DNA encoding liraglutide precursor was obtained through PCR of the
`gene for GLP-1 [7-37] from synthetic oligonucleotides.
`
`The pKV308 was transformed into S. cerevisiae. After evaluation of transformants by Southern blot
`and liquid chromatography (HPLC) yields of liraglutide precursor, the liraglutide precursor producing
`strain was designated as initial cell clone (ICC). The master cell bank (MCB) was derived from a
`single cell of the ICC. The working cell bank (WCB) was derived from the MCB.
`
`(b) Characterization and control of cell banks
`The MCB, the WCB, a fermentation extended beyond the number of generations used in production
`(LEC; run in pilot scale for *** hours from the WCB), and a fermentation in production scale (EPC;
`run in production scale for *** hours from the WCB) were characterized [see Table 1 and Table 2],
`and all test results complied with the acceptance criteria.
`
`
`Table 1. Test results for characterization of MCB and WCB
`Test results
`
`Specification analyses
`
`Acceptance criteria
`
`MCB
` (Batch number, ****)
`
`WCB
` (Batch number, ****)
`
`Microbial purity
`
`No colonies from organisms other than S.
`cerevisiae
`
`Complies
`
`Complies
`
`Viability
`
`Phenotype
`
`*** × 10* CFU/mL
`(***)
`
`*** × 10* CFU/mL
`(*＊*)
`
`Complies
`
`Complies
`
`Complies
`
`Complies
`
`** copies/cell
`
`No plasmid loss
`S. cerevisiae ***** ex
`***********
`
`Complies
`
`Complies
`
`Complies
`
`－
`
`－
`
`－
`
`－
`
`≥ 10* CFU/mL
`
`***＊＊＊＊********** immunoblotting
`must show positive reaction for all colonies
`measured (at least ***)
`Product identity (HPLC) The product must be *************** as
`identified by HPLC
`Structural context of
`The fragment pattern of the plasmid must
`expression plasmid
`be as expected after digestion with
`(Southern blot)
`appropriate restriction enzymes
`Supplementary analyses (for MCB only)
`Coding DNA sequence identical with
`DNA sequencing
`expected DNA sequence from ICC
`Not applicable. Based on scientific
`evaluation
`Not applicable. Based on scientific
`evaluation
`Not applicable. Based on scientific
`evaluation
`
`Plasmid copy number
`
`Plasmid loss
`
`Strain identification
`
`
`
`
`
`6
`
`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00006
`
`

`

`
`
`Specification analyses
`
`Table 2. Test results for characterization of LEC and EPC
`Test results
`
`Acceptance criteria
`
`LEC
`Complies
`*** × 10* CFU/mL
`****% without positive
`response, positive for all
`*** colonies measured
`Complies
`
`EPC
`Complies
`*** × 10* CFU/mL
`****% without positive
`response, positive for all
`*** colonies measured
`Complies
`
`*%-*% with plasmid
`rearrangements
`
`*% with plasmid
`rearrangements
`
`－
`
`－
`
`－
`
`Complies
`
`**** copies/cell
`
`No plasmid loss
`
`Microbial purity
`Viability
`
`No contamination
`No acceptance criterion for LEC and EPC
`
`Phenotype
`
`***% without positive response
`
`****% with plasmid rearrangements
`
`Product identity (HPLC) The product must be ************** as
`identified by HPLC
`Structural context of
`expression plasmid
`(Southern blot)
`Supplementary analyses (for EPC only)
`Coding DNA sequence identical with the
`DNA sequencing
`coding DNA sequence of MCB (*****)
`Not applicable. Based on scientific
`evaluation
`Not applicable. Based on scientific
`evaluation
`
`Plasmid copy number
`
`Plasmid loss
`
`
`To confirm the stability of the cell banks, stability data of the MCB and WCB stored at ***°C for **
`months were submitted and all results complied with the acceptance criteria. This study will be
`continued and stability will be monitored on an annual basis. The MCB is expected to last the lifetime
`of the product. One WCB will theoretically last for ** years and a new WCB will be generated when
`the number of vials left reaches between *** and *** vials. A new WCB will be characterized as
`indicated in Table 1 (except for supplementary analyses) and compliance with the acceptance criteria
`will be checked.
`
`(c) Manufacturing process
`The manufacturing process of the drug substance comprises fermentation, recovery, and purification
`processes and the drug substance will be manufactured at Novo Nordisk A/S ********.
`
`In the fermentation process of the drug substance, the cell in the WCB vial is inoculated onto *****
`agar surface in a fernbach flask (Step 1). After that, the yeast cells are further propagated in the seed
`tank with fermentation fluid containing carbohydrate source (******* or ******) and complex
`medium (*********, salt, vitamin) (Step 2, seed fermentation) before propagation in the
`************* phase followed by the ********* phase (Step 3, main fermentation).
`
`In the recovery process, ** is adjusted to ******* after the fermentation to ensure dissolution of the
`liraglutide precursor and the yeast cells are removed with ** centrifugations (Step 4, clarification), and
`************ capture chromatograph is utilized to capture liraglutide precursor (Step 5, capture). The
`eluate from Step 5 is precipitated at ******** to *** (Step 6, precipitation).
`
`In the purification process, the precipitate from Step 6 is dissolved in *********** buffer, and after
`
`
`
`7
`
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00007
`
`

`

`
`
`pH is adjusted, ******************** buffer and ******** are added, and ******* are isolated
`(Step 7, ***********). After ******** from Step 7 are dissolved in a buffer containing ***,
`impurities are eluted (elution 1) with ****** exchange chromatograph and then liraglutide precursor
`is obtained (elution 2) (Step 8, ****** exchange chromatography) which is further purified with
`********* chromatograph (Step 9, **** chromatography [**-HPLC]). pH of the eluate from Step 9
`is adjusted to *** to *** and the process solution is cooled and the precipitate is isolated by
`centrifugation (Step 10, precipitation). The liraglutide precursor from Step 10 is substituted on the
`ε-amino group of lysine in position 26 with ****************** palmitic acid under ******
`acylation conditions to give the target substance, liraglutide (Step 11, acylation). After further
`purification with **** exchange chromatograph (Step 12, ***** exchange chromatography) and
`************ chromatograph (Step 13, **-HPLC), pH is adjusted to *** to *** and the precipitate is
`isolated by centrifugation (Step 14, precipitation). The precipitate from Step 14 is dissolved in
`************* aqueous solution and the liraglutide solution is ****** at **°C to **°C under pH
`about ** for about ** ***** and then freeze-dried (Step 15, freeze drying) to obtain the drug
`substance. If the drug substance does not meet the specifications of total viable count and loss on
`drying and *************** ****************, ******** by repeating Step **. If it does not meet
`********************** *********** , ******** by repeating Step ** and Step **, and if the
`acceptance criteria of the in-process control test at Step 10 (test method, RP-HPLC) are not met,
`******** by repeating steps *, *, and **.
`
`For in-process control tests, infection of the remaining broth is set at Step 1, sterility and infection at
`Step 2, pH, sterility, infection, phenotype, and structural context of expression plasmid at Step 3, pH at
`Step 4 and Step 5, liraglutide precursor and impurities (rRt **********) at Step 6, load and ********
`and ******** concentration during elution 1 at Step 8, retention volume of the main peak at Step 9,
`impurities (rRt ************) and host cell proteins (HCP) at Step 10, **** concentration and pH at
`Step 11, load and ************************** (****) at Step 12, **** concentration in eluate,
`********** for ************* and ************** at Step 13, hydrophilic impurities and Peak 4
`(********************-liraglutide and *******-liraglutide) at Step 14 and pH, temperature, and
`time at Step 15.
`
`For process validation, infection of the remaining broth with foreign microorganisms was evaluated at
`Step 1 in the fermentation process, sterility and infection with foreign microorganisms at Step 2,
`sterility, infection with foreign microorganisms, phenotype of fermentation cell, structural context of
`expression plasmid, and pH (as validation of operational parameter) at Step 3.
`
`At Step 6 in the recovery process, the acceptance criteria for the identity of liraglutide precursor were
`met and the levels of impurities (rRt **** and rRt ****) were ≤ **% and ≤ **%, respectively.
`
`
`
`8
`
`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00008
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`

`
`
`
`HCP content was evaluated at Step 7 in the purification process, impurity (rRt ****)), load, and
`********** and ******* concentration during elution 1 at Step 8, HCP content and retention volume
`of the main peak at Step 9, impurities (rRt ****, rRt ****, rRt ****), HCP content, and purity of
`liraglutide precursor at Step 10, purity of liraglutide, ************* concentration, and pH at Step 11,
`Peak 4 (*********************-liraglutide and *******-liraglutide), load, and ********** for
`************** at Step 12, *** concentration in solvent SO24 and SO25, ******** for *****
`********
`and
`*****
`*********
`at Step
`13,
`hydrophilic
`impurities, Peak
`4
`(******************-liraglutide and *******-liraglutide), and sum of impurities at Step 14 and
`impurities
`in
`***************,
`pH
`and
`temperature
`**************,
`********,
`*******************, and residual solvents at Step 15.
`
`(d) Controls of critical process steps and intermediates
`Main fermentation (Step 3), **-HPLC (Step *, Step **), acylation (Step 11), ***** exchange
`chromatography (Step **), and freeze drying (Step 15) are regarded as critical process steps.
`
`Critical operational parameters are pH (Steps 3, 4, 5), load, ***** of elution (impurities), and ******
`concentration during elution (Step 8), retention volume of the main peak (Step 9), **********
`concentration before acylation and pH (Step 11), load and ********* for *************** (Step 12),
`**** concentration in elution solvent SO24 and SO25, ***********, and ************ **(Step 13),
`and pH and temperature ************, and ****** (Step 15). There are no critical intermediates.
`
`(e) Manufacturing process development
`During development, the drug substance manufacturing process was changed roughly ** times
`(Campaigns 1-7). For cell lines, the expression vector ****** was changed in Campaign 3 to pKV308
`where the ampicillin resistance gene was deleted, and the cell line was changed from ********* to the
`currently used ********. In Step 3, the fermentation method was changed in Campaign 4 and
`onwards from ********** fermentation (*** m3) to ********** fermentation (** m3
`) which also
`included a change in medium. In Step 5 where the liraglutide precursor is concentrated, the column
`material was changed from ****** exchange column to the present ************ column ******
`before Campaign 2. Step 6, where precipitation occurs, was introduced for Campaign 2 to obtain a
`stable intermediate.
`
`In Step 7, for Campaign 4A and onwards, ************ buffer was used to avoid degradation of the
`peptide at **** ** **** ****. In Campaign 2, the order of Step 8 and 9 was reversed. In Step 11,
`before Campaign 4A, acylation was undertaken
`in approximately **% organic solvent
`(******************) but it was changed to the conditions in which a more pure product was
`
`
`
`9
`
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`

`
`
`obtained (< *%). After Step 11, precipitation and isolation by centrifugation were introduced in
`Campaign 4B, which had no influence on the quality of the product and these steps were omitted for
`Campaign 6 and onwards. Step 12 was introduced for Campaign 4B and onwards to reduce ********
`of liraglutide. In Step 15, for Campaign 3 and onwards, freeze-drying was performed from *******
`******** ** *** instead of from ************* for Campaign 2. For Campaign 4Ar and onwards,
`** was changed from ***** *** to ***** ** ** to improve stability. In Campaign 4B, the precipitate
`from Step 14 was dissolved in ******* (≤ **°C), which was changed to dissolution at room
`temperature for Campaign 4Br and onwards as it was found that the precipitate from Step 14 can
`reliably be dissolved at room temperature. For Campaign 6 and onwards, ****** under ******
`condition was introduced to minimize ***************, and ***** ********** before freeze drying
`was changed to ***** ***. Between Campaigns 6 and 7, purification facility was transferred from
`pilot scale to production scale.
`
`2.A.(1).2) Characterization
`For characterization of the drug substance, the structure (N-terminal amino acid sequence, amino acid
`composition, peptide mapping, circular dichroism [CD], mass spectrometry, bioassay [cAMP
`determination]) and the physicochemical properties (SDS-PAGE, isoelectric focusing, description
`[appearance], solubility, pH, ultraviolet [UV] absorbance spectra, water absorption, RP-HPLC, size
`exclusion chromatography [SE-HPLC]) have been studied.
`
`The N-terminal amino acid sequence determined by Edman degradation agreed with the theoretical
`one, and amino acid composition analysis (acid hydrolysis, ninhydrin reaction, separation on anion
`exchange column) showed that the amino acid composition of the primary structure corresponded to
`theoretical values, except for serine. Serine recovery was low after hydrolysis.
`
`As a result of peptide mapping (Glu-C digestion), though peaks due to incomplete digestion were
`detected, the retention times of four peptide fragments (P1-P4) were identical to those of secondary
`reference material.
`
`The CD spectra indicated that the peptide back bone of the drug substance had a secondary structure
`consisting partly of alpha-helix.
`
`As a result of SDS-PAGE, the molecular size was between 3000 and 4000 Da, and with mass
`spectrometry (MALDI-TOF MS), the molecular mass was determined to be 3751.1 Da which
`corresponded to the theoretical mass. According to isoelectric focusing (IEF), the isoelectric point of
`the drug substance was approximately 4.9.
`
`
`
`
`10
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`Mylan Pharms. Inc. v. Novo Nordisk A/S
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`

`
`
`The drug substance appeared as a white powder. Solubility was ≥ 270 mg/ml at basic pH. The
`solubility decreased with decreasing pH and reached its lowest value (approximately 0.05 mg/mL) at
`pH 4 to 5, i.e., around the isoelectric point of the drug substance. The solubility was ≤ 0.8 mg/ml at pH
`2.5. The pH of a 1 mg/ml aqueous solution of the drug substance was approximately 9.3. According to
`UV absorbance spectra, λmax
` was 282 nm. The increase in water absorption was constant at a relative
`humidity of 20% to 60% and the average water content at a relative humidity of 50% was around 10%,
`whereas water absorption was accelerated at a relative humidity of 60% to 100%.
`
`As a result of RP-HPLC, the retention time of the main peak was 16 to 20 minutes. With SE-HPLC,
`the monomeric liraglutide peak and high molecular weight protein (HMWP) peaks (mainly dimeric
`and trimeric liraglutide) were detected.
`
`As for biological activity, in vitro bioactivity assay was developed based on the fact that liraglutide
`stimulates BHK cells transfected with human GLP-1 receptors to produce cAMP, which is an
`intracellular messenger for human GLP-1 receptors, in a dose-dependent manner. “Specific
`bioactivity” is defined as bioactivity (mg/mg) relative to content by RP-HPLC (mg/mg). The drug
`substance had a specific bioactivity of about 1.
`
`2.A.(1).3) Product-related substances and impurities
`(a) Product-related substances
`*********************-liraglutide,
`are
`substances
`The
`product-related
`******************-liraglutide, liraglutide ****, and *******liraglutide which are detected with
`RP-HPLC.
`
`(b) Product-related impurities
`The product-related impurities are ******* liraglutide, **********-liraglutide, *************
`liraglutide,
`liraglutide****, ************-liraglutide, ********
`liraglutide, ****
`liraglutide,
`liraglutide** oxygen, liraglutide** oxygen, liraglutide************-liraglutide, ******* liraglutide,
`and liraglutide dimer which are detected with RP-HPLC, and HMWP which is detected with
`**-HPLC.
`
`(a) and (b) are controlled in the drug substance specifications [see 2.A.(1).4) Control of drug
`substance] and also with in-process limits, as precursor, ******-liraglutide at Step 6 and
`liraglutide****, *******-liraglutide, and ***************liraglutide at Step 10, and as liraglutide,
`*******-liraglutide, ***-liraglutide, *******liraglutide, ******-liraglutide, *******-liraglutide, and
`liraglutide***** at Step 14 are controlled.
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`11
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`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00011
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`According to the batch analysis of Campaign 7 commercial production scale batches, the total of
`liraglutide-related impurities was ***% to ***%, liraglutide-related impurities A which corresponded
`to Peak 4 (*******************-liraglutide, ******-liraglutide) were ≤ ***%, liraglutide-related
`impurities
`B
`(******************-liraglutide,
`liraglutide****,
`**********-liraglutide,
`***********liraglutide) were ***% to ***%, liraglutide-related impurities C (liraglutide****) were
`***% to ***%, other ********* liraglutide-related impurities (**************-liraglutide,
`*******-liraglutide, ****liraglutide, liraglutide** oxygen, liraglutide** oxygen, liraglutide****,
`*******liraglutide, *******liraglutide, ******-liraglutide) were ***% to ***%, other ***********
`liraglutide-related impurities (liraglutide dimer) were ≤ ***%, and HMWP was ≤ ***%.
`
`(c) Process-related impurities
`Process-related impurities are HCP and residual solvents and buffer components (ethanol, TEA, NMP,
`Tris, acetate, NHS [N-hydroxy succinimide]), which have been shown to be adequately removed in the
`purification process consistently. The content of HCP is controlled below *** ppm with in-process
`control test (Step **) because HCP in the drug substance will be ********* ******** during the
`********* step.
`
`2.A.(1).4) Control of drug substance
`The drug substance specifications have been set for description (appearance), identification
`(******************-HPLC), purity (the total of liraglutide-related impurities, liraglutide-related
`impurities A, liraglutide-related impurities B, liraglutide-related impurities C, other **********
`liraglutide-related impurities, other ********** liraglutide-related impurities, HMWP, ***), loss on
`drying, bacterial endotoxins, total viable count, specific bioactivity, and assay. The product-related
`substances and the product-related impurities are controlled as liraglutide-related impurities A
`(*********************-liraglutide,
`*******-liraglutide),
`liraglutide-related
`impurities B
`(******************-liraglutide, liraglutide****, **********liraglutide, ***********-liraglutide),
`liraglutide-related impurities C (liraglutide ****), other ********** liraglutide-related impurities
`(***************-liraglutide,
`*******liraglutide,
`***-liraglutide,
`liraglutide**
`oxygen,
`liraglutide** oxygen, liraglutide****, ********liraglutide, *****-liraglutide, ******-liraglutide), and
`other ********** liraglutide-related impurities (liraglutide dimer).
`
`2.A.(1).5) Reference materials
`Primary reference material (PRM) and secondary reference material (SRM) are produced in the same
`manner as the drug substance manufacturing process, and PRM is used as the standard in identification
`and liraglutide assay of SRM. The PRM specifications have been set for identification (amino acid
`sequence, molecular mass), purity (the total of liraglutide-related impurities), homogeneity
`(SE-HPLC/RP-HPLC), and content. The PRM is stable for * years when stored below -18°C.
`
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`Novo Nordisk Exhibit 2067
`Mylan Pharms. Inc. v. Novo Nordisk A/S
`IPR2023-00724
`Page 00012
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`SRM serves for release testing and stability testing of the drug substance and the drug product. The
`SRM specifications have been set for identification (RP-HPLC), purity (the total of liraglutide-related
`impurities, HMWP), homogeneity (RP-HPLC), and content. The SRM is filled into glass vials, which
`is stable for * years when stored below -14°C.
`
`2.A.(1).6) Container closure system
`The drug substance is stored in * L and ** L ******************* (****) tight containers with caps.
`*********** rubber seal ring is mounted in an HDPE cap before closing the container.
`
`2.A.(1).7) Stability
`Long-term testing (*** ± *°C/** months) and accelerated testing (* ± *°C/12 months) were conducted
`for three pilot scale drug substance batches, and stress test for one drug substance batch. The
`containers/closures for samples used in the stability studies are 50 ml **** tight containers with
`closures made of ************. On the other hand, the closures for production containers are made
`from ****. The difference was evaluated with respect to hygroscopicity and compatibility of the drug
`substance with the two containers (25°C ± 2°C, liraglutide-related impurities, HMWP, foreign
`components [leachables/extractables] after * weeks of storage) was studied, which demonstrated that
`the stability study condition represents the normal storage condition in the production. In the
`photostability study, an appropriate amount of the sample was taken into glass containers.
`
`For test items of the long-term testing and the accelerated testing, description (appearance),
`identification (**-HPLC), assay, the total of liraglutide-related impurities, liraglutide-related
`impurities A, liraglutide-related impurities B, liraglutide-related impurities C, other **********
`liraglutide-related impurities, other ********* liraglutide-related impurities, HMWP, loss on drying,
`specific bioactivity, and total viable count were chosen. As a result, after storage of ** months in the
`long-term testing and ** months in the accelerated testing, no significant change was seen for all the
`test items.
`
`In the stress testing, the drug substance was subjected to degradation under light (25°C, ≥ 1.2 million
`lx·hr) and heat (50°C, 60°C, 70°C/one week). An amount of 150 mg of the drug substance was filled
`in each glass vial with a cap and stored after closing the vial. For test items of the stress testing, purity
`(the total of liraglutide-related impurities, liraglutide-related impurities A, liraglutide-related
`impurities B, liraglutide-related impurities C, other ********** liraglutide-related impurities, other
`*********** liraglutide-related impurities), HMWP, and assay were chosen. The main peak was
`identified with mass spectrometry. In the heat condition, the levels of other ***********
`liraglutide-related impurities, liraglutide-related impurities B, and other liraglutide ***********
`
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`Novo Nordisk E