UNITED STATES PATENT AND TRADEMARK OFFICE
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN INSTITUTIONAL LLC,
`Petitioner,
`
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
`______________
`
`Case IPR2020-00324
`Patent 8,114,833
`______________
`
`DECLARATION OF DORTHE KOT ENGELUND
`
`Novo Nordisk Ex. 2099, P. 1
`Mylan Institutional v. Novo Nordisk
` IPR2020-00324
`
`
`______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________
`
`MYLAN INSTITUTIONAL LLC,
`Petitioner,
`
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
`______________
`
`Case IPR2020-00324
`Patent 8,114,833
`______________
`
`DECLARATION OF DORTHE KOT ENGELUND
`
`Novo Nordisk Ex. 2099, P. 1
`Mylan Institutional v. Novo Nordisk
` IPR2020-00324
`
`
`
`IPR2020-00324
`Patent 8,114,833 B2
`
`Table of Contents
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`INTRODUCTION ......................................................................................... 1
`I.
`SUMMARY .................................................................................................... 2
`II.
`III. THE ’833 PATENT ....................................................................................... 3
`IV. OUR FORMULATION DEVELOPMENT WORK .................................. 5
`A.
`Problems with Mannitol ...................................................................... 5
`B.
`Testing of Different Isotonicity Agents .............................................. 9
`i.
`Simulated Filling Experiments .............................................. 10
`ii.
`Drop Tests ................................................................................ 11
`iii.
`Initial Clogging Tests .............................................................. 12
`iv.
`Physical and Chemical Stability Tests .................................. 14
`v.
`Antimicrobial Preservative Tests .......................................... 21
`As of
`, We Recommended Replacing Mannitol With
`Propylene Glycol as the New Isotonic Agent in the Liraglutide
`Formulation ........................................................................................ 23
`UNEXPECTED RESULTS ........................................................................ 24
`A.
`Liraglutide Formulations Containing Propylene Glycol Were
`Superior to Liraglutide Formulations Containing Mannitol ........ 25
`Liraglutide Formulations Containing Propylene Glycol Were
`Superior to Liraglutide Formulations Containing Glycerol ......... 26
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`V.
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`C.
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`B.
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`I, Dorthe Kot Engelund, hereby declare as follows:
`I.
`INTRODUCTION
`1.
`I am an inventor named in U.S. Patent No. 8,114,833 (the “’833
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`patent”) owned by Novo Nordisk A/S (“Novo Nordisk”), which I understand is
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`currently the subject of Inter Partes Review No. 2020-00324.
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`2.
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`I am currently the Scientific Director in the CMC Drug Product
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`Development Division at Novo Nordisk, a position I have held since 2015. As the
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`Scientific Director, I am a scientific drug product and process specialist within the
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`areas of injectable protein formulations for diabetes and biopharmaceutical projects.
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`3.
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`I received my M.Sc. in Pharmacy in 1989 from The Royal Danish
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`School of Pharmacy. After I received my M.Sc. in 1989, I joined Novo Nordisk as
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`a Research Scientist in the Health Care Group, Diabetes Care Division. I was
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`involved in research related to drug product formulation and manufacturing
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`processes for marketed insulin products. From 1995 to 2000, I was a Research
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`Scientist in the Health Care D&D, Biologics Development Division and was
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`involved in the development of drug product formulation and manufacturing
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`processes of soluble and crystalline injectable insulin analogues. From 2000 to
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`2004, I was a Research Scientist in the Protein Drug Delivery Division, where I
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`worked on development of the liraglutide drug product and other ready-to-use liquid
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`formulations.
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`4.
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`In 2004, I was promoted to Principal Scientist in the Biopharm
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`Formulation Development Division, where I was a specialist regarding the drug
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`production formulation of liraglutide and other ready-to-use liquid formulations. In
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`2015, I was promoted again and assumed my current position as the Scientific
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`Director in the CMC Drug Product Development Division.
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`5.
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`I am a full-time employee of Novo Nordisk, and I am not being
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`separately compensated for my work preparing this declaration.
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`6.
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`I have personal knowledge of all information set forth in this
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`declaration unless I specifically note otherwise.
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`II.
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`SUMMARY
`I make this declaration in support of Novo Nordisk’s Patent Owner
`7.
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`Response, including to establish an invention date for the claimed subject matter of
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`the ’833 patent.
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`8.
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`I also make this declaration to show that propylene glycol unexpectedly
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`and surprisingly reduced clogging and deposits compared to mannitol. Mannitol
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`was known to act as an isotonic agent in formulations, whereas propylene glycol was
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`not known for chronic, subcutaneous use as an isotonic agent. However, as
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`described below, it was surprising and unexpected that mannitol presented problems
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`when used in a formulation containing liraglutide, a GLP-1 agonist, whereas
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`propylene glycol did not present any of those problems. Thus, it was surprising and
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`unexpected that propylene glycol, an excipient that was not known for chronic,
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`subcutaneous use as an isotonic agent, demonstrated an optimal collection of
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`properties related to: (a) reducing deposits on production equipment during
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`production; (b) reducing the clogging of injection devices and deposits on needles;
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`(c) physical and chemical stability; and (d) antimicrobial preservative efficacy.
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`III. THE ’833 PATENT
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`9.
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`I understand that all claims (claims 1-31) are at issue in this proceeding.
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`Claims 1-15 are directed to pharmaceutical formulations having a pH from about 7
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`to 10 and containing a GLP-1 agonist, a disodium phosphate buffer, and propylene
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`glycol. Claims 16-22 are directed to methods of preparing such formulations. The
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`remainder of the claims are directed to methods of reducing deposits on the
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`production equipment (claims 23-25), reducing deposits in the final product (claims
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`26-28), and reducing clogging of injection devices (claims 29-31) by “replacing the
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`isotonicity agent previously utilized” in a GLP-1 agonist formulation with propylene
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`glycol.
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`10.
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`For the initial phase 1 and 2 clinical trials, we made small scale batches
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`containing liraglutide, a mixture of disodium phosphate and sodium phosphate
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`buffer, phenol, and mannitol at a pH of 7.4. Since we only made these as small scale
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`batches, we did not see any issues related to deposits on production equipment. In
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`early development, we found that the liraglutide formulations were not physically
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`stable due to observed fibrillation. Based on these observations, we focused on
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`determining the optimal pH range, as well as testing other excipients, including
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`preservatives, buffers, and stabilizers, to obtain a liraglutide formulation that was
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`physically and chemically stable. We conducted a number of physical and chemical
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`stability tests in the laboratory and found that the optimal pH range of the small
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`bench scale formulations was around 7.7 to 8.5. This early set of formulations did
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`not focus on isotonicity agents, but the formulations that did include an isotonicity
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`agent included mannitol or glycerol. This early formulation work is reflected in WO
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`03/002136 (Ex1004).
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`11. As Novo Nordisk prepared for larger scale clinical trials, we
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`encountered problems during production of large scale formulations containing
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`mannitol, which were related to significant production problems in the form of
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`deposits on the production equipment as well as clogging of injection needles. It
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`was concluded that mannitol, the excipient that was included as an isotonic agent,
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`was causing the problems with deposits and clogging of needles. Our formulation
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`team was then assigned the task of developing a solution to these problems.
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`12. We developed and tested alternative formulations in order to find one
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`that would solve the problems associated with the use of mannitol and at the same
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`time maintain physical and chemical stability. In the course of this testing, we tested
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`a number of candidate formulations with different excipients that could function as
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`isotonicity agents. After testing those formulations in a battery of tests, we
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`concluded that the superior formulations included propylene glycol as an isotonic
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`agent. As of
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`, my team and I had made and tested formulations containing
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`a GLP-1 agonist, a disodium phosphate buffer, phenol, and propylene glycol at a pH
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`of about 7.85. We found that such formulations reduced deposits and reduced
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`clogging of injection devices. Furthermore, chemical and physical stability as well
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`as antimicrobial preservation was maintained in formulations with propylene glycol
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`compared to mannitol. Accordingly, by
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`, we had recommended replacing mannitol, as the isotonic
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`agent in the injectable liraglutide formulation, with propylene glycol.
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`IV. OUR FORMULATION DEVELOPMENT WORK
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`Problems with Mannitol
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`A.
`13.
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`14. Meeting these parameters was challenging because formulating
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`liraglutide was not an easy task. For many peptide and protein-based drug products,
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`it is a significant technical challenge to ensure prolonged stability during storage
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`(shelf life) due to the inherent lability of macromolecules. Hence, peptides and
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`proteins are sensitive to both chemical and physical degradation. As of December
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`2000, GLP-1 was known to be prone to instability due to its strong tendency to
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`fibrillate. Fibrillation is highly undesirable because it can lead to loss of biological
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`activity. In view of these challenges, the stability of liraglutide with different
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`excipients like preservatives, buffers, isotonic agents, and varying pH, was
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`unpredictable and had to be carefully balanced to achieve a liraglutide formulation
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`that may be administered in humans to treat Type 2 diabetes as well as fulfill the
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`desired product claims related to shelf life and in-use storage period and temperature.
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`15. Since liraglutide had to be administered as a subcutaneous, injectable
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`formulation, we also believed the commercial formulation would need to be isotonic
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`with physiological fluids to minimize injection pain, irritation, and other undesirable
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`side effects. The inclusion of an isotonicity agent added another unpredictable
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`variable that may affect the physical and chemical stability of the formulation.
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`16.
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`17.
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`18.
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`1 In citing to a Danish language Exhibit, I have provided the page number of the
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`original Danish language document and the certified English translation thereof.
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`22.
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`B.
`23.
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`Testing of Different Isotonicity Agents
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`i.
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`Simulated Filling Experiments
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`24.
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`25.
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`26.
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`27. The simulated filling tests and related results are described in Examples
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`1 and 2 of the ’833 patent. Ex1001 at 15:61-19:36.
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`ii. Drop Tests
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`28.
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`29.
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`30. The drop test and related results are described in Example 1 of the ’833
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`patent. Ex1001 at 16:60-17:17:8.
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`iii.
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`Initial Clogging Tests
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`31.
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`32.
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`33.
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`34.
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`The initial clogging tests and related results are described in Example
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`1 of the ’833 patent. Ex1001 at 17:9-61, Table 3.
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`iv.
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`Physical and Chemical Stability Tests
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`35.
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`36.
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`38.
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`The ThT test is a method to evaluate physical
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`stability of formulations and a specific method for fibrillated protein.
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`During the ThT test, the formulation is exposed to the presence of ThT, which is a
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`fluorophore that interacts with protein fibrils. The ThT test gives a quantitative
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`measure of instability based on the degree of fibrillation. When ThT interacts with
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`protein fibrils there is an increase in the fluorescence intensity due to a shift in the
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`fluorescence behavior of ThT. The tendency to form fibrils indicates the physical
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`stability of the formulation—that is, the more fibrils, the higher value of
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`fluorescence, and the less physically stable the formulation. Id.
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`39.
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`41.
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`43.
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`44. Propylene glycol’s satisfactory performance in the physical stability
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`testing is noted in Example 1 of the ’833 patent. Ex1001 at 18:60-63.
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`45.
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`46.
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`47.
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`49. Propylene glycol’s satisfactory performance in the chemical stability
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`tests is noted in Example 1 of the ’833 patent. Ex1001 at 18:56-59.
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`50.
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`51.
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`v. Antimicrobial Preservative Tests
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`52.
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`53. Example 1 of the ’833 patent describes the results of the antimicrobial
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`preservative test as a factor in the selection of propylene glycol. Ex1001 at 18:64-
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`65.
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`, We Recommended Replacing Mannitol With
`C. As of
`Propylene Glycol as the New Isotonic Agent in the Liraglutide
`Formulation
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`54.
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` The composite results of this
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`testing and analysis demonstrated that a formulation in which mannitol, the
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`previously used isotonicity agent, had been replaced with propylene glycol would
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`work for its intended purpose, i.e., to deliver liraglutide in an injectable formulation
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`for chronic use that is both physically and chemically stable.
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`56.
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`V.
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`UNEXPECTED RESULTS
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`57. As explained above, by
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`, my team and I ultimately selected
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`propylene glycol as the best candidate due to its superior properties over the other
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`excipients tested. See supra at ¶¶ 54-56. Propylene glycol surprisingly showed that
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`it had the best collective balance of properties based on the simulated filling tests,
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`the drop tests, the clogging tests, the physical and chemical stability tests, the
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`antimicrobial preservative test, and the toxicity studies. See supra at ¶¶ 23-53. This
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`finding was unexpected when we embarked on this work, as is further evidenced by
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`the fact that we had not even included propylene glycol in our initial list of possible
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`excipients to test as potential replacement isotonicity agents.
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`A.
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`58.
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`Liraglutide Formulations Containing Propylene Glycol Were
`Superior to Liraglutide Formulations Containing Mannitol
`It was surprising that propylene glycol did not present the same
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`problems as mannitol, but rather solved the problems associated with the use of
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`mannitol in liraglutide formulations including frequent cleaning of the filling
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`equipment during production, reduced production capability, reduced product yield,
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`and the need to discard formulation that contained deposits. See supra at ¶¶ 13-34.
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`In addition to reducing deposits and clogging, it was surprising that propylene glycol
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`did not affect the physical and chemical stability of liraglutide in the formulations.
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`Thus, my team and I could not have
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`predicted the superior properties of propylene glycol in liraglutide formulations
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`without performing all of the experiments detailed above. See supra at ¶¶ 23-53.
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`59.
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`it was surprising and unexpected to discover through our experimentation that
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`propylene glycol could be used as an isotonic agent for chronic, subcutaneous use in
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`an injectable formulation and that it exhibited other beneficial properties including
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`reducing deposits and clogging.
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`B.
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`60.
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`61.
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`Liraglutide Formulations Containing Propylene Glycol Were
`Superior to Liraglutide Formulations Containing Glycerol
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`62.
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`64. Overall, this testing demonstrated propylene glycol’s superiority to
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`glycerol as an isotonic agent for use in the liraglutide drug product due to its superior
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`physical stability as compared to glycerol.
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`Novo Nordisk Ex. 2099, P. 31
`Mylan Institutional v. Novo Nordisk
` IPR2020-00324
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