UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`MYLAN PHARMACEUTICALS INC.,
`Petitioner,
`v.
`
`NOVO NORDISK A/S,
`Patent Owner.
`
`Case No. IPR2023-00722
`Patent No. 8,536,122
`
`DECLARATION OF PAUL DALBY, PH.D., IN SUPPORT OF PETITION
`FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,536,122
`
`MPI EXHIBIT 1024 PAGE 1
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`

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`TABLE OF CONTENTS
`
`
`Page
`
`
`I.
`
`Qualifications and Background ............................................................. 5
`A.
`Education and Experience; Prior Testimony .................................. 5
`B.
`Basis for Opinions and Materials Considered................................. 9
`C.
`Retention and Compensation ....................................................... 9
`Legal Standards ................................................................................ 10
`II.
`III. Person of Ordinary Skill in the Art ...................................................... 12
`IV. The ’122 Patent [Ex. 1001] ................................................................ 14
`V. Claim Construction ........................................................................... 17
`VI. Summary of Opinions ....................................................................... 18
`VII. Background on GLP-1 Compound Formulations ................................... 20
`A.
`Pharmaceutical formulations generally ....................................... 20
`B. GLP-1 compounds were well known .......................................... 21
`C.
`Liraglutide and formulations of liraglutide were well known ......... 24
`VIII. Scope and Content of the Prior Art ...................................................... 24
`A. Knudsen 2004 [Ex. 1010] ......................................................... 25
`B. Knudsen 2001 [Ex. 1011] ......................................................... 26
`C.
`The Knudsen Patent [Ex. 1012] ................................................. 27
`D. Dong [Ex. 1013] ...................................................................... 29
`E.
`Bridon [Ex. 1014] .................................................................... 29
`F.
`Other art that informs the POSA’s knowledge ............................. 30
`1. WO 03/002136 (“Flink”) [Ex. 1093] ................................. 30
`2.
`Remington [Ex. 1088] ..................................................... 31
`3.
`Boylan [Ex. 1089]........................................................... 32
`4.
`Additional prior art and references .................................... 32
`IX. Unpatentability of the Claims of the ’122 Patent ................................... 33
`
`2
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`TABLE OF CONTENTS
`(continued)
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`Page
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`A. A POSA would have been motivated for formulation reasons to
`modify liraglutide with a di-AEEA spacer and a C18 diacid, and
`would have reasonably expected it to result in a GLP-1
`analogue that is easier to formulate............................................. 34
`B. A POSA would have been motivated to formulate a modified
`liraglutide into a pharmaceutical composition with a
`“pharmaceutically acceptable excipient” with a reasonable
`expectation of success .............................................................. 39
`C. No secondary considerations overcome prima facie obviousness .... 43
`1.
`The formulations recited in the ’122 patent produce no
`unexpected results........................................................... 43
`There was no long-felt but unmet need for the
`formulations recited in the ’122 patent ............................... 44
`There was no praise of the formulations recited in the
`’122 patent ..................................................................... 44
`There was no industry skepticism of the formulations
`recited in the ’122 patent.................................................. 45
`X. Reservation of Rights ........................................................................ 45
`
`2.
`
`3.
`
`4.
`
`3
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`TABLE OF ABBREVIATIONS
`
`Full Name of Cited Reference
`U.S. Patent No. 8,536,122
`U.S. Patent No. 7,022,674
`Boylan, Parenteral Products, in MODERN PHARMACEUTICS
`(Gilbert S. Banker et al. eds., 3d ed. 1996)
`U.S. Patent No. 6,514,500
`Dong, Glucagon-Like Peptide-1 Analogs with Significantly
`Improved in vivo Activity, in PEPTIDES: THE WAVE OF THE
`FUTURE (Michal Lebl et al. eds., 2001)
`WO 03/002136
`Knudsen, Potent Derivatives of Glucagon-Like Peptide-1
`with Pharmacokinetic Properties Suitable for Once Daily
`Administration, 43(9) J. MED. CHEM. 1664 (2000)
`Knudsen, GLP-1 Derivatives as Novel Compounds for the
`Treatment of Type 2 Diabetes: Selection of NN2211 for
`Clinical Development, 26(7) DRUGS OF THE FUTURE (2001)
`Knudsen, Glucagon-Like Peptide-1: The Basis of a New
`Class of Treatment for Type 2 Diabetes, 47(17) J. MED.
`CHEM. 4128 (2004)
`U.S. Patent No. 6,268,343
`Rando, Functional Incorporation of Synthetic Glycolipids
`into Cells, 77(5) PROC. NATL. ACAD. SCI. USA 2510 (1980)
`REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY
`(Alfonso R. Gennaro ed., 20th ed. 2000)
`WO 00/37098
`
`Abbreviation
`’122 patent
`’674 patent
`Boylan
`
`Bridon
`Dong
`
`Flink
`Knudsen 2000
`
`Knudsen 2001
`
`Knudsen 2004
`
`Knudsen Patent
`Rando
`
`Remington
`
`WO098
`
`
`
`
`
`
`
`
`
`
`4
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`1. My name is Paul Dalby, Ph.D. I have been retained by Mylan
`
`Pharmaceuticals Inc. (“Mylan”) to provide my expert opinions regarding the
`
`unpatentability of U.S. Patent No. 8,536,122 (“the ’122 patent”) (Ex. 1001). I
`
`understand that Mylan intends to petition for inter partes review (“IPR”) of the
`
`’122 patent, which is assigned to Novo Nordisk A/S (“Patent Owner”). I also
`
`understand that, in the IPR petition, Mylan will request that the United States Patent
`
`and Trademark Office cancel claims 1-2, 4-11, 13, and 15 (“the challenged claims”)
`
`of the ’122 patent as unpatentable. I submit this expert declaration to address and
`
`support Mylan’s IPR petition for the ’122 patent.
`
`I.
`
`QUALIFICATIONS AND BACKGROUND
`
`A. Education and Experience; Prior Testimony
`
`2.
`
`I earned my doctorate at Cambridge University, UK, in 1998 where I
`
`studied protein folding mechanisms, using protein engineering to alter the relative
`
`stabilities of the native, denatured, intermediate and transition states, and evaluating
`
`the effects of a range of temperature, pH and presence of viscosity modifiers in the
`
`formulation. From 1998 to 2000, I was a postdoctoral fellow at the University of
`
`Pennsylvania, where I studied the relationship between protein structure, stability,
`
`and function through protein engineering and biophysical characterization, and also
`
`methods to improve stability and minimize aggregation in protein therapeutic
`
`formulations. In 2000, I was appointed Lecturer at University College London
`
`5
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`(UCL) in the Department of Biochemical Engineering. My research focused on new
`
`
`
`strategies for evolutionary protein and enzyme design, researching factors to
`
`strengthen protein stability during biopharmaceutical downstream processes, and
`
`developing stability analysis methods to optimize the process and maintain proper
`
`protein formulation.
`
`3.
`
`From 2004-2006, I was principal investigator on a project funded by
`
`the Department of Trade and Industry in conjunction with the Health Protection
`
`Agency, UK, to establish protein, process, and formulation engineering methods for
`
`novel protein fusions. During that time, I was an active member of the Protein
`
`Society, the Royal Society of Chemistry, the RSC Biotechnology Group Committee,
`
`the Institution of Chemical Engineers, and the American Chemical Society. I
`
`organized conferences on behalf of these organizations including the 2006
`
`“Therapeutic Proteins: Chemical & Enzymatic Modification” in London. Based on
`
`my work with the previous organizations, I was invited to a joint BIA & Bioprocess
`
`UK workshop in 2005. The workshop led to the establishment of biopharmaceutical
`
`formulation as a funding priority in the DTI technology transfer program.
`
`4.
`
`In 2006, I began a long-term collaboration with the National Institute
`
`of Biological Standards and Controls in the UK to improve the tools and techniques
`
`used in liquid and freeze-dried protein formulation development. The projects
`
`undertaken used biophysical analysis and statistical design of experiments
`
`6
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`approaches, to optimize formulations, and to characterize and understand the impact
`
`
`
`of different excipients on their properties.
`
`5.
`
`In 2007, I was appointed Senior Lecturer at UCL and in 2009 I was
`
`appointed Reader at UCL in the Department of Biochemical Engineering. From
`
`2011 until 2016, I was Co-Director of the Engineering and Physical Sciences
`
`Research Council (EPSRC) Centre for Innovative Manufacturing at UCL.
`
`6.
`
`I am currently Co-Director of the EPSRC Future Targeted Healthcare
`
`Manufacturing Hub and Director of the EPSRC Doctoral Training Centre for
`
`Innovative Manufacturing at UCL. In 2013, I was appointed Professor at UCL,
`
`Department of Biochemical Engineering, and in 2016 was named Deputy Head,
`
`Department of Biochemical Engineering (Research) at UCL. Over the course of my
`
`career at UCL, I have supervised numerous projects resulting in novel research and
`
`development in the field of protein stability. These projects resulted in developing a
`
`novel method for measuring protein stability in microtiter plates; development of
`
`enhanced bioprocessing for advanced pharmaceutical proteins, using directed
`
`evolution; and new methods of protein engineering and formulation resulting in
`
`improved biopharmaceutical stability. The various projects are listed in my CV. I
`
`have presented the results of my research on protein therapeutics and formulation at
`
`numerous international conferences including the Protein Science Forum 2005, the
`
`Cambridge Healthtech Institute 2006, ACHEMA 2006, BioProcess International
`
`7
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`
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`2007, 2011 & 2012, Recovery XIV 2010, World Biopharm Forum 2011, and the
`
`
`
`Royal Society of Chemistry MiBIO 2012.
`
`7.
`
`I am considered a key influencer of research priorities in the UK in the
`
`area of biopharmaceutical formulation. I have been appointed to lead government
`
`and industry groups for establishment of biopharmaceutical formulation protocols. I
`
`have provided consultancy services to a number of companies, including:
`
`Ajinomoto, Angel Biotechnology, Cambridge Antibody Technology (now
`
`MedImmune and owned by AstraZeneca), and Clear Capital Ltd. I also serve on the
`
`Scientific Advisory Board for Leukocare GmbH in Germany, and UMabs in the
`
`USA and China, and have presented my work at international conferences on
`
`biopharmaceutical formulation development.
`
`8.
`
`I have been given numerous research grants to research and supervise
`
`projects impacting the biochemical protein industry. My research interests include:
`
`accelerating therapeutic protein and vaccine formulation design for stability in both
`
`liquid and lyophilized forms; biophysical characterization of protein aggregation and
`
`stability in formulations and bioprocess manufacturing; protein engineering for
`
`stability; using directed evolution, structural analysis, bioinformatics and
`
`computational design, high-throughput bioprocess design, including precipitation
`
`and inclusion body refolding; design and development of novel analytical methods
`
`for bioprocess monitoring and characterization of formulations.
`
`8
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`9.
`
`In the previous four years, I have provided testimony in the following
`
`
`
`proceedings:
`
`• Celltrion, Inc. v. Genentech, Inc., IPR2022-00578, -579 (PTAB);
`• XOMA (US) LLC v. MorphoSys AG, Case No. 01-21-0004-4508
`(ICDR, Nov. 2022);
`• Novo Nordisk Inc. v. Mylan Institutional LLC, C.A. No. 1:19-cv-01551-
`KAJ-SRF (D. Del.); and
`
`• Merck & Co Inc. v. Wyeth, NSD1381/2017 (Australia).
`10. My qualifications are further described on my curriculum vitae, which
`
`can be found at Exhibit 1025.
`
`B. Basis for Opinions and Materials Considered
`
`11. Exhibit A includes a list of the materials I considered, in addition to my
`
`experience, education, and training, to provide the opinions contained in this
`
`declaration.
`
`C. Retention and Compensation
`
`12. Mylan retained me as a technical expert to provide various opinions
`
`about the ’122 patent. I am being compensated at a rate of 360 GBP per hour plus
`
`expenses for this work. My compensation is in no way tied to the outcome of this
`
`proceeding or to the content of this declaration, and it has not altered my opinions.
`
`9
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`II. LEGAL STANDARDS
`
`
`
`13. To prepare and form my opinions set forth in this declaration, I have
`
`been informed of the relevant legal principles. I applied my understanding of those
`
`principles in forming my opinions. My understanding of those principles is
`
`summarized below.1 I took these principles into account when forming my opinions
`
`in this case.
`
`14.
`
`I have been informed that Mylan bears the burden of proving
`
`unpatentability by a preponderance of the evidence. I have been told that this means
`
`it must be more likely than not that the claims are unpatentable.
`
`15.
`
`I understand that my opinions regarding unpatentability are from the
`
`viewpoint of a person of ordinary skill in the art (“POSA”) in the field of technology
`
`of the patent as of the patent’s priority date. I have also been informed by counsel
`
`that in defining a POSA, the following factors may be considered: (1) the educational
`
`level of the inventors; (2) the type of problems encountered in the art; (3) prior art
`
`
`1 As support for my analysis and to help me reach my opinions and conclusions, I
`
`was informed of and advised to apply various legal principles relating to unpatenta-
`
`bility, which I set forth here. By setting forth these legal standards, I do not intend
`
`to testify about the law. I only provide my understanding of the law, as explained to
`
`me by counsel, as a context for the opinions and conclusions I provide in this case.
`
`10
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`solutions to those problems; (4) rapidity with which innovations are made; and (5)
`
`
`
`sophistication of the technology and educational level of active workers in the field.
`
`Further, I understand a POSA is generally skilled in the relevant art (i.e., the subject
`
`matter claimed and described in the patent).
`
`16.
`
`I am told that the concept of patent obviousness involves four factual
`
`inquiries: (1) the scope and content of the prior art; (2) the differences between the
`
`claimed invention and the prior art; (3) the level of ordinary skill in the art; and
`
`(4) secondary considerations of non-obviousness.
`
`17.
`
`I understand that when there is some recognized reason to solve a
`
`problem, and there are a finite number of identified, predictable, and known
`
`solutions, a person of ordinary skill in the art has good reason to pursue the known
`
`options within his or her technical grasp. If such an approach leads to the expected
`
`success, it is likely not the product of innovation but of ordinary skill and common
`
`sense. I understand that any need or problem known in the field of endeavor at the
`
`time of invention or addressed by the patent can provide a reason for combining
`
`prior art elements to arrive at the claimed subject matter. I understand that only a
`
`reasonable expectation of success is necessary to show obviousness.
`
`11
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`III. PERSON OF ORDINARY SKILL IN THE ART
`
`18.
`
`In my opinion, the following definition of a POSA applies to the claims
`
`of the ’122 patent. I reserve the right to amend and/or supplement my opinions on
`
`unpatentability if a different definition of a POSA is adopted or agreed to.
`
`19. A POSA would have understood the prior-art references referred to
`
`herein and would have the capability to draw inferences from the prior-art
`
`references. It is understood that, to the extent necessary, a POSA may collaborate
`
`with one or more other POSAs for one or more aspects with which the other POSA
`
`may have expertise, experience, and/or knowledge. Additionally, a POSA could
`
`have had a lower level of formal education than what I describe in the following
`
`definitions if the person has a higher degree of experience.
`
`20.
`
`In my opinion, the following definition of a POSA applies to the claims
`
`of the ’122 patent. The subject matter of the claims of the ’122 patent falls within
`
`the medicinal, chemical, and pharmacological arts and encompasses the skills,
`
`education, and expertise of a team of individuals working together to develop and
`
`formulate GLP-1 analogues, as well as to use the GLP-1 analogues to treat patients
`
`having type-2 diabetes or related conditions. Such a team would have included
`
`individuals with an M.D., Pharm.D., or doctoral degree(s) in chemistry,
`
`biochemistry, pharmaceutics, pharmaceutical sciences, chemical engineering,
`
`biochemical engineering or related fields, with at least two years of experience in
`
`12
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`
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`developing therapeutic peptides or proteins, and experience with the development,
`
`
`
`design, manufacture, formulation, or administration of therapeutic peptides or
`
`proteins, and the literature concerning protein or peptide formulation and design or
`
`diabetes treatments.
`
`21. Alternatively, the POSA would (1) be a highly skilled scientist lacking
`
`an M.D., Pharm.D., or doctoral degree, but (2) (a) would have more than five years
`
`of experience in the area of developing therapeutic proteins or peptides and/or (b)
`
`would have experience with the development, design, manufacture, formulation, or
`
`administration of therapeutic agents for diabetes, and the literature concerning
`
`protein or peptide formulation and design or diabetes treatments. In either case, a
`
`higher educational level could substitute for some amount of the requisite
`
`experience.
`
`22. Such a team also would have included persons with an appropriate level
`
`of skill in medicinal, synthetic chemistry, including the synthesis and chemical
`
`modification of peptides or proteins.
`
`23. With respect to claim 13 of the ’122 patent, the team would have
`
`included an individual with a PhD in chemistry, biochemistry, pharmaceutics,
`
`pharmaceutical sciences, chemical engineering, biochemical engineering or related
`
`fields, with at least two years of experience in the formulation of therapeutic peptides
`
`or proteins.
`
`13
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`24. As explained above, and as is evident from my CV, I met the
`
`
`
`qualifications of a POSA as of the priority date of the ’122 patent. Within this
`
`definition, my background focuses on the formulation aspects of the claims of the
`
`’122 patent.
`
`IV. THE ’122 PATENT [EX. 1001]
`
`25.
`
`I have read the ’122 patent, including its claims, which is titled
`
`“Acylated GLP-1 Compounds.” I understand that the ’122 patent has 16 issued
`
`claims, of which only claim 1 is an independent claim. The ’122 patent lists Jesper
`
`Lau, Florencio Zaragoza Doerwald, Paw Bloch, and Thomas Kruse Hansen as
`
`inventors.
`
`26. The ’122 patent was filed on March 5, 2012, as U.S. Patent Application
`
`No. 13/412,283, a continuation of application No. 11/908,834, filed as application
`
`No. PCT/EP2006/060855, filed on March 20, 2006, and now U.S. Patent No.
`
`8,129,343. The ’122 patent also claims priority to U.S. Provisional Application No.
`
`60/664,497, filed on March 23, 2005, as well as European application No. 05102171,
`
`filed March 18, 2005.
`
`27.
`
`I understand the earliest priority date to which the challenged claims of
`
`the ’122 patent are entitled is March 18, 2005, the filing date of European application
`
`No. 05102171. Therefore, references that pre-date March 18, 2005, are prior art to
`
`the ’122 patent. To the extent Patent Owner later asserts and/or proves that the
`
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`challenged claims are entitled to an earlier priority or invention date, I reserve the
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`
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`right to supplement this declaration.
`
`28. The ’122 patent has one independent claim, which recites:
`
`1. A compound of formula II (SEQ ID No. 3):
`
`
`
`wherein
`
`Xaa7 is L-histidine, D-histidine, desamino-histidine, 2-
`amino-histidine, β-hydroxy-histidine, homohistid-
`ine, Nα-acetyl-histidine, a-fluoromethyl-histidine,
`a-methyl-histidine, 3-pyridylalanine, 2-pyridylala-
`nine, or 4-pyridylalanine;
`
`Xaa8 is Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl)
`carboxylic acid, (1-aminocyclobutyl) carboxylic
`
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`
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`(1-aminocyclopentyl) carboxylic acid,
`acid,
`(1-aminocyclohexyl) carboxylic acid, (1-amino-
`cycloheptyl) carboxylic acid, or
`(1-amino-
`cyclooctyl) carboxylic acid;
`
`Xaa16 is Val or Leu;
`
`Xaa18 is Ser, Lys, or Arg;
`
`Xaa19 is Tyr or Gln;
`
`Xaa20 is Leu or Met;
`
`Xaa22 is Gly, Glu, or Aib;
`
`Xaa23 is Gln, Glu, Lys, or Arg;
`
`Xaa25 is Ala or Val;
`
`Xaa27 is Glu or Leu;
`
`Xaa30 is Ala, Glu, or Arg2;
`
`Xaa33 is Val or Lys;
`
`Xaa34 is Lys, Glu, Asn, or Arg;
`
`
`2 I understand that while claim 1 originally recited “Xaa33 is Ala, Glu, or Arg,” a
`
`certificate of correction was issued by the USPTO on April 4, 2015, to revise this
`
`claim term to read “Xaa30 is Ala, Glu, or Arg.”
`
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`
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`Xaa35 is Gly or Aib;
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`Xaa36 is Arg, Gly, Lys, or is absent;
`
`Xaa37 is Gly, Ala, Glu, Pro, Lys, or is absent;
`
`Xaa38 is Lys, Ser, amide, or is absent;
`
`and where U is a spacer selected from [various spacers];
`and
`
`where B is an acidic group selected from
`
`
`
`29. Dependent claim 13 recites:
`
`13. A pharmaceutical composition comprising a
`compound according
`to claim 1, and a
`pharmaceutically acceptable excipient.
`
`V. CLAIM CONSTRUCTION
`
`30.
`
`I have been informed that claim terms should be given their plain and
`
`ordinary meaning in light of the intrinsic evidence (i.e., the specification and the
`
`prosecution history) from the perspective of a POSA. I also understand that while
`
`extrinsic evidence (e.g., scientific publications) may be considered when interpreting
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`the meaning of claim terms in some circumstances, it is generally given less weight
`
`
`
`than intrinsic evidence.
`
`31. No terms relevant to my opinions require construction beyond the plain
`
`and ordinary meaning.
`
`VI. SUMMARY OF OPINIONS
`
`32. As explained above, my background is related to the development of
`
`pharmaceutical formulations. Thus, my opinions focus on pharmaceutical
`
`formulation aspects of the challenged claims.
`
`33.
`
`I understand Mylan’s expert, Dr. Peter Flatt, is offering opinions from
`
`the perspective of a POSA with a background focused on chemical, biological,
`
`and/or biochemical aspects of the claims of the ’122 patent. In particular, I
`
`understand Dr. Flatt has offered opinions that the compound known as semaglutide,
`
`which I understand Dr. Flatt explains is encompassed by claim 1 of the ’122 patent,
`
`would have been obvious (i.e., a POSA would have been motivated to make
`
`semaglutide). Thus, I rely on Dr. Flatt’s opinions to conclude that semaglutide would
`
`have been obvious.
`
`34.
`
`I also understand Mylan has retained Dr. Christopher Soares, who
`
`opines from the perspective of a medicinal chemist, and Dr. John Bantle, who opines
`
`from the perspective of a medical doctor. As discussed above, my opinions are from
`
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`the perspective of a formulator who would collaborate with other POSAs like Drs.
`
`
`
`Flatt, Soares, and Bantle.
`
`35. First, while I offer no opinions on whether a POSA would have been
`
`motivated to make the compound semaglutide, I offer limited opinions in support of
`
`Dr. Flatt with respect to certain chemical modifications required to make
`
`semaglutide. Infra Section IX.A.
`
`36. Second, claim 13 of the ’122 patent is directed to a pharmaceutical
`
`composition comprising the compound of claim 1 (i.e., semaglutide) and a
`
`pharmaceutically acceptable excipient. Supra Section IV. In my opinion,
`
`formulating semaglutide and a pharmaceutically acceptable excipient into a
`
`pharmaceutical composition required no more than standard knowledge and routine
`
`skill. Indeed, as discussed in detail below, the prior art disclosed that many GLP-1
`
`analogues, including a first-generation GLP-1 analogue known as liraglutide, had
`
`been formulated into pharmaceutical compositions that contained excipients. See,
`
`e.g., Ex. 1012 (Knudsen Patent) at 4:36-38, 167:63-168:8, 169:54-57, 170:5-10,
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`216:17-222:18. In addition, a POSA would have had a reasonable expectation of
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`success in doing so in light of the prior art and/or the knowledge and skill of a POSA.
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`VII. BACKGROUND ON GLP-1 COMPOUND FORMULATIONS
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`A.
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`Pharmaceutical formulations generally
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`37. Well before the priority date of the ’122 patent, POSAs regularly
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`formulated drug substances, including therapeutic peptides, into pharmaceutical
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`compositions. Indeed, commercially available drug products rarely, if ever, contain
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`a drug substance on its own. Rather, drug substances must be formulated into
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`suitable pharmaceutical compositions that contain additional inactive ingredients, or
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`excipients, for administration to patients. See generally, e.g., Ex. 1088 (Remington);
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`Ex. 1089 (Boylan). By the priority date of the ’122 patent, a vast number of
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`excipients were commonly used to formulate drug substances. See, e.g., Ex. 1088
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`(Remington) at 41; Ex. 1089 (Boylan) at 18-24. Further, pharmaceutical
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`compositions could be made using commonly employed techniques that were well
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`understood by POSAs. See, e.g., Ex. 1088 (Remington) at 37-38; Ex. 1089 (Boylan)
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`at 18-19.
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`38. As just one example, therapeutic peptides were regularly formulated in
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`parenteral formulations. See, e.g., Ex. 1089 (Boylan) at 35-36. Parenteral
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`formulations can be administered though intravenous, subcutaneous, intradermal,
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`intramuscular, intraarticular, and intrathecal injection. See, e.g., Ex. 1089 (Boylan)
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`at 8-9 (Table 1). And POSAs were well aware of specific excipients that were
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`commonly used to make suitable parenteral formulations of therapeutic peptides.
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`See, e.g., Ex. 1088 (Remington) at 41; Ex. 1089 (Boylan) at 18-24. Those are just
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`examples, of course. The point is that there were a range of excipients that were in
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`standard use in pharmaceutical compositions that had known purposes.
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`39. Further, POSAs recognized the importance of maintaining the physical
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`and chemical stability of a drug formulation to minimize the risk of impurities during
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`manufacturing, storage, and handling. See, e.g., Ex. 1088 (Remington) at 28-29, 37-
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`38; Ex. 1089 (Boylan) at 7-8, 39. Indeed, because excipients can have profound
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`effects on the performance of a drug, POSAs understood that it was important that
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`parenteral preparations be “of the very best quality and provide the maximum safety
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`for the patient.” Ex. 1088 (Remington) at 37. Further, regulatory agencies like FDA
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`require the role and amount of each excipient to be justified, require the developer
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`to ensure there are no incompatibilities between the excipients and the active drug,
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`and require ongoing quality control of each excipient during manufacturing. See,
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`e.g., Ex. 1089 (Boylan) at 47. Accordingly, the role of excipients in pharmaceutical
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`formulations was well understood industry-wide.
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`B. GLP-1 compounds were well known
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`40. Before the priority date of the ’122 patent, POSAs were aware of the
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`two different truncated forms of naturally occurring glucagon-like peptide-1
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`(GLP-1): GLP-1(7-36) and GLP-1(1-37). Ex. 1012 (Knudsen Patent) at 4:48-60.
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`GLP-1(7-37) has the following sequence where X is Gly:
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`Id. The prior art explained that these naturally occurring peptides showed great
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`promise for their antidiabetic effect, and so scientists sought to use these peptides as
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`therapeutic agents. See, e.g., Ex. 1010 (Knudsen 2004) at 1; Ex. 1011 (Knudsen
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`2001) at 1-2.
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`41. The prior art also taught that chemically modified versions of these
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`naturally occurring peptides (i.e., analogues) had been made and were advancing in
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`clinical trials. See generally, e.g., Ex. 1010 (Knudsen 2004); Ex. 1011 (Knudsen
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`2001). As these analogues were being developed, so too were pharmaceutical
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`formulations suitable to deliver the analogues to patients. See, e.g., Ex. 1093 (Flink)
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`at Abstract; Ex. 1012 (Knudsen Patent) at 4:36-38, 167:63-168:8, 169:54-57, 170:5-
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`10, 216:17-222:18. Thus, many formulations of GLP-1 analogues were described in
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`the art by the priority date of the ’122 patent. See, e.g., Ex. 1093 (Flink) at 37:25-
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`46:5; Ex. 1012 (Knudsen Patent) at 4:36-38, 167:63-168:8, 169:54-57, 170:5-10,
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`216:17-222:18.
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`42. As discussed above, before the priority date of the ’122 patent, POSAs
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`were provided with substantial guidance to prepare formulations of peptides
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`generally. Supra Section VII.A. To no surprise, POSAs utilized this guidance to
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`make GLP-1 formulations, including, for example, parenteral formulations that
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`included various well-known excipients such as buffers, preservatives, isotonic
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`agents, and vehicles. See, e.g., Ex. 1093 (Flink) at 37:25-46:5; Ex. 1012 (Knudsen
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`Patent) at 4:36-38, 167:63-168:8, 169:54-57, 170:5-10, 216:17-222:18. The prior art
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`also taught that GLP-1 compounds could be formulated into injectable formulations.
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`Ex. 1012 (Knudsen Patent) at 216:15-57.
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`43. However, it was also well known that GLP-1 compounds had problems
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`with solubility and stability. See, e.g., Ex. 1092 (WO098) at 3-4; Ex. 1093 (Flink) at
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`3:21-24. Therefore, POSAs sought to optimize GLP-1 compounds, and formulations
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`that could alleviate these issues, to provide more soluble and stable formulations.
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`See, e.g., Ex. 1012 (Knudsen Patent) at 5:13-15; Ex. 1092 (WO098) at 7 (“In order
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`to overcome the problems of chemical and physical stability of GLP-1 formulations,
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`the present inventors have developed a shelf-stable formulation of GLP-1.”); Ex.
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`1091 (’674 patent) at 5:39-43 (“The discoveries described . . . have been combined
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`to provide novel preparations of polypeptide compositions for parenteral
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`administration comprising glycerin that have improved chemical stability compared
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`to polypeptide compositions previously known.”).
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`C. Liraglutide and formulations of liraglutide were well known
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`44. As discussed above, before the priority date of the ’122 patent, GLP-1
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`analogues and related formulations were well known in the art. Supra Section VII.B.
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`Indeed, the ’122 patent identifies examples of suitable GLP-1 analogues. Ex. 1001
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`(’122 patent) at 1:23-43 (citing WO 96/29342; WO 98/08871; WO 99/43708; WO
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`00/34331; WO 00/69911; WO 02/46227). These references likewise disclosed
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`pharmaceutical formulations containing the GLP-1 analogues that are physically and
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`chemically stable at high concentrations, which are suitable for subcutaneous
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`injection. See, e.g., Ex. 1093 (Flink) at 4:17-30.
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`45. One GLP-1 analogue that was well-published in the art before the
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`priority date of the ’122 patent was Novo Nordisk’s liraglutide (also called
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`NN2211). See, e.g., Ex. 1010 (Knudsen 2004) at 1; Ex. 1011 (Knudsen 2001) at 1-2.
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`And like other GLP-1 analogues under investigation, pharmaceutical formulations
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`of liraglutide had been developed and disclosed. Ex. 1012 (Knudsen Patent) at 4:36-
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`38, 167:63-168:8, 169:54-57, 170:5-10, 216:17-222:18.
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`VIII. SCOPE AND CONTENT OF THE PRIOR ART
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`46.
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`I identify below the prior art references supporting my expert opinions
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`on unpatentability of claim 13 of the ’122 patent, including references rendering the
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`claim obvious. All the references I cite in this document would have been known
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`and publicly available to a POSA as of the relevant priority date.
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`47. The prior-art disclosures identified in this expert declaration would
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`
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`have been understood by a POSA in light of the background knowledge that he or
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`she would have had by the applicable priority dates of the ’122 patent. Thus, to the
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`extent I list or describe a reference below but do not rely on it as a ground for arguing
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`unpatentability, that prior art should be unde