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`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 RESPONSE
`
`
`
`
`
`
`
`

`

`
`
`TABLE OF CONTENTS
`
`IPR2020-00324
`Patent 8,114,833
`
`I.
`II.
`
`C.
`D.
`
`Page
`INTRODUCTION.....................................................................................1
`BACKGROUND ......................................................................................4
`A.
`Formulating Peptides Is Challenging and Unpredictable ....................4
`B. GLP-1 Was Known to Have Unique Properties that Made It
`Difficult to Formulate ......................................................................5
`Parenteral Formulations and Isotonicity ............................................6
`The Prior Art Contained Red Flags that Would Have Steered
`Skilled Artisans Away From Propylene Glycol .................................7
`III. THE ’833 PATENT...................................................................................9
`IV. CLAIM CONSTRUCTION .....................................................................13
`V. GROUND 1: FLINK DOES NOT ANTICIPATE CLAIMS 1-15 ..............15
`A.
`The Anticipation Standard..............................................................16
`B.
`Flink Does Not Disclose or Lead the Skilled Artisan to
`“Immediately Envisage” the Claimed Formulations ........................18
`C. On A Complete Record, The Board’s Preliminary Conclusions
`Regarding Flink and Anticipation Should Not Stand .......................23
`The Cases Mylan Relies On Do Not Control This IPR.....................27
`Flink Does Not Anticipate the Specific Ranges of Propylene
`Glycol in Claims 1-4 ......................................................................30
`Flink Does Not Enable the Claimed Formulations and
`Therefore Does Not Anticipate .......................................................32
`VI. GROUND 2: CLAIMS 1-15 ARE NOT OBVIOUS OVER FLINK...........34
`A.
`Flink Does Not Teach Persons of Ordinary Skill to Use
`Propylene Glycol in a GLP-1 Formulation ......................................35
`
`D.
`E.
`
`F.
`
`i
`
`

`

`
`
`TABLE OF CONTENTS
`(CONTINUED)
`
`IPR2020-00324
`Patent 8,114,833
`
`Page
`
`C.
`
`D.
`
`B. One of Ordinary Skill Would Not Have Chosen Propylene
`Glycol or Had a Reasonable Expectation of Success In Using It ......37
`Flink Provides No Reason or Motivation to Combine Propylene
`Glycol and Disodium Phosphate Dihydrate in a GLP-1
`Formulation ...................................................................................41
`Propylene Glycol’s Unexpectedly Superior Properties Are
`Powerful Evidence of Nonobviousness ...........................................45
`VII. GROUND 3: CLAIMS 1-31 ARE NOT OBVIOUS OVER FLINK IN
`VIEW OF BETZ .....................................................................................48
`A.
`...........................................48
`B.
`Betz Does Not Teach What Mylan Claims It Teaches......................52
`C. Mylan Provides No Credible Rationale for Combining the
`Teachings of Betz and Flink ...........................................................55
`D. Claims 16-22 Would Not Have Been Obvious Over Flink In
`View of Betz .................................................................................59
`Claims 23-31 Would Not Have Been Obvious Over Flink In
`View of Betz .................................................................................60
`VIII. CONCLUSION .......................................................................................62
`
`
`
`
`
`E.
`
`ii
`
`

`

`
`
`TABLE OF AUTHORITIES
`
`IPR2020-00324
`Patent 8,114,833
`
`Page(s)
`
`CASES
`Akzo v. ITC,
`808 F.2d 1471 (Fed. Cir. 1986) .....................................................................25
`Application of LeGrice, 301 F.2d 929 (CCPA 1962)...........................................21
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2003) ............................................................... 13, 14
`Coherus Biosciences, Inc. v. Abbvie Biotechnology Ltd.,
`IPR2017-00822, Paper No. 14 (P.T.A.B. Sept. 7, 2017) .................................17
`Complex Innovations, LLC v. AstraZeneca AB,
`IPR2017-00631, Paper No. 13 (P.T.A.B. July 24, 2017) ................................17
`Cooper v. Goldfarb,
`154 F.3d 1321 (Fed. Cir. 1998) ............................................................... 48, 49
`Eaton Corp. v Rockwell Int’l Corp.,
`323 F.3d 1332 (Fed. Cir. 2003) ............................................................... 14, 15
`Eli Lilly and Co. v. Zenith Goldline Pharm., Inc.,
`471 F.3d 1369 (Fed. Cir. 2006) .....................................................................26
`Endo Pharms., Inc. v. Depomed, Inc.,
`IPR2014-00651, Paper No. 12, (P.T.A.B. Sept. 29, 2014) ..............................17
`Griffin v. Bertina,
`285 F.3d 1029 (Fed. Cir. 2002) ............................................................... 14, 15
`In re Arkley,
`455 F.3d 586 (CCPA 1972) ..........................................................................26
`In re Kotzab,
`217 F.3d 1365 (Fed. Cir. 2000) .....................................................................41
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) ................................................................. 21, 24
`
`iii
`
`

`

`
`
`TABLE OF AUTHORITIES
`(Continued)
`
`IPR2020-00324
`Patent 8,114,833
`
`Page(s)
`
`In re Petering,
`301 F.2d 676 (CCPA 1962) .................................................................... 17, 18
`In re Samour,
`571 F.2d 559 (CCPA 1978) ..........................................................................21
`In re Soni,
`54 F.3d 746 (Fed. Cir. 1995).........................................................................45
`In re Stepan Co.,
`868 F.3d 1342 (Fed. Cir. 2017) ............................................................... 37, 41
`Invitrogen Corp. v. Biocrest Mfg., L.P.,
`327 F.3d 1364 (Fed. Cir. 2003) .....................................................................14
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376 (Fed. Cir. 2015) .............................................................. passim
`KVK-Tech, Inc. v. Shire PLC,
`IPR2018-00290, Paper No. 58 (P.T.A.B. July 3, 2019) ..................................17
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ............................................................... 53, 61
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .....................................................................49
`Millennium Pharms., Inc. v. Sandoz Inc.,
`862 F.3d 1356 (Fed. Cir. 2017) .....................................................................61
`Monarch Knitting Machinery Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) .......................................................................57
`Net MoneyIN, Inc. v. VeriSign, Inc.,
`545 F.3d 1359 (Fed. Cir. 2008) .....................................................................16
`Novartis Pharm. Corp. v. Watson Labs., Inc.,
`611 Fed.Appx. 988 (Fed. Cir. 2015) ..............................................................61
`
`iv
`
`

`

`
`
`TABLE OF AUTHORITIES
`(Continued)
`
`IPR2020-00324
`Patent 8,114,833
`
`Page(s)
`
`Oracle Corp. v. Crossroads Sys., Inc.,
`IPR2014-01207, Paper 78 (P.T.A.B. Jan. 29, 2016) .......................................42
`Ortho-McNeil Pharm., Inc. v. Mylan Labs., Inc.,
`520 F.3d 1358 (Fed. Cir. 2008) ............................................................... 43, 57
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368 (Fed. Cir. 2005) .....................................................................30
`Pitney Bowes, Inc. v. Hewlett-Packard Co.,
`182 F.3d 1298 (Fed. Cir. 1999) .....................................................................13
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009) ................................................................. 45, 55
`Rambus Inc. v. Rea,
`527 Fed.Appx. 902 (Fed. Cir. 2013) ..............................................................32
`Sanofi-Synthelabo v. Apotex, Inc.,
`550 F.3d 1075 (Fed. Cir. 2008) ............................................................... 32, 33
`Süd-Chemie, Inc. v. Multisorb Techs., Inc.,
`554 F.3d 1001 (Fed. Cir. 2009) .....................................................................46
`Trintec Indus., Inc. v. Top-U.S.A. Corp.,
`295 F.3d 1292 (Fed. Cir. 2002) .....................................................................16
`Wasica Fin. GmbH v. Cont’l Auto. Sys.,
`853 F.3d 1272 (Fed. Cir. 2017) ............................................................... 17, 19
`Wm. Wrigley Jr. Co. v. Cadbury Adams USA, LLC,
`683 F.3d 1356 (Fed. Cir. 2012) .............................................................. passim
`STATUTES
`35 U.S.C. § 102(e) ...................................................................................... 48, 49
`
`v
`
`

`

`TABLE OF EXHIBITS
`
`EXHIBIT
`
`DESCRIPTION
`
`IPR2020-003 24
`
`Patent 8,1 14,833
`
`Declaration ofRyan P. Johnson in Support ofPatent Owner’s
`Motion for AdmissionPro Hac Vice of Ryan P. Johnson Under 3 7
`C.F.R. § 42.10(c)
`Declaration ofLaura T- Moran in Support ofPatent Owner ’5 Motion for
`42. 1 0
`
`C- Goolcharran, et al-, ChemicalPathways ofPeptide and Protein
`Degradation, in PHARMACEUTICAL FORMULATION
`DEVELOPMENT OF PEPTIDES AND PROTEINS 70 (Sven Frokjaer
`& Lars Hov aard eds-,2000 “Goolcharran”
`
`Mark C- Manning et al-, Stability ofProtein Pharmaceuticals, 6
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`
`R.W. Payne, et a1. , Peptide Formulation: Challenges and Strategies,
`
`2012
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`Dean K. Clodfelter et al-, Effects ofNon-CovalentSelf-Association
`on the SubcutaneousAbsorption ofa TherapeuticPeptide, 15
`PHARM. RES. 254 (1998) (“Clodfelter”)
`Eva Y. Chi et al., Physical Stability ofProteins in Aqueous Solution:
`Mechanism and Driving Forces in Normative Protein Aggregation,
`20 PHARM. RESEARCH 1325 (2003) (“Chi”)
`US. Patent No. 5,932,547
`
`Lotte Knudsen, et al., PotentDerivatives ofGlucagon—likePeptide—I
`with Pharmacokinetic Properties Suitablefor Once Daily
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`
`U. S. Patent Application Publication No- 2002/006183 8
`Humira® Packa e Insert revised 01/2003
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`Norditro . in® A . . roved Labelin ; revised 05/2000
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`United States Pharmacopeia andNational Formulary (USP 26-NF
`21) 2003 (“USP 2003”)
`Alfred Doenicke, et al. , Osmolalities ofPropylene Glycol-
`ContainingDmg Formulationsfor Parenteral Use. Should
`Propylene Glycol Be Used as a Solvent? , 75 ANESTH. ANALG. 431
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`201 l
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`2017
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`patients and a study of influencing factors, 77 DIABETES RESEARCH &
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`Kenneth Strauss et al., A pan‐European epidemiologic study of
`insulin injection technique in patients with diabetes, 19 PRACTICAL
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`U.S. Food & Drug Admin., New and Revised Draft Q&As on
`Biosimilar Development and the BPCI Act (Revision 2), Guidance
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`Declaration of Peter M. Tessier, Ph.D. dated September 18, 2020
`(Confidential – Protective Order Material)
`Declaration of Dorthe Kot Engelund dated September 16, 2020
`(Confidential – Protective Order Material)
`Declaration of Tina Bjeldskov Pedersen, Ph.D. dated September 17, 2020
`Declaration of David Nolan dated September 17, 2020
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`Fu, R. C. C., et al. The biocompatibility of parenteral vehicles—in
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`Naccache, P., & Sha'afi, R. I. Patterns of nonelectrolyte permeability in
`human red blood cell membrane. 62 THE JOURNAL OF GENERAL
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`Padrick, S. B., & Miranker, A. D. Islet amyloid polypeptide:
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`current techniques. 1 JOURNAL OF HEMATOTHERAPY, 233-250 (1992)
`Schellekens, H. Bioequivalence and the immunogenicity of
`biopharmaceuticals. 1 NATURE REVIEWS DRUG DISCOVERY, 457-462
`(2002) (“Schellekens”)
`Senderoff, R. I., et al. Consideration of conformational transitions and
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`PHARMACEUTICAL ASSOCIATION (SCIENTIFIC ED.), 628-630 (1959)
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`Stratton, L. P., et al. Controlling deamidation rates in a model peptide:
`Effects of temperature, peptide concentration, and additives. 90 JOURNAL
`OF PHARMACEUTICAL SCIENCES, 2141-2148 (2001)
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`cryoprotectants for mouse sperm cryopreservation. 42
`CRYOBIOLOGY, 28-39 (2001) (“Sztein”)
`Thorens, B., & Waeber, G. Glucagon-like peptide-I and the control of
`insulin secretion in the normal state and in NIDDM. 42 DIABETES, 1219-
`1225 (1993)
`Yang, X., et al. Subzero nonfreezing storage of the mammalian cardiac
`explant: I. Methanol, ethanol, ethylene glycol, and propylene glycol as
`colligative cryoprotectants. 30 CRYOBIOLOGY, 366-375 (1993)
`Wolffenbuttel, B. H., & Graal, M. B. New treatments for patients with
`type 2 diabetes mellitus. 72 POSTGRADUATE MEDICAL JOURNAL, 657-662
`(1996)
`Highlights of Prescribing Information, Revised 08/2020 (“Victoza®
`Prescribing Information”)
`Internal Novo Nordisk Report, dated December 3, 2001 (Confidential –
`Protective Order Material)
`Internal Novo Nordisk Email Chain, beginning December 19, 2001 and
`certified translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Report, dated December 19, 2001 and certified
`translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Protocol, dated January 22, 2002 and certified
`translation thereof (Confidential – Protective Order Material)
`De Vos, A. M., et al. Human growth hormone and extracellular domain
`of its receptor: crystal structure of the complex. 255 SCIENCE, 306-312
`(1992)
`Internal Novo Nordisk Meeting Minutes, dated April 12, 2002 and
`certified translation thereof (Confidential – Protective Order Material)
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`Protective Order Material)
`Internal Novo Nordisk Protocol, dated June 3, 2002 and certified
`translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Study Plan, dated June 5, 2002 and certified
`translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Memo, dated June 27, 2002 and certified
`translation thereof (Confidential – Protective Order Material)
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`certified translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Meeting Minutes, dated November 14, 2002 and
`certified translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Design Review Presentation, dated November 29,
`2002 (Confidential – Protective Order Material)
`Internal Novo Nordisk Meeting Minutes, dated February 3, 2003 and
`certified translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Statement, dated April 9, 2003 (Confidential –
`Protective Order Material)
`Internal Novo Nordisk Report, dated April 10, 2003 (Confidential –
`Protective Order Material)
`Internal Novo Nordisk Report, dated April 22, 2003 (Confidential –
`Protective Order Material) (“April 22, 2003 Report”)
`Internal Novo Nordisk Report, dated June 10, 2003 and certified
`translation thereof (Confidential – Protective Order Material)
`Internal Novo Nordisk Trial Protocol, dated June 11, 2003 (Confidential
`– Protective Order Material)
`Internal Novo Nordisk Report, dated June 18, 2003 (Confidential –
`Protective Order Material)
`Internal Novo Nordisk Report, dated June 27, 2003 (Confidential –
`Protective Order Material)
`Internal Novo Nordisk Protocol, dated January 30, 2018 (Confidential –
`Protective Order Material)
`Internal Novo Nordisk Report, dated May 17, 2018 (Confidential –
`Protective Order Material)
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`Protective Order Material)
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`Deposition Transcript of Laird Forrest, Ph.D., dated September 3, 2020
`
`x
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`

`IPR2020-00324
`Patent 8,114,833
`
`Redacted Version of Declaration of Peter Tessier, Ph.D. dated September
`18, 2020
`Remington’s Pharmaceutical Science, Vol. I, 19th ed., Chapter 36 (1995)
`(“Remington 1995”)
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`

`
`I.
`
`INTRODUCTION
`The invention of Novo Nordisk A/S’s (“Novo Nordisk”) U.S. Patent No.
`
`IPR2020-00324
`Patent 8,114,833
`
`8,114,833 (the “’833 patent”) is a unique combination of three specific ingredients
`
`arising out of reformulation efforts necessitated by problems discovered during scale
`
`up. Mannitol had been widely used in the art and at Novo Nordisk as an “isotonicity
`
`agent” in injectable drug formulations. But when Novo Nordisk tried to scale up its
`
`formulation of the new GLP-1 peptide liraglutide, mannitol began forming
`
`problematic deposits. The ’833 patent’s inventors were asked to search for a solution
`
`by reformulating with a new isotonicity agent—no small feat, since GLP-1 peptides
`
`were notoriously difficult to formulate. They made an array of formulations, devised
`
`and conducted various tests, and ultimately found a surprising solution: propylene
`
`glycol.
`
`Those in the field knew that propylene glycol had properties that would make
`
`it difficult, if not impossible, to use as an isotonicity agent. It was also known to
`
`cause instability problems and several troubling adverse events. Formulators went
`
`so far as to recommend removing it from formulations. Yet the inventors found that
`
`it worked, solving mannitol’s crystallization problem, besting the other candidate
`
`agents they tried, and unexpectedly showing no effect on stability. So, the inventors
`
`replaced mannitol with propylene glycol in their GLP-1 formulation and filed a
`
`patent application on their discovery. Their patent (the ’833) claims formulations
`
`1
`
`

`

`
`containing GLP-1, propylene glycol at specific concentration ranges, and a specific
`
`IPR2020-00324
`Patent 8,114,833
`
`buffer, disodium phosphate dihydrate.
`
`Petitioner Mylan Institutional LLC (“Mylan”) contends that all of the ’833
`
`patent’s claims are invalid. The key reference underlying all three Grounds is WO
`
`03/002136 (“Flink”). Flink describes Novo Nordisk’s earlier, laboratory-scale
`
`formulation work with GLP-1. It focuses on regulating formulation pH and testing
`
`excipients as possible stabilizers. Flink says almost nothing about isotonicity agents,
`
`apart from using just two of them repeatedly in Examples and “typical”
`
`formulations: mannitol and, to a lesser extent, glycerol.
`
`The Board should deny Ground 1 (anticipation) because Flink does not
`
`disclose the claimed formulations, nor would it cause a skilled artisan to
`
`“immediately envision” them. Per Mylan, one of ordinary skill would: (1) start with
`
`Flink’s claim 14, which depends from all of claims 1-13; (2) read Flink’s
`
`specification’s sole mention of propylene glycol, as one of five examples of a
`
`polyhydric alcohol, in a listing of six genuses of chemicals offered as potential
`
`isotonicity agents; (3) read Flink’s sole mention of the claimed disodium phosphate
`
`dihydrate buffer, appearing in Example 7 (without comment) but nowhere else in
`
`the reference; and (4) “immediately envision” a formulation combining the two. The
`
`law of anticipation does not stretch so far. Flink’s general discussions of both
`
`isotonicity agents and buffers suggests numerous options for each, resulting in a vast
`
`2
`
`

`

`
`number of permutations. Mylan’s theory hinges on a myopic reading of Flink that
`
`IPR2020-00324
`Patent 8,114,833
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`improperly picks specific but unrelated pieces of the reference out of a crowded field
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`and combines them in a way that clashes with a skilled artisan’s background
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`knowledge. And even if one followed that untenable path, they still would have no
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`idea what concentration of propylene glycol to use. That limitation, at an absolute
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`minimum, is not anticipated.
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`The Board should deny Ground 2 (obviousness over Flink) because neither
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`Flink nor any other art provides the required motivation to create a formulation
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`containing GLP-1 and propylene glycol, much less combine them with the claimed
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`buffer. Mylan has also failed to offer any persuasive reason why one of ordinary
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`skill would have reasonably expected that formulation to be successful, given what
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`was known about GLP-1’s instability and propylene glycol’s drawbacks, which in
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`fact taught away from using it with GLP-1.
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`The ’833 patent’s inventors’ powerful unexpected results with propylene
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`glycol confirm nonobviousness. Indeed, not only did they gather the surprising data,
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`they had to create many of the tests used to generate them. These inventors, who
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`faced a difficult problem in a notoriously unpredictable field and discovered an
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`unexpected solution, should not be penalized by a stray mention of propylene glycol
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`in Flink, which indisputably focuses on using other chemicals as isotonicity agents.
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`Finally, the Board should deny Ground 3 (obviousness over Flink in view of
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`the “Betz” reference (WO 04/004781))
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`, it does nothing to remedy the deficiencies of Ground 2.
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`Betz concerns an entirely different issue relating to an entirely different protein and
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`provides no credible rationale for using propylene glycol with GLP-1 or in place of
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`mannitol. In view of the full evidence, all of Petitioner’s grounds fall short and the
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`claims of the ’833 patent should not be found unpatentable.
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`II. BACKGROUND
`Formulating Peptides Is Challenging and Unpredictable
`A.
`Formulating therapeutic peptides for parenteral administration “presents
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`unique challenges to … pharmaceutical scientists.” (Ex2004, 12; Ex2003, 1, 3;
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`Declaration of Peter M. Tessier, PhD (Ex2022), ¶¶44-50.) As Dr. Tessier explains
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`in his declaration, there are several reasons for this that were well-known in the prior
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`art. (Ex2022, ¶¶44-50.) One is the susceptibility of peptides to chemical and
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`physical degradation. (Ex2003, 1, 3; Ex2005, 1, 7, 11; Ex2004, 12-13.) Formulators
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`must carefully evaluate excipients and external factors because they can have
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`significant and unpredictable effects on peptide stability. (Ex2022, ¶¶45-46, 50;
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`Ex2003, 1, 3; Ex2006, 2-3.) One well-known type of instability is fibrillation, when
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`peptides self-associate to form long fibrils that fall out of solution and become
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`inactive. (Ex2022, ¶¶47, 52, 81; Ex2008, 1; Ex2009, 1, 4.)
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`Furthermore, unlike larger proteins, peptides rarely possess an organized,
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`higher-order structure. (Ex2007, 1; Ex2008, 7.) This means that a peptide’s
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`conformation (its three-dimensional shape) can easily change based on the attributes
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`of the formulation containing it, further exacerbating the potential for instability.
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`(Ex2022, ¶¶46, 48; Ex2007, 7; Ex2008, 7.) And because peptides are generally non-
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`globular, amino acid side chains are exposed to solvents and other reactive
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`excipients, which can cause undesired changes in structure and instability. (Ex2022,
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`¶46; Ex2008, 1; Ex2006, 1.)
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`B. GLP-1 Was Known to Have Unique Properties that Made It
`Difficult to Formulate
`The ’833 patent concerns formulations containing a peptide called “GLP-
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`1.” As Dr. Tessier explains, the prior art taught that GLP-1 was particularly
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`challenging to formulate. (Ex2022, ¶¶51-55, 81-82.) It was known to gel and
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`aggregate and had a strong tendency to fibrillate, making it difficult to handle.
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`(Ex2012, [0004]; Ex2011, 1; Ex2079, 90:8-96:11.) Scientists noted that it was
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`“difficult to make stable [GLP-1] … formulations” and that even “seemingly
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`innocuous” and “widely used” excipients had a dramatic effect on the peptide.
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`(Ex2012, [0004]; Ex2008, 7) Even Flink, the focus of all three Grounds, described
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`GLP-1 as “prone to instability.” (Ex1004, 3:18-20.)
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`Parenteral Formulations and Isotonicity
`C.
`Parenteral formulations are those delivered by non-oral routes (e.g.,
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`subcutaneous administration). Parenteral formulations must clear several hurdles to
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`be successful, including stability, excipient compatibility, non-toxicity, microbial
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`safety, and suitable pharmacokinetics. (Ex2003, 1, 3.)
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`A consideration unique to parenteral formulations is ensuring that the
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`formulation is “isotonic.” (Ex2022, ¶¶56-58.) A solution is isotonic with cells (for
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`instance, at the site of injection) if it does not cause cells to gain or lose water.
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`(Ex1013, 305; Ex2022, ¶56.) A parenteral formulation that is not isotonic may cause
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`patients pain, irritation, and other unwanted side effects. (Ex1013, 308; Ex2022,
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`¶¶57, 68-70.)
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`Often formulators must add an excipient to parenteral formulations to balance
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`tonicity. (Ex2022, ¶57.) These excipients are referred to as “tonicity agents” or
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`“isotonicity agents.” (Id.; Ex1067, 1, 3, 11-12.) In selecting an isotonicity agent,
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`formulators must take care not to select an excipient that would impair the
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`formulation’s performance by, for example, rendering the active ingredient unstable
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`or causing adverse events. Determining the type and concentration of isotonicity
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`agent to use is unpredictable and requires experimentation. (Ex2022, ¶¶57, 65-67,
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`163; Ex1013, 305, 311.)
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`Mannitol was one of the more commonly used isotonicity agents in the prior
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`art. (Ex2022, ¶¶58, 88.) Marketed parenteral products like Humira®, Norditropin®,
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`and Forteo® used mannitol to adjust tonicity. (Id.; Ex2013, 2; Ex2078, 2; Ex2014,
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`2.; Ex2077, 2; Ex2061, 2.) And standard texts that formulators would have
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`consulted, such as The Handbook of Pharmaceutical Excipients and the United
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`States Pharmacopeia and National Formulary (“USP”), recommended mannitol as
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`an isotonicity agent, as does Akers, an article on “Excipient-Drug Interactions in
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`Parenteral Formulations” that Mylan cites. (Ex1023, 12; Ex2015, 5-6; Ex1067, 3.)
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`D. The Prior Art Contained Red Flags that Would Have Steered
`Skilled Artisans Away From Propylene Glycol
`As of 2004, propylene glycol was not commonly used as an isotonicity agent.
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`(Ex2022, ¶¶59-64.) Leading treatises that formulators would have consulted did not
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`recommend propylene glycol as an isotonicity agent—not the Handbook of
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`Pharmaceutical Excipients, not the USP, and not Remington’s, which Mylan
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`acknowledges would have been a “standard treatise.” (Ex1023, 17-19; Ex2015, 5-
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`6; Ex1013, 308; Mylan’s Petition (“Pet.”), 25.) Rather, propylene glycol was
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`described as having several other functions, including solvent or cosolvent.
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`(Ex2022, ¶¶59, 60-62, 72, 79; Ex1023, 17; Ex2015, 4; Ex1013, 312.)
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`Peptides are susceptible to degradation in the presence of solvents, including
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`the notoriously unstable GLP-1. (Ex2003, 1, 3; Ex1067, 2; Ex2008, 1, 7-8; Ex1004,
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`3:8-20.) Accordingly, as Dr. Tessier explains, using propylene glycol with GLP-1
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`would have raised significant red flags. (Ex2022, ¶¶68-80.)
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`The prior art cautioned against using propylene glycol as an isotonicity agent
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`for several other reasons. First, Remington’s explains that its effects on tonicity are
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`unpredictable. (Ex1013, 312.) Per Remington’s, propylene glycol can affect a
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`solution’s osmotic pressure in vitro (i.e., depress the solution’s freezing point) but
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`not render it isotonic with cells in vivo (i.e., not have an effect on “tone”), the
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`property that truly matters. (Ex2022, ¶65; Ex2079, 123:17-21.)
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`In fact, the prior art taught that propylene glycol was likely to fail at adjusting
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`tonicity. (Ex2022, ¶¶65-80.) Propylene glycol was known to freely pass through
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`cellular membranes; for this reason, it was used as a cryoprotectant. (Id.) This same
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`ability to pass through cellular membranes would have been expected to prevent
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`propylene glycol from rendering a solution isotonic, since an isotonicity agent’s
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`primary function is to adjust osmotic pressure outside cells. (Id.)
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`Furthermore, propylene glycol was associated with adverse events. It was
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`known to “cause hemolysis [i.e., rupture or destruction of red blood cells] even when
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`[it is] present in a concentration that is isoosmotic,” indicating that “such solutions
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`obviously are not isotonic.” (Ex1013, 311.) Other references echo this property and
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`suggest using other chemicals to modify tonicity. (Ex1067, 3 (suggesting using
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`other excipients as “tonicity-adjusting ag