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
`______________
`
`
`PATENT OWNER PRELIMINARY RESPONSE
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`TABLE OF CONTENTS
`
`IPR2020-00324
`Patent 8,114,833
`
`
`B.
`
`
`I.
`II.
`
`
`
`Introduction ...................................................................................................... 1
`Background ...................................................................................................... 4
`A.
`Peptide Formulation .............................................................................. 4
`B. GLP-1 Formulation ............................................................................... 7
`C.
`Parenteral Formulations and Isotonicity ................................................ 8
`D.
`Propylene Glycol ................................................................................. 10
`III. The ’833 Patent .............................................................................................. 14
`A.
`The Invention of the ’833 Patent ......................................................... 14
`B.
`The ’833 Patent Claims ....................................................................... 17
`IV. Person of Ordinary Skill in the Art ................................................................ 17
`V.
`Claim Construction ........................................................................................ 17
`VI. Ground 1: Mylan Failed To Show a Reasonable Likelihood that Any of
`Claims 1-15 Are Anticipated by Flink .......................................................... 18
`A.
`Flink’s Claim 14 and the Unclear Network of Claims on Which It
`Depends Do Not Anticipate ’833 Patent Claims 1-10 ........................ 18
`Even Beyond Claim 14, Flink Does Not Disclose the Formulations
`Claimed in the ’833 Patent .................................................................. 25
`Caselaw Supports Rejection of Mylan’s Anticipation Theory ........... 30
`C.
`Flink’s Claims 21-25 Do Not Anticipate ’833 Patent Claims 11-15 .. 34
`D.
`VII. Ground 2: Mylan Failed To Show a Reasonable Likelihood That Any of
`Claims 1-15 Would Have Been Obvious Over Flink .................................... 35
`A.
`The Inventors Solved an Unknown Problem, Making Their Invention
`Non-Obvious as a Matter of Law ........................................................ 36
`i
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`

`

`B.
`
`C.
`
`IPR2020-00324
`Patent 8,114,833
`
`
`Flink Does Not Motivate Persons of Ordinary Skill To Combine
`Propylene Glycol with Disodium Phosphate Dihydrate ..................... 41
`C. Mylan Has Not Identified Any Motivation To Use Propylene Glycol
`or Established a Reasonable Expectation of Success .......................... 44
`VIII. Ground 3: Mylan Failed to Show a Reasonable Likelihood That Any of
`Claims 1-31 Would Have Been Obvious Over Flink in View of Betz ......... 47
`A. Betz Does Not Teach What Mylan Claims It Teaches ........................ 47
`B. Mylan Provides No Credible Rationale for Combining the Teachings
`of Betz and Flink ................................................................................. 52
`Claims 16-22 Would Not Have Been Obvious over Flink in View of
`Betz ...................................................................................................... 57
`D. Claims 23-31 Would Not Have Been Obvious over Flink in View of
`Betz ...................................................................................................... 58
`IX. Conclusion ..................................................................................................... 61
`
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`ii
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`TABLE OF AUTHORITIES
`
`IPR2020-00324
`Patent 8,114,833
`
`
`
`CASES
`Akzo N.V. v. U.S. Int’l Trade Comm’n,
`808 F.2d 1471 (Fed. Cir. 1986) ........................................................ 29, 35, 41, 44
`Aquestive Therapeutics, Inc. v. Neurelis, Inc.,
`IPR2019-00449, Paper No. 7 (P.T.A.B. Aug. 1, 2019) ...................................... 25
`Complex Innovations, LLC v. AstraZeneca AB,
`IPR2017-00631, Paper No. 13 (P.T.A.B. July 24, 2017) ................................... 30
`Conopco, Inc. dba Unilever v. Procter & Gamble Co.,
`IPR2013-00509, Paper No. 10 (P.T.A.B. Feb. 12, 2014) ................................... 34
`Endo Pharm., Inc. v. Depomed, Inc.,
`IPR2014-00651, Paper No. 12 (P.T.A.B. Sept. 29, 2014) ............................ 26, 29
`Grünenthal GMBH v. Antecip Bioventures II LLC,
`PGR2017-00022, Paper No. 50 (P.T.A.B. Nov. 14, 2018) .................... 26, 29, 30
`In re Arkley,
`455 F.2d 586 (C.C.P.A. 1972) ............................................................................ 33
`In re Chudik,
`851 F.3d 1365 (Fed. Cir. 2017) .......................................................................... 23
`In re Huai-Hung Kao,
`639 F.3d 1057 (Fed. Cir. 2011) .......................................................................... 59
`In re Kotzab,
`217 F.3d 1365 (Fed. Cir. 2000) .................................................................... 42, 47
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) .......................................................................... 42
`Innogenetics, N.V. v. Abbott Labs.,
`512 F.3d 1363 (Fed. Cir. 2008) .......................................................................... 24
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) .......................................................................... 32
`iii
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`Patent 8,114,833
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`
`King Pharms., Inc. v. Eon Labs, Inc.,
`616 F.3d 1267 (Fed. Cir. 2010) .......................................................................... 60
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .............................................................. 36, 41, 58
`Millennium Pharm., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .......................................................................... 59
`Monarch Knitting Machinery Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ...................................................................... 41, 55
`Mylan Pharm. Inc. v. 3M Co.,
`IPR2015-02002, Paper No. 8 (P.T.A.B. Apr. 4, 2016)................................. 25, 33
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .......................................................................... 25
`Novartis Pharms. Corp. v. Watson Labs., Inc.,
`611 Fed. App’x 988 (Fed. Cir. 2015) ............................................... 36, 41, 48, 58
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) .................................................................... 44, 55
`Otonomy, Inc. v. Auris Med., AG,
`743 F. App’x 430 (Fed. Cir. 2018) ................................................... 26, 27, 30, 34
`Par Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 59
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) (en banc) .......................................................... 24
`Procter & Gamble Co. v. Teva Pharms. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ................................................................ 46, 53, 57
`Samsung Elecs. Co. v. U.S. Ethernet Innovations, LLC,
`IPR2013-00384, Paper No. 9 (P.T.A.B. Dec. 30, 2013) .................................... 18
`W.L. Gore v. Garlock, Inc.,
`721 F.3d 1540 (Fed. Cir. 1983) .......................................................................... 19
`
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`Wasica Fin. GmbH v. Cont’l Auto. Sys.,
`853 F.3d 1272 (Fed. Cir. 2017) .............................................................. 19, 25, 34
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA, LLC,
`683 F.3d 1356 (Fed. Cir. 2012) .................................................................... 31, 32
`STATUTES & RULES
`35 U.S.C. § 102(b) ................................................................................................... 13
`35 U.S.C. § 312 ........................................................................................................ 20
`35 U.S.C. § 313 .......................................................................................................... 1
`37 C.F.R. § 42.104 ............................................................................................passim
`37 C.F.R. § 42.108 ................................................................................................... 61
`MPEP 608.01(n) ..................................................................................... 19, 20, 21, 22
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`
`EXHIBIT
`2001
`
`2002
`
`2003
`
`2004
`
`2006
`
`2007
`
`TABLE OF EXHIBITS
`DESCRIPTION
`Declaration of Ryan P. Johnson in Support of Patent Owner’s
`Motion for Admission Pro Hac Vice of Ryan P. Johnson Under 37
`C.F.R. § 42.10(c)
`
`Declaration of Laura T. Moran in Support of Patent Owner’s Motion
`for Admission Pro Hac Vice of Laura T. Moran Under 37 C.F.R. §
`42.10(c)
`
`Chien-Hua Niu, FDA Perspective on Peptide Formulation and
`Stability Issues, 87 J. PHARM. SCIENCES 1331 (1998) (“Niu”)
`
`C. Goolcharran, et al., Chemical Pathways of Peptide and Protein
`Degradation, in PHARMACEUTICAL FORMULATION DEVELOPMENT OF
`PEPTIDES AND PROTEINS 70 (Sven Frokjaer & Lars Hovgaard eds.,
`2000) (“Goolcharran”)
`
`2005 Mark C. Manning et al., Stability of Protein Pharmaceuticals, 6
`PHARM. RESEARCH 903 (1989) (“Manning”)
`
`R.W. Payne, et al., Peptide Formulation: Challenges and Strategies,
`INNOVATIONS PHARM. TECH. 64 (2009) (“Payne”)
`
`E.T. Kaiser et al., Secondary structures of proteins and peptides in
`amphiphilic environments (A Review), 80 PROC. NATL. ACAD. SCI.
`USA 1137 (1983) (“Kaiser”)
`
`Dean K. Clodfelter et al., Effects of Non-Covalent Self-Association
`on the Subcutaneous Absorption of a Therapeutic Peptide, 15
`PHARM. RES. 254 (1998) (“Clodfelter”)
`
`Eva Y. Chi et al., Physical Stability of Proteins in Aqueous Solution:
`Mechanism and Driving Forces in Nonnative Protein Aggregation,
`20 PHARM. RESEARCH 1325 (2003) (“Chi”)
`
`U.S. Patent No. 5,932,547
`
`
`2008
`
`2009
`
`2010
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`
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`
`DESCRIPTION
`Lotte Knudsen, et al., Potent Derivatives of Glucagon-like Peptide-1
`with Pharmacokinetic Properties Suitable for Once Daily
`Administration, 43 J. MED. CHEM. 1664 (2000) (“Knudsen 2000”)
`
`U.S. Patent Application Publication No. 2002/0061838
`
`Humira® Package Insert (revised 01/2003)
`
`Norditropin® Approved Labeling (revised 05/2000)
`
`United States Pharmacopeia and National Formulary (USP 26-NF
`21) 2003 (“USP 2003”)
`
`Alfred Doenicke, et al., Osmolalities of Propylene Glycol-
`Containing Drug Formulations for Parenteral Use. Should
`Propylene Glycol Be Used as a Solvent?, 75 ANESTH. ANALG. 431
`(1992) (“Doenicke”)
`
`Joseph M. Catanzaro et al., Propylene glycol dermatitis, 24 J. AM.
`ACAD. DERMATOLOGY 90 (1991) (“Catanzaro”)
`
`Bahar Vardar et al., Incidence of lipohypertrophy in diabetic
`patients and a study of influencing factors, 77 DIABETES RESEARCH
`& CLINICAL PRAC. 231 (2007) (“Vardar”)
`
`Kenneth Strauss et al., A pan‐European epidemiologic study of
`insulin injection technique in patients with diabetes, 19 PRACTICAL
`DIABETES INT’L 71 (2002) (“Strauss”)
`
`Omnitrope® Highlights of Prescribing Information (dated 06/2009)
`
`U.S. Food & Drug Admin., New and Revised Draft Q&As on
`Biosimilar Development and the BPCI Act (Revision 2), Guidance
`for Industry (Dec. 2018) (“FDA Draft Guidance”)
`
`
`
`
`vii
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`EXHIBIT
`2011
`
`2012
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`2013
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`2014
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`2015
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`2016
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`2017
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`2018
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`2019
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`2020
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`2021
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`IPR2020-00324
`Patent 8,114,833
`
`Pursuant to 35 U.S.C. § 313, Patent Owner Novo Nordisk A/S (“Novo
`
`Nordisk”), submits this Preliminary Response to Mylan Institutional LLC’s
`
`(“Mylan”) Petition for Inter Partes Review (the “Petition” or “Pet.”) of U.S. Patent
`
`No. 8,114,833 (“the ’833 patent”).
`
`I.
`
`INTRODUCTION
`The ’833 patent resulted from two important discoveries. First, the inventors
`
`discovered that mannitol, a widely used “isotonic agent” in prior art peptide
`
`formulations, had several previously unknown and troublesome properties.
`
`Specifically, it caused undesirable deposits on their manufacturing equipment and in
`
`their finished formulations, and it tended to clog the injection devices used to
`
`administer their formulations. Next, they discovered a solution to these problems in
`
`the form of propylene glycol, which proved superior to mannitol and several other
`
`potential alternatives in a battery of tests. This outcome was unexpected, since
`
`propylene glycol was not a commonly used isotonic agent, was known to have
`
`unpredictable effects on tonicity, and had several properties that would have given
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`a pharmaceutical formulator pause before using it. The ’833 patent claims, inter
`
`alia, pharmaceutical peptide formulations containing specific amounts of propylene
`
`glycol in combination with a specific buffer: the dihydrate form of disodium
`
`phosphate.
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`1
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`IPR2020-00324
`Patent 8,114,833
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`Mylan argues that “Flink,” a 2003 PCT publication, anticipates the ’833
`
`patent’s claims and renders them obvious, both alone and in combination with
`
`“Betz,” a 2004 PCT publication. But Mylan has no reasonable likelihood of
`
`prevailing on any of those three theories.
`
`First, Mylan’s anticipation theory is ambiguous and confusing, falling far
`
`short of the specificity and clarity that the law demands. The foundation of Mylan’s
`
`theory is Flink’s claim 14, but that claim, via various improper chains of multiple
`
`claim dependencies, depends on every one of the claims that precede it, several of
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`which likewise depend on multiple other claims. This network of multiple
`
`dependencies creates a complex web of ambiguous subject matter that would not
`
`have taught anything specific to one of ordinary skill regarding the claimed
`
`inventions of the ’833 patent. Critically, neither claim 14 nor any of the claims from
`
`which it depends disclose propylene glycol or disodium phosphate dihydrate. Thus,
`
`whatever claim 14 might cover, it is not directed to those two specific chemicals that
`
`the ’833 patent requires. In fact, there is no formulation disclosed or even hinted at
`
`in Flink—not in claim 14, nor elsewhere—that describes the combination of
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`propylene glycol and disodium phosphate dihydrate that the claims require.
`
`Mylan’s obviousness arguments likewise fail as a matter of law. The solution
`
`to an unknown problem cannot have been obvious. Here, there is no prior art
`
`suggesting that mannitol could cause the problems that the inventors discovered, nor
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`IPR2020-00324
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`is there any suggestion that propylene glycol could solve them. Indeed, Flink barely
`
`mentions propylene glycol and instead focuses on mannitol, using it in dozens of
`
`formulations and identifying it as one of two most preferred isotonic agents. Thus,
`
`rather than teaching the invention, Flink drives persons of skill toward formulations
`
`that would suffer from the problem, without any hint that the problem exists, much
`
`less a suggestion of how to solve it. Mylan’s claim that mannitol was known to be
`
`problematic is contradicted by the many references recommending its use in the type
`
`of formulation at issue here.
`
`Furthermore, Mylan arrives at the claimed combination of propylene glycol
`
`and disodium phosphate dihydrate by plucking the former from the reference’s
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`broadest list of potential excipients, ignoring the preferred embodiments and the
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`examples, none of which use it; and selecting the latter by looking only at one of
`
`seven examples, since there is no mention of it elsewhere in the reference. This kind
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`of selective picking and choosing of otherwise unrelated excerpts of a prior art
`
`reference, and combining them while ignoring anything that does not suit a
`
`challenger’s needs, is an improper use of hindsight. Mylan never would have arrived
`
`at the specific claimed combination without the roadmap provided by the ’833
`
`patent’s claims.
`
`Finally, Mylan’s hopeful reliance on Betz as a secondary reference to combine
`
`with Flink—chosen purely because it finds a use for propylene glycol—cannot
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`IPR2020-00324
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`sustain a conclusion of obviousness. Betz is a textbook example of a secondary
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`reference chosen only by working backwards from the claimed invention—it
`
`concerns an unrelated active ingredient and an entirely different use for propylene
`
`glycol. Specifically, Betz concerns a totally unrelated protein: human growth
`
`hormone (“hGH”). Mylan fails to show any reason a person of ordinary skill would
`
`even consult Betz. Nor would one of ordinary skill extrapolate any finding for
`
`propylene glycol’s effects on hGH to GLP-1, a far different composition.
`
`Additionally, the data presented in Betz would not have taught a person of ordinary
`
`skill to substitute propylene glycol for mannitol, as Mylan suggests. In fact, the very
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`limited experimental results presented in Betz are insufficient to show any clear
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`benefit of propylene glycol relative to any other excipients.
`
`In sum, Mylan has failed to demonstrate a reasonable likelihood of prevailing
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`on its three Grounds, and the Board should deny institution.
`
`II. BACKGROUND
`A.
`Peptide Formulation
`Formulating therapeutic peptides for parenteral administration presents
`
`unique challenges. (Ex2003 at 1, 3; Ex2004 at 12 (“[P]eptides and proteins now
`
`comprise a significant portion of drugs under clinical development. However, the
`
`instability of
`
`these macromolecules presents unique challenges
`
`to
`
`the
`
`pharmaceutical scientists who are responsible for developing stable and efficacious
`
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`formulations or delivery systems for these molecules”).) One significant challenge
`
`is the susceptibility of peptides to chemical and physical degradation. (Ex2003 at 1,
`
`3; Ex2005 at 1, 7, 11; Ex2004 at 12-13.) Formulators must carefully evaluate
`
`excipients (like preservatives, buffers, and isotonic agents) and external factors (such
`
`as pH, temperature, and osmotic pressure) because they can have significant and
`
`unpredictable effects on peptide stability. (Ex2003 at 1, 3; Ex2006 at 2-3.)
`
`Furthermore, unlike larger proteins, peptides rarely possess an organized,
`
`higher-order structure. (Ex2007 at 1; Ex2008 at 7 (“Peptides typically exhibit
`
`relatively free-ranging backbone conformations with little secondary and/or tertiary
`
`structure.”).) This means that a peptide’s conformation (its three-dimensional
`
`shape) can easily change based on the attributes of the formulation containing it,
`
`further exacerbating the potential for instability. (Ex2007 at 7 (“[I]ntermediate-size
`
`peptides can and do assume radically different shapes and structures depending on
`
`the environment.”); Ex2008 at 7 (explaining that peptide conformation is key to
`
`pharmacological activity, but formulating peptides so they retain their active
`
`conformation is challenging).) And because peptides are generally non-globular,
`
`amino acid side chains are exposed to solvents and other potentially reactive
`
`excipients, which can cause undesired changes in structure and decrease stability.
`
`(Ex2008 at 1 (acylating the GLP-1 peptide and finding that the effect of doing so on
`
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`IPR2020-00324
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`the peptide’s “structure, conformation, and self-association” were “highly solvent
`
`dependent”); Ex2006 at 1.)
`
`In addition, peptides are well-known to “fibrillate:” they self-associate to form
`
`long fibrils that fall out of solution and become pharmacologically inactive.
`
`(Ex2008 at 1 (explaining that proteins and peptides exhibit “non-covalent
`
`aggregation” which is “a well recognized problem that has been studied largely in
`
`the context of [inter alia] . . . fibrils”); Ex2009 at 1, 4.) Fibrillation is universally
`
`recognized as an enormous challenge for peptide formulations, although some
`
`peptides are more susceptible than others. (Ex2010 at 13, col.8, ll.18-24.) Given
`
`these complexities, developing a viable peptide formulation is a substantial
`
`challenge. (Ex2003 at 1, 3.)
`
`The Petition admits
`
`this, explaining
`
`that peptides “require unique
`
`considerations” to “develop[ ] a successful formulation” and acknowledging that
`
`peptides are “vulnerable to precipitating out” of formulations. (Pet. at 15, 18.) The
`
`Petition lists a litany of factors that can affect stability and acknowledges that
`
`“[c]areful consideration of excipients, including buffers and isotonicity agents” is
`
`required. (Pet. at 18.) Thus, Mylan acknowledges the inherent difficulty reported
`
`in the art of developing a working parenteral peptide formulation and the potential
`
`negative effects of an excipients, which must be chosen “careful[ly].” (Id.)
`
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`

`B. GLP-1 Formulation
`The ’833 patent concerns formulations containing a peptide called “GLP-1”
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`IPR2020-00324
`Patent 8,114,833
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`
`and acylated forms thereof. The prior art taught that GLP-1 was challenging to
`
`formulate. (Ex2011 at 1; Ex2012 at 10, [0004] (“GLP-1 is known to gel and
`
`aggregate under numerous conditions, making it difficult to make stable soluble
`
`peptide formulations.”). Specifically, “[d]ue to its strong tendency to fibrillate,
`
`GLP-1” was known as “a very difficult molecule to handle in solution.” (Ex2011 at
`
`1.) Peptide aggregation, including fibrillation, was known to be a challenge in
`
`harnessing the therapeutic potential of GLP-1 analogs. (Ex2011 at 1; Ex2008 at
`
`1.) The Flink reference echoes these concerns, noting that “GLP-1 is known to be
`
`prone to instability due to aggregation. Both [chemical and physical] degradation
`
`pathways may ultimately lead to loss of biological activity of the protein
`
`drug.” (Ex1004 at 3, ll.18-20; see also Ex2008 at 7 (“The present study [on GLP-1]
`
`shows that when formulating a therapeutic peptide for short term stability, caution
`
`must be exercised. Even the seemingly innocuous selection of a widely used
`
`‘standard physiological diluent’ may have a dramatic effect on bioavailability.”).)
`
`The Petition alleges that a “wealth of background knowledge” was available
`
`to those seeking to formulate a GLP-1 peptide, including “numerous disclosures of
`
`prior art GLP-1 agonists.” (Pet. at 12-13.) But Mylan does not actually discuss any
`
`of this allegedly voluminous and helpful background, nor does it address the
`
`
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`IPR2020-00324
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`teachings cited above regarding the known difficulties involved in formulating GLP-
`
`1. Instead, Mylan focuses on a single GLP-1 reference: Flink. But Flink contradicts
`
`Mylan’s position that a “wealth” of information was available on GLP-1 by
`
`explaining: “hitherto little is known about [the] physico-chemical and solution
`
`structural properties” of “acylated GLP-1 compounds.” (Ex1004 at 3, ll.7-9.) Thus,
`
`Mylan’s assertions regarding the allegedly well-developed state of the art on
`
`formulating GLP-1, and the alleged ease with which one could formulate it, are
`
`unsupported and incorrect.
`
`C.
`Parenteral Formulations and Isotonicity
`Parenteral formulations are those delivered by non-oral routes, such as
`
`intravenous or subcutaneous administration. A parenteral formulation must clear
`
`several hurdles to be successful, including stability, excipient compatibility, lack of
`
`toxicity, microbial safety, and suitable pharmacokinetics, to name just a few.
`
`(Ex2003 at 1 (“Dosage strength/potency, integrity, and stability of peptide drugs are
`
`of the upmost concern in the design of parenteral formulations.”); id at 3 (“[F]or a
`
`successful [peptide] formulation, one should consider the clinical indication,
`
`pharmacokinetics, toxicity, and physiochemical stability of the drug product”).) One
`
`consideration unique to parenteral formulations is ensuring that the formulation is
`
`“isotonic.” A solution is considered isotonic with cells if there is no net gain or loss
`
`of water in the cell when it is in contact with the solution. (Ex1013 at 305.) If a
`
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`parenteral formulation is not isotonic, administration may cause pain, irritation, and
`
`other unwanted side effects. (Ex1013 at 308.) To address this issue, formulators
`
`add excipients to adjust a formulation’s tonicity/osmotic pressure to match that of
`
`the cells at the injection site. These excipients are referred to as “tonicity agents” or
`
`“isotonicity agents.” (Ex1067 at 1, 3, 11-12.)
`
`Mannitol was one of the more commonly used tonicity agents in the prior art.
`
`Marketed parenteral products like Humira® and Norditropin® used mannitol to
`
`adjust tonicity. (Ex2013 at 2; Ex2014 at 2.) Additionally, standard guides and texts
`
`that formulators would have consulted identified mannitol, as well as several other
`
`chemicals, as isotonic agents. For example, The Handbook of Pharmaceutical
`
`Excipients identified mannitol as a “tonicity agent.” (Ex1023 at 12.) The United
`
`States Pharmacopeia and National Formulary (“USP”) identified “dextrose,
`
`glycerin, mannitol, potassium chloride, and sodium chloride” as “tonicity agents.”
`
`(Ex2015 at 5-6.) Likewise, the Akers reference, a review article on “Excipient-Drug
`
`Interactions in Parenteral Formulations” on which Mylan relies, identifies mannitol,
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`along with sodium chloride, glycerin, and dextrose as “[t]onicity-adjusting agents.”
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`(Ex1067 at 3.) Remington’s taught that “[w]hen formulating parenterals, solutions
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`otherwise hypotonic usually have their tonicity adjusted by the addition of dextrose
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`or sodium chloride.” (Ex1013 at 308, 311.) Although certain chemicals were
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`consistently used to adjust tonicity, determining the type and concentration of
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`isotonicity agent to use in a particular formulation was unpredictable and required
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`experimentation. (Ex1013 at 305, 311.)
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`D.
`Propylene Glycol
`As of 2004, propylene glycol was not commonly used as an isotonic agent.
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`Leading treatises that would have been consulted by formulators did not recommend
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`propylene glycol as a tonicity agent—not the Handbook of Pharmaceutical
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`Excipients, not the USP, and not Remington’s, which Mylan acknowledges would
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`have been a “standard treatise.” (Ex1023 at 17-19; Ex2015 at 5-6; Ex1013 at 308;
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`Pet. at 25.) Rather, the Handbook of Pharmaceutical Excipients describes propylene
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`glycol as an “antimicrobial preservative; disinfectant; humectant; plasticizer;
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`solvent; stabilizer for vitamins; [and] water-miscible cosolvent.” (Ex1023 at 17.)
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`The USP and Remington’s also describe propylene glycol as a “solvent” or
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`“surfactant.” (Ex2015 at 4; Ex1013 at 312.) As explained above, peptides are
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`particularly susceptible to degradation in the presence of solvents; this was known
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`to be true of GLP-1. See supra Sections II.A, II.B.
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`Furthermore, Remington’s raises significant concerns about propylene
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`glycol’s unpredictable effects on tonicity when used as a solvent. While discussing
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`the importance of tonicity, Remington’s emphasizes that, “[i]n solving isotonicity
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`adjustment problems . . . it should be kept in mind that while these solvent
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`components [including propylene glycol] contribute to the freezing-point depression
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`they may or may not have an effect on the ‘tone’ of the tissue to which they are
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`applied, i.e., an isoosmotic solution may not be isotonic.” (Ex1013 at 312 (emphasis
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`in original).) In other words, propylene glycol can affect a solution’s osmotic
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`pressure in vitro (i.e., depress the solution’s freeing point) but not render it isotonic
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`with cells in vivo (i.e., not have an effect on “tone”), the property that truly matters.
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`Mylan alleges that identifying a suitable amount of propylene glycol to use as
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`an isotonic agent is a matter of simple math. (Pet. at 44-47.) However, even if one
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`tried using propylene glycol to adjust tonicity—something the art as a whole did not
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`suggest—the passage from Remington’s quoted above makes clear that propylene
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`glycol’s effects on tonicity (“tone”) are unpredictable and cannot be derived from in
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`vitro experiments, let alone mathematical calculations.
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`Remington’s also identifies propylene glycol as one of several solutes that
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`“cause hemolysis [i.e., rupture or destruction of red blood cells] even when they are
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`present in a concentration that is isoosmotic,” indicating that “such solutions
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`obviously are not isotonic.” (Ex1013 at 311.) This further confirms that amounts
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`of propylene glycol that might, theoretically, confer isotonicity instead cause the
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`very problems that isotonic agents are intended to cure (e.g., cell rupture). Other
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`references echo this disturbing property, such as Akers, which taught that solutions
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`containing propylene glycol were among those “most prone to elicit a hemolytic
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`response,” and instead suggested using other excipients, including sodium chloride,
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`glycerin, mannitol, and dextrose as “tonicity-adjusting agents.” (Ex1067 at 3.)
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`This tendency to destroy cells was just one of propylene glycol’s negative
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`properties called out in the prior art. Akers also cautions against the use of propylene
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`glycol as a co-solvent because glycols “can cause some stability or compatibility
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`problems.” (Ex1067 at 2.) Doenicke assesses the effects of propylene glycol on the
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`osmolality of injectable formulations and cautions against its use, due to adverse
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`effects, including “pain on intravenous injection and thrombophlebitis.” (Ex2016 at
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`3.) Additionally, propylene glycol was known to cause dermatitis (a skin reaction)
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`even when used in oral formulations, making it a dubious choice for a GLP-1
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`formulation, which would be administered subcutaneously (i.e., under the skin).
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`(Ex2017 at 1-3.) These known negatives would have been exacerbated by the fact
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`that diabetes is a chronic disease, and therefore a parenteral GLP-1 formulation
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`containing propylene glycol would be administered at least daily, without any end
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`date for treatment, compounding the possibility of these side effect and safety
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`concerns.
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`In sum, propylene glycol was not generally known as an isotonic agent, would
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`have been difficult to use in that way, had not been used for chronic subcutaneous
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`administration, and had properties that would have given a formulator pause before
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`using it—for any reason—in a parenteral formulation. Mylan alleges that propylene
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`glycol was a commonly used and innocuous excipient but addresses none of the art
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`flagging significant problems with using propylene glycol
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`in parenteral
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`formulations.
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`Mylan also claims that propylene glycol was “well known to function as an
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`isotonicity agent in liquid formulations.” (Pet. at 19.) But the absence of propylene
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`glycol from discussions of tonicity in leading pharmaceutical formulation texts at
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`the time of the ’833 patented invention belies Mylan’s claim. Nor has Mylan
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`identified a single FDA-approved product in the prior art that actually used
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`propylene glycol as an isotonicity agent, or even one exemplary parenteral
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`formulation described in a prior art reference that uses propylene glycol to adjust
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`tonicity.
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`Instead, Mylan supports its claim that propylene glycol was “well known to
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`function as an isotonicity agent” with citations to six patents. (Pet. at 19.) These six
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`references offer no details of propylene glycol’s effects on isotonicity and no
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`examples of it actually used as such in an injectable formulation, as in the ’833
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`patent. They therefore teach persons of skill nothing about its use to adjust tonicity.
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`Two of the six patents share the same disclosure (see Ex1017; Ex1025), and the
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`other four concern solutions for ocular or ophthalmic uses, such as contact lens baths,
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`not injectable peptide formulations (see Ex1007; Ex1063; Ex1064; Ex1065).
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`Persons of ordinary skill focused on formulating injectable peptides would not have
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`considered sources concerning contact lens baths. These references hardly conf