Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`________________________
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`________________________
`
`
`FRESENIUS KABI USA, LLC,
`Petitioner
`
`v.
`
`
`NOVO NORDISK A/S,
`Patent Owner
`
`________________________
`
`U.S. Patent No. 8,114,833
`Issue Date: February 14, 2012
`Title: Propylene glycol-containing peptide formulations which are optimal for
`production and for use in injection devices
`
`Case No. IPR2022-00657
`________________________
`
`DECLARATION OF LAIRD FORREST, PH.D. IN SUPPORT OF PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,114,833
`
`
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`Page
`
`INTRODUCTION AND QUALIFICATIONS .............................................. 1
`A.
`INTRODUCTION ................................................................................ 1
`B. QUALIFICATIONS AND EXPERIENCE ......................................... 1
`C. MATERIALS CONSIDERED ............................................................. 6
`D.
`SCOPE OF WORK .............................................................................. 6
`II.
`SUMMARY OF OPINIONS .......................................................................... 6
`III. LEGAL STANDARDS .................................................................................. 8
`IV. PERSON OF ORDINARY SKILL IN THE ART ....................................... 10
`V.
`THE ’833 PATENT ...................................................................................... 11
`VI. CLAIM CONSTRUCTION ......................................................................... 14
`VII. TECHNOLOGY BACKGROUND .............................................................. 15
`A. GLP-1 AGONISTS, INCLUDING LIRAGLUTIDE, WERE
`WELL KNOWN IN THE ART ......................................................... 15
`PARENTERAL PEPTIDE DOSAGE FORMS ................................. 16
`STABILITY OF PEPTIDE FORMULATIONS AND
`SELECTION OF EXCIPIENTS ........................................................ 26
`1.
`USE OF PROPYLENE GLYCOL IN PEPTIDE
`FORMULATIONS .................................................................. 28
`PROPYLENE GLYCOL IS SAFE .......................................... 31
`PROPYLENE GLYCOL’S ADVANTAGES OVER
`OTHER ISOTONIC AGENTS ................................................ 31
`VIII. SCOPE AND CONTENT OF THE PRIOR ART REFERENCES ............. 35
`A.
`FLINK (EX. 1004) ............................................................................. 35
`B.
`BETZ (EX. 1005) ............................................................................... 45
`C. OTHER ART THAT INFORMS THE PERSON OF
`ORDINARY SKILL’S KNOWLEDGE ............................................ 47
`
`B.
`C.
`
`2.
`3.
`
`
`
`i
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`

`

`2.
`
`3.
`4.
`5.
`6.
`
`7.
`
`8.
`
`9.
`
`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`1.
`
`U.S. PATENT NO. 6,268,343 (“KNUDSEN I”) (EX.
`1006) ........................................................................................ 47
`EUR. PATENT APP. PUB. NO. EP0923950
`(“IBARAKI”) (EX. 1007) ........................................................ 48
`POWELL (EX. 1008) .............................................................. 49
`EPPERSON (EX. 1009) ........................................................... 49
`JACOBS (EX. 1011) ................................................................ 50
`INT’L PATENT PUB. NO. WO 1999/040788
`(“YOUNG”) (EX. 1025) .......................................................... 50
`INT’L PATENT PUB. NO. WO 03/072195 (“KHAN”)
`(EX. 1014) ................................................................................ 51
`INT’L PATENT PUB. NO. WO 95/022560 (“DIX”)
`(EX. 1019) ................................................................................ 52
`U.S. PATENT NO. 6,458,924 (“KNUDSEN II”) (EX.
`1020) ........................................................................................ 53
`INT’L PATENT PUB. NO. WO 00/037098 (EX. 1021) ........ 53
`10.
`11. HANDBOOK OF PHARMACEUTICAL EXCIPIENTS
`2000, 2003 (EXS. 1022-1023) ................................................. 54
`12. NAIL & AKERS (EX. 1024) ................................................... 54
`13. BONTEMPO (EX. 1026) ......................................................... 57
`14. GATLIN (EX. 1027) ................................................................ 59
`15. REMINGTON’S 1990 (EX. 1013) .......................................... 61
`16. STURIS (EX. 1046) ................................................................. 63
`17. CHANG (EX. 1059) ................................................................ 64
`18. U.S. PATENT NO. 4,425,346 (“HORLINGTON”) (EX.
`1063) ........................................................................................ 64
`19. U.S. PATENT NO. 6,207,684 (“ABERG”) (EX. 1064) ......... 65
`20. U.S. PATENT NO. 6,440,460 (“GURNY”) (EX. 1065) ......... 66
`
`
`
`ii
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`21. ADDITIONAL PRIOR ART REFERENCES AND
`KNOWLEDGE ........................................................................ 66
`IX. UNPATENTABILITY OF THE ’833 PATENT ......................................... 67
`A.
`CLAIMS 1-15 OF THE ’833 PATENT WERE ANTICIPATED
`BY OR WOULD HAVE BEEN OBVIOUS OVER FLINK ............. 67
`1.
`CLAIM 1 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 67
`CLAIMS 2-4 WERE ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 79
`CLAIMS 5-7 WERE ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 80
`CLAIMS 8 AND 9 WERE ANTICIPATED BY OR
`WOULD HAVE BEEN OBVIOUS OVER FLINK ............... 80
`CLAIM 10 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 80
`CLAIM 11 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 81
`CLAIM 12 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 82
`CLAIM 13 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 83
`CLAIM 14 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 84
`10. CLAIM 15 WAS ANTICIPATED BY OR WOULD
`HAVE BEEN OBVIOUS OVER FLINK ............................... 85
`CLAIMS 1-31 OF THE ’833 PATENT WOULD HAVE BEEN
`OBVIOUS OVER FLINK IN VIEW OF BETZ ................................ 86
`1.
`CLAIMS 1-15 WOULD HAVE BEEN OBVIOUS
`OVER FLINK IN VIEW OF BETZ ........................................ 86
`CLAIM 16 WOULD HAVE BEEN OBVIOUS OVER
`FLINK IN VIEW OF BETZ .................................................... 94
`
`7.
`
`8.
`
`9.
`
`2.
`
`B.
`
`
`
`iii
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`CLAIMS 17-19 WOULD HAVE BEEN OBVIOUS
`OVER FLINK IN VIEW OF BETZ ........................................ 96
`CLAIMS 20-22 WOULD HAVE BEEN OBVIOUS
`OVER FLINK IN VIEW OF BETZ ........................................ 97
`CLAIMS 23, 26, AND 29 WOULD HAVE BEEN
`OBVIOUS OVER FLINK IN VIEW OF BETZ ..................... 97
`CLAIMS 24, 27, AND 30 WOULD HAVE BEEN
`OBVIOUS OVER FLINK IN VIEW OF BETZ ..................... 98
`CLAIMS 25, 28, AND 31 WOULD HAVE BEEN
`OBVIOUS OVER FLINK IN VIEW OF BETZ ................... 101
`X. NO SECONDARY CONSIDERATIONS OVERCOME PRIMA
`FACIE OBVIOUSNESS OF THE CLAIMED INVENTIONS ................. 101
`A.
`THE METHODS RECITED IN THE ’833 PATENT
`PRODUCE NO UNEXPECTED RESULTS. .................................. 101
`THERE WAS NO LONG-FELT BUT UNMET NEED ................. 103
`THERE WAS NO INDUSTRY SKEPTICISM ............................... 103
`COPYING BY GENERIC DRUG MAKERS IS
`IRRELEVANT ................................................................................. 103
`E. A BLOCKING PATENT EXISTED AT THE TIME OF THE
`CLAIMED INVENTION ................................................................. 104
`XI. CONCLUSION ........................................................................................... 105
`
`B.
`C.
`D.
`
`
`
`iv
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`I, Laird Forrest, Ph.D., declare as follows:
`
`I.
`
`INTRODUCTION AND QUALIFICATIONS
`Introduction
`A.
`1. My name is Laird Forrest, Ph.D. I have been retained by counsel for
`
`Fresenius Kabi USA, LLC (“Fresenius”). I understand that Fresenius intends to
`
`petition for inter partes review (“IPR”) of U.S. Patent No. 8,114,833 (“the ’833
`
`patent”), Ex. 1001, which is assigned to Novo Nordisk A/S. I also understand that,
`
`in the IPR petition, Fresenius will request that the United States Patent and
`
`Trademark Office cancel all claims of the ’833 patent as unpatentable. I submit this
`
`expert declaration to address and support Fresenius’s IPR petition for the ’833
`
`patent.
`
`B. Qualifications and Experience
`2. My qualifications for forming the opinions set forth in this
`
`Declaration are summarized here and explained in more detail in my curriculum
`
`vitae, which I have attached to my Declaration as Exhibit A.
`
`3.
`
`I am currently a Professor in the Department of Pharmaceutical
`
`Chemistry at the University of Kansas in Lawrence, Kansas, a position I have held
`
`since 2017. I am also Professor in the Bioengineering Center, a position I have
`
`held since 2011, and Professor in the Department of Medicinal Chemistry, a
`
`position I have held since 2015, both also at the University of Kansas. I have been
`1
`
`
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`a faculty at the University of Kansas since 2007.
`
`4.
`
`I received a Bachelor of Science in Chemical Engineering from
`
`Auburn University in 1998, a Master of Science in Chemical Engineering from the
`
`University of Illinois in 2001, and a Ph.D. in Chemical and Biomolecular
`
`Engineering from the University of Illinois in 2003. I was a Postdoctoral Fellow in
`
`the Division of Pharmaceutical Sciences at the University of Wisconsin, Madison,
`
`from 2004 to 2006. In 2006, I became Adjunct Assistant Professor in the
`
`Department of Pharmaceutical Sciences at Washington State University, a position
`
`I held until 2011. In 2007, I accepted a position as Assistant Professor in the
`
`Department of Pharmaceutical Chemistry at the University of Kansas. I was
`
`promoted to Associate Professor at the University of Kansas in 2013. I was then
`
`promoted to the rank of Professor in 2017.
`
`5.
`
`Since 2009, I have been a Member of the Scientific and Medical
`
`Advisory Board of Exogenesis Corporation, which develops nanoscale surface
`
`modifications for implantable medical devices. I am the co-founder of HylaPharm
`
`LLC, founded in 2011, which specializes in reformulation of anti-cancer
`
`chemotherapeutics by modification of the delivery route and pharmacokinetics.
`
`Also, I am a co-founder of Hafion LLC, founded in 2016, which specializes in
`
`development of vaccines, and Aerobyx LLC, founded in 2017, which specializes in
`
`
`
`2
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`the development of medications for treatment of neurological and metabolic
`
`disease. In addition, I am a co-founder of Vesarex, founded in 2018, which
`
`specializes in the development of ultrasound imaging devices and contrast agents. I
`
`also am a co-founder of Ferroximend, founded in 2020, which specializes in the
`
`development of medical devices and medicines for improving the healing of bone
`
`fractures. My research toward drug formulation has been competitively funded by
`
`multiple awards from the National Institutes of Health, the National Cancer
`
`Institute, the National Institute of Aging, the National Institute of Allergy and
`
`Infectious Disease, the American Cancer Society, the Department of Defense,
`
`Susan G. Komen Race for the Cure, and the Pharmaceutical Research and
`
`Manufacturers of America Foundation (“PhRMA”), among others. In addition, I
`
`have been funded by the Food and Drug Administration (“FDA”) to develop
`
`methodologies for the in vitro determination of bioequivalence in follow-on
`
`complex botanical and biosimilar drug formulations.
`
`6.
`
`I have received many awards and honors, including the Baxendale
`
`Innovation Award (2016), the University of Kansas Leading Light award (2014),
`
`the Japan Society for Promotion of Science Visiting Scholar Fellow (2010), the
`
`American Cancer Society Research Scholar (2008 to 2012), the American
`
`Association of Colleges of Pharmacy, New Investigators Award (2007), and the
`
`
`
`3
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`PhRMA Foundation Postdoctoral Fellow (2006), among others.
`
`7.
`
`I am currently or have been in the past a member of various
`
`professional societies, including the American Association for Cancer Research,
`
`the American Association of Pharmaceutical Scientists, and the American Institute
`
`of Chemical Engineers. I serve or have served on numerous scientific review
`
`panels for the National Institutes of Health, the American Cancer Society, and the
`
`Association for International Cancer Research (United Kingdom). I am a previous
`
`standing member and current ad hoc member of the American Cancer Society
`
`review panel on Cancer Drug Development.
`
`8.
`
`I have authored more than 100 peer-reviewed journal articles and 5
`
`book chapters. I have also edited 2 special journal issues on drug delivery and a
`
`book on drug delivery and formulation.
`
`9.
`
`I have taught drug formulation and biopharmaceutics, including all
`
`aspects of drug excipient choice and the effects of excipient modification on drug
`
`pharmacokinetics, ionic equilibrium, drug chemical stability, drug dissolution, and
`
`drug absorption, to clinical pharmacy students and graduate students studying
`
`pharmaceutical sciences since 2007.
`
`10.
`
`I have experience in all aspects of parenteral, topical, and oral drug
`
`formulation and pharmacokinetics through my research and teaching. Additionally,
`
`
`
`4
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`as part of my work with HylaPharm, Exogenesis Inc., Atrin Pharmaceutics, Eli
`
`Lilly, Roche AG, and Akari Therapeutics Inc., I have worked on pharmaceutical
`
`formulations for intramuscular, subcutaneous, intravenous, topical, and oral
`
`formulation.
`
`11.
`
`In the past six years, I have testified in the following litigations:
`
`• Merck Sharp & Dohme Corp. v. Savior Lifetec Corp., No. 5:15-cv-
`
`00415-TWB (E.D.N.C.);
`
`• Halozyme, Inc. v. Joseph Matal (on behalf of USPTO), No. 1:16-cv-
`
`1580 (E.D. Va.);
`
`• Bracco Diagnostics v. Maia Pharm., Inc., No. 3:17-cv-13151
`
`(D.N.J.); and
`
`• Horizon Medicines LLC v. Dr. Reddy’s Labs. Inc., No. 2:15-cv-
`
`03324-SRC-CLW (D.N.J.) (consolidated).
`
`• Indivior Inc. v. Dr. Reddy’s Laboratories, No. 18-5288-KM-CLW
`
`(D.N.J.).
`
`In addition, I also gave sworn depositions in the following Inter Partes Reviews,
`
`which were consolidated: Mylan Institutional LLC v. Novo Nordisk A/S, IPR2020-
`
`00324 (PTAB 2019) and Pfizer Inc. v. Novo Nordisk A/S, IPR2020-01252 (PTAB
`
`2020).
`
`
`
`5
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`C. Materials Considered
`12. Exhibit B includes a list of the materials I considered, in addition to
`
`my experience, education, and training, in providing the opinions contained in this
`
`declaration.
`
`D.
`13.
`
`Scope of Work
`I have been retained by Fresensius as a technical expert to provide
`
`various opinions regarding the ’833 patent. I am being compensated for my
`
`time at my standard consulting rate of $700/hour. Neither the amount of my
`
`compensation nor the fact that I am being compensated has altered the opinions
`
`that I have given in this Declaration. My compensation is in no way dependent on
`
`the outcome of this proceeding. I do not have any current or past affiliation with
`
`Novo Nordisk A/S, or any of its affiliates presently known to me, or the named
`
`inventors on the ’833 patent.
`
`II.
`
`SUMMARY OF OPINIONS
`In my view, claims 1-15 of the ’833 patent were anticipated by
`14.
`
`International Patent Publication No. WO 2003/0002136 to Flink et al. (“Flink”) (Ex.
`
`1004), as described in detail below. Flink’s claim 14 disclosed, in the context of the
`
`specification, each element of the inventions claimed in claims 1-15 of the
`
`’833 patent.
`
`
`
`6
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`15. Also, claims 1-15 of the ’833 patent would have been obvious
`
`over Flink, as described in detail below. In short, to the extent Flink would have
`
`been viewed as not anticipating the inventions claimed in the ’833 patent, the
`
`inventions would have been obvious to a person of ordinary skill in the art
`
`because the POSA would have been motivated to combine the claimed elements
`
`with a reasonable expectation of success.
`
`16. Additionally, claims 1-31 of the ’833 patent would have been
`
`obvious over Flink in view of International Patent Publication No. WO
`
`2004/0004781 to Betz and Stevens (“Betz”) (Ex. 1005), as described in detail
`
`below. To the extent Flink would have been viewed as neither anticipating nor
`
`rendering obvious the claims of the ’833 patent, a POSA would have understood
`
`from Betz to use propylene glycol in the GLP-1 formulation disclosed in Flink,
`
`with a reasonable expectation of success.
`
`17. Finally, there are no apparent secondary considerations
`
`supporting nonobviousness of the claims. There is no evidence of unexpected
`
`results in view of the prior art, which also satisfied any need for the claimed
`
`invention. Further, there is no evidence of industry skepticism of the claimed
`
`invention, and any allegation that the invention is nonobvious because it was
`
`copied does not weight in this context. Finally, a blocking patent existed at the
`
`
`
`7
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`time of the claimed invention, which would have dissuaded anyone from
`
`developing the claimed formulations and methods, and reduces the weight to
`
`be given to any secondary considerations asserted in favor of patentability. I
`
`reserve the right to address any secondary considerations put forth by Patent
`
`Owner in any later response to this declaration or the petition it accompanies.
`
`III. LEGAL STANDARDS
`In preparing and forming my opinions set forth in this report, counsel
`18.
`
`has informed me regarding the relevant legal principles.
`
`19. Counsel informed me that Fresenius bears the burden of proving
`
`unpatentability by a preponderance of the evidence. Counsel informed that this
`
`“preponderance of the evidence” standard means that Fresenius must show that
`
`unpatentability is more probable than not. I have taken these principles into
`
`account when forming my opinions in this case.
`
`20.
`
`I have also been told that claims should be given their plain and
`
`ordinary meaning in light of the specification from the perspective of a person of
`
`ordinary skill in the art.
`
`21. Counsel informed me that the question of whether the claims of a
`
`patent are anticipated by, or obvious in view of, the prior art is to be considered
`
`from the perspective of the person of ordinary skill in the art (“POSA”). Counsel
`
`
`
`8
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`further informed me that the answer to this question is determined as of the time
`
`the invention was made. I understand from counsel 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 scope and content of
`
`the prior art; (3) the level of ordinary skill in the art; and (4) whether there are
`
`additional factors present that may argue against a conclusion of obviousness (i.e.,
`
`“secondary considerations”) such as unexpected results attributable to the
`
`invention, or whether the invention met a long-felt but unmet need.
`
`22. Counsel informed me that an invention may be found obvious when
`
`there is some recognized reason to solve a problem, and there are a finite number
`
`of identified, predictable, and known solutions, and 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. In such a circumstance, when a
`
`patent simply arranges old elements with each performing its known function and
`
`yields no more than what one would expect from such an arrangement, the
`
`combination is obvious.
`
`23. Counsel informed me that a prior art reference anticipates a claimed
`
`invention if the prior art reference disclosed each of the claimed elements of the
`
`
`
`9
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`invention either expressly or inherently. A claim element is inherent in the
`
`anticipating reference if that element, or characteristic, is the natural result that
`
`flows from the reference’s explicit limitations. In this regard, counsel informed me
`
`that a reference can anticipate a claim even if the reference does not expressly spell
`
`out all the limitations arranged or combined as in the claim, if a person of skill in
`
`the art, reading the reference, would at once envisage the claimed arrangement or
`
`combination. Counsel has informed me that if a patent claims a composition in
`
`terms of a function, property, or characteristic, and the composition itself is in the
`
`prior art, then the claim may be anticipated or obvious in view of the prior art
`
`reference disclosing the composition.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`I have been informed by counsel that the obviousness analysis is to
`24.
`
`be conducted from the perspective of a person of ordinary skill in the art (a “person
`
`of ordinary skill” or “skilled artisan”) at the time of the invention.
`
`25.
`
`I have also been informed by counsel that in defining a person of
`
`ordinary skill the following factors may be considered: (1) the educational level of
`
`the inventor; (2) the type of problems encountered in the art; (3) prior art 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
`
`
`
`10
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`field.
`
`26. Thus, in this report, unless stated otherwise, I opine from the
`
`perspective of the person of ordinary skill in the art at the time of the invention
`
`(POSA). The POSA is (1) a Pharm. D., or a Ph.D. in pharmacy, chemical
`
`engineering, bioengineering, chemistry, or related discipline; with (2) at least two
`
`years of experience in the area of protein or peptide therapeutic development
`
`and/or manufacturing; and (3) experience with the development, design,
`
`manufacture, or formulation of therapeutic agents, and the literature concerning
`
`protein or peptide formulation and design.
`
`27. For purposes of this declaration, my opinion is based on the
`
`knowledge or understanding of a POSA as of the earliest possible priority date
`
`claimed on the cover of the ’833 patent, November 20, 2003 (see below, ¶28),
`
`unless specified otherwise.
`
`V. THE ’833 PATENT
`I have read the ’833 patent, entitled “Propylene glycol-containing
`28.
`
`peptide formulations which are optimal for production and for use in injection
`
`devices.” According to its cover page, the ’833 patent was filed on May 17, 2006
`
`as U.S. Patent Application No. 11/435,977, a continuation application of No.
`
`PCT/DK2004/000792, filed on November 18, 2004. U.S. Patent Application No.
`
`
`
`11
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`

`

`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`11/435,977 also claims priority to U.S. Provisional Application No. 60/524,653,
`
`filed on November 24, 2003, as well as a Danish application filed November 20,
`
`2003.
`
`29.
`
`I understand that Fresenius is challenging claims 1-31 of the ’833
`
`patent as unpatentable. The ’833 patent includes five independent claims: claims 1,
`
`16, 23, 26, and 29.
`
`30.
`
`Independent claim 1 recites:
`
`A pharmaceutical formulation comprising at least one
`GLP-1 agonist, a disodium phosphate dihydrate buffer and
`propylene glycol, wherein said propylene glycol is present
`in said formulation in a final concentration of from about
`1 mg/ml to about 100 mg/ml and wherein said formulation
`has a pH of from about 7.0 to about 10.0.
`31. Dependent claims 2-15 depend from claim 1. Dependent claims 2-4
`
`relate to the concentration of propylene glycol in the formulation. Dependent
`
`claims 5-7 relate to the pH of the formulation. Dependent claims 8-9 recite that the
`
`formulation contains a preservative, and identifies its concentration, respectively.
`
`Dependent claims 10-15 relate to the identity of the GLP-1 agonist.
`
`32.
`
`Independent claim 16 recites:
`
`A method of preparing a GLP-1 agonist formulation
`suitable for use in an injection device, said method
`comprising preparing a formulation containing a GLP-1
`agonist, propylene glycol, a disodium phosphate dihydrate
`buffer, and a preservative, wherein said propylene glycol
`
`
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`is present in a concentration from about 1 mg/ml to about
`100 mg/ml, and wherein said formulation has a pH from
`about 7.0 to about 10.0, and wherein said GLP-1 agonist,
`said propylene glycol and said buffer and preservative are
`mixed together to produce said formulation as follows:
`a) preparing a first solution by dissolving preservative,
`propylene glycol and buffer in water;
`b) preparing a second solution by dissolving the GLP-1
`agonist in water;
`c) mixing the first and second solutions; and
`adjusting the pH of the mixture in c) to a pH of from about
`7.0 to about 10.0.
`33. Dependent claims 17-22 depend from claim 16. Dependent claims
`
`17- 19 relate to the concentration of propylene glycol in the formulation.
`
`Dependent claims 20-22 relate to the pH of the formulation.
`
`34.
`
`Independent claim 23 recites:
`
`A method for reducing deposits on production equipment
`during production of a GLP-1 agonist formulation, said
`method comprising replacing
`the
`isotonicity agent
`previously utilized in said formulation with propylene
`glycol at a concentration of between 1-100 mg/ml, and
`wherein said GLP-1 agonist formulation comprises a
`disodium phosphate dihydrate buffer.
`35. Dependent claims 24 and 25 depend from claim 23. Dependent claim
`
`24 recites that the reduction in deposits is measured by a simulated filling
`
`experiment. Dependent claim 25 recites the group of isotonicity agents that could
`
`be replaced.
`
`
`
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`

`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`
`36.
`
`Independent claim 26 recites:
`
`A method for reducing deposits in the final product during
`production of a GLP-1 agonist formulation, said method
`comprising replacing the isotonicity agent previously
`utilized in said formulation with propylene glycol at a
`concentration of between 1-100 mg/ml, and wherein said
`GLP-1 agonist
`formulation comprises a disodium
`phosphate dihydrate buffer.
`37. Dependent claims 27 and 28 depend from claim 26. Dependent claim
`
`27 recites that the reduction in deposits is measured by the number of vials and/or
`
`cartridges that must be discarded due to deposits. Dependent claim 28 recites the
`
`group of isotonicity agents that could be replaced.
`
`38.
`
`Independent claim 29 recites:
`
`A method for reducing the clogging of injection devices
`by a GLP-1 agonist formulation, said method comprising
`replacing the isotonicity agent previously utilized in said
`formulation with propylene glycol at a concentration of
`between 1-100 mg/ml, and wherein said GLP-1 agonist
`formulation comprises a disodium phosphate dihydrate
`buffer.
`39. Dependent claims 30 and 31 depend from claim 29. Dependent claim
`
`30 recites that the reduction in clogging is measured by a simulated in use study.
`
`Dependent claim 31 recites the group of isotonicity agents that could be replaced.
`
`VI. CLAIM CONSTRUCTION
`I understand that the claim terms used in the ’833 patent are to be
`40.
`
`understood according to their ordinary and customary meaning in light of the
`14
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`specification of the patent in which they appear. I further understand that Petitioner
`
`is not seeking to construe differently any terms in the claims of the ’833 patent,
`
`although Petitioner does argue that the preambles of certain claims should be
`
`construed as not limiting the scopes of those claims.
`
`VII. TECHNOLOGY BACKGROUND
`A. GLP-1 Agonists, Including Liraglutide, Were Well Known in the
`Art
`41. Human GLP-1 is a 37-amino acid peptide hormone (“GLP-1(1-
`
`37)”) originating from preproglucagon. Processing of preproglucagon, yields two
`
`shorter forms of GLP-1: GLP-1(7-36)amide and GLP-1(1-37). Ex. 1006, 4:17-24.
`
`GLP- 1(7-36) and GLP-1(1-37) have the following sequence:
`
`His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-
`Leu-Glu-Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-
`Leu-Val-Lys- Gly-Arg-X
`where X is H2 for GLP-1(7-36) and X is Gly for GLP-1(7-37). Ex. 1006, 4:50-60.
`42. By the priority date, GLP-1 agonists were well known in the art. The
`
`’833 patent itself identifies numerous disclosures of prior art GLP-1 agonists. See
`
`Ex. 1001, 4:38-52 (citing WO93/19175, WO99/43705, WO 99/43706,
`
`WO99/43707, WO98/08871, WO02/46227, WO99/43708, WO99/43341,
`
`WO87/06941, WO90/11296, WO91/11457, WO98/43658, EP0708179,
`
`EP0699686, and WO01/98331) (Exs. 1031-1045, respectively); see also Ex. 1006
`
`
`
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`Declaration of Laird Forrest, Ph.D. in Support of
`Petition for Inter Partes Review of
`U.S. Patent No. 8,114,833
`
`(U.S. Patent No. 6,268,343) at 268:15-16 (claim 23) (claiming liraglutide).
`
`Parenteral Peptide Dosage Forms
`B.
`43. Parenteral dosage forms are medicinal preparations that are intended
`
`to be given by injection into subcutaneous or muscular tissues, veins or arteries,
`
`joints, the spinal canal, and other routes that are para enteron (Greek for “beside
`
`the intestine”). Ex. 1013 at 157-58, 354. In contrast, non-parenteral formulations
`
`are designed to be taken orally, topically, vaginally, via the rectum, and generally
`
`routes that require the medicament to pass through protective mucosal membranes.
`
`Ex 1013 at 157-58, 203, 354.
`
`44. A POSA would understand that parenteral dosage forms have
`
`advantages in treating a patient for certain circumstances and conditions.