`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Filed: March 24, 2021
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`MYLAN INSTITUTIONAL LLC and PFIZER INC.,
`Petitioners,
`
`v.
`
`NOVO NORDISK A/S,
`
`Patent Owner.
`
`
`Case No. IPR2020-003241
`U.S. Patent No. 8,114,833
`
`PETITIONERS’ DEMONSTRATIVE EXHIBITS
`
`
`
`
`
`1
`IPR2020-01252 has been joined with this proceeding.
`
`
`
`United States Patent and Trademark Office
`Before the Patent Trial and Appeal Board
`
`MYLAN INSTITUTIONAL LLC
`and PFIZER INC.,
`Petitioners
`v.
`NOVO NORDISK A/S,
`Patent Owner
`
`IPR2020-00324*
`U.S. Patent No. 8,114,833
`*IPR2020-01252 has been joined with this proceeding
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Grounds of Unpatentability
`
`Ground 1: Claims 1-15 of the ’833 patent are anticipated by Flink
`(Ex. 1004)
`
`Ground 2: Claims 1-15 of the ’833 patent are obvious over Flink
`(Ex. 1004)
`
`Ground 3: Claims 1-31 of the ’833 patent are obvious over Flink
`(Ex. 1004) in view Betz (Ex. 1005)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`2
`
`Pet. 3
`
`
`
`Claim 1 of the ’833 Patent
`
`1. 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.
`
`‘833 patent (Ex.1001), claim 1 (annotated)
`
`1. GLP-1 agonist
`2. Disodium phosphate dihydrate buffer
`3. Propylene glycol at a concentration of 1-100
`mg/ml
`4. pH of 7-10
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`3
`
`Pet. 7-8, 28
`
`
`
`Claim 16 of the ’833 Patent
`
`16. 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 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.
`
`‘833 patent (Ex.1001), claim 16 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`4
`
`Pet. 7-8, 53-54
`
`
`
`Claims 23, 26 & 29 of the ’833 Patent
`
`23. 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.
`
`26. 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.
`
`29. 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.
`
`‘833 patent (Ex.1001), claims 23, 26 & 29 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`5
`
`Pet. 7-8, 10-11, 54-57; Reply 5-7
`
`
`
`Ground 1:
`Flink Anticipates Claims 1-15
`
`6
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`
`’833 patent (Ex.1001) claim 1 (annotated)
`
`Flink (Ex.1004), 47-48 (claims 5, 13 & 14) (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`7
`
`Pet. 23-39; Reply 7-14;
`Ex. 1002 ¶¶81-92, 148-169; Ex. 1106 ¶¶14-31
`
`
`
`How a POSA Evaluates Patent Claims
`
`Q: Okay. And when you say there is an isotonic agent in the
`claim, what are you referring to?
`
`DR. TESSIER: As a POSA, I would have evaluated the entire
`patent, and looked at what the patent defines as isotonic
`agents. And therefore, I would have went and reviewed the
`specification, and reviewed the list of agents that are listed.
`And then I would have reviewed the examples. And I would
`conclude that propylene glycol is -- in claim 1 is listed as an
`isotonic agent.
`
`Q: And that’s how a person of skill in the art would read
`the patent claims in any patent, correct?
`
`DR. TESSIER: Yes.
`
`Ex.1077, 17:18-18:14 (objections omitted) (emphasis added)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`8
`
`Pet. 29-31; Reply 5, 9-10 Ex. 1002 ¶¶152-154, 157
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Disodium Phosphate Buffer
`Disodium hydrogen phosphate is one of 4
`specifically identified preferred buffers.
`
`Flink (Ex.1004), 47 (claim 5) (annotated)
`
`Flink (Ex.1004), 18, 27-35 (annotated)
`
`Pet. 24, 27-39; Reply 5, 7-14, 18;
`Ex. 1002 ¶¶84, 92, 148-169; Ex. 1106 ¶¶14-31
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`9
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Flink’s Examples Disclose Dihydrate Form
`
`Flink’s Example 7 Employs the
`Dihydrate Form of Disodium
`Phosphate
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`10
`
`Flink (Ex.1004), 45-46 (annotated)
`
`Pet. 30, 40-42, 48; Reply 11;
`Ex. 1002 ¶¶152, 156, 188; Ex. 1106 ¶¶24, 26-27, 58-59
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Disodium Phosphate Buffer
`
`[W]hen I say disodium phosphate, do you
`Q:
`understand that differently than if I said disodium
`hydrogen phosphate?
`DR. TESSIER: . . . .
`I would understand that disodium hydrogen
`phosphate and disodium phosphate,
`I would
`understand those two names -- often a POSA
`would understand that that’s the same buffer.
`
`Ex.1077, 77:22-78:11
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`11
`
`Pet. 30 n.9; Ex. 1002 ¶154 n.3
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Hydrates Behave Similarly
`
`Ex.1002, ¶154 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`12
`
`Pet. 30 n.9
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Hydrates Behave Similarly
`
`Q: What is the impact of using a different hydrated form of a disodium phosphate buffer in a
`solution?
`
`DR. TESSIER: We need to be careful -- I need to be careful
`in answering this, first, by clearly
`differentiating the fact that disodium phosphate and disodium phosphate of a certain hydrate form,
`those are different chemicals.
`
`Now, you’re asking, what is the difference between them, once they’re in solution. I would point out a
`POSA would be influenced -- you know, if we’re talking about in solution, I need to be clear that a
`POSA may choose one or the other, based on things like, how well it goes into solution, for example.
`So the hydrate form dissolves faster, in general, than the non-hydrate form. At least that’s my
`general experience. And so there would be some interest in using the dihydrate form in certain
`applications, generally, if that was an issue.
`
`Now, once they’re in solution, the remaining question would be is, would the resulting solution pH,
`for example, from those components be the same. And would they buffer the same. So in terms of
`the resulting properties in solution, once they’re in solution, I would expect them to be
`generally similar. There may be subtle differences in pH, but I would expect they’d generally
`behave similar.
`
`Ex.1077, 78:17-80:1 (objection omitted) (emphasis added)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`13
`
`Pet. 30 n.9; Ex. 1002 ¶154
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Flink’s Disclosure versus the ’833 Patent’s Disclosure
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`14
`
`Reply 11-12; Ex. 1106 ¶¶26-27 (annotated)
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Disodium Phosphate Buffer
`
`• Flink claims a GLP-1 formulation with a buffer
`
`• Flink discloses that disodium phosphate buffers are within the
`scope of the claims
`
`• The POSA understands that disodium hydrogen phosphate is the
`same as disodium phosphate
`
`• The POSA understands that the dihydrate form is one of several
`hydrates of disodium phosphate, each of which can be used as a
`buffer
`
`• The POSA understands that different hydrates and the anhydrate
`are indistinguishable in solution
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`15
`
`Pet. 27-39, 48; Reply 7-14;
`Ex. 1002 ¶¶148-169, 188; Ex. 1106 ¶¶14-31, 58-59
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Propylene Glycol
`
`Propylene glycol is one of
`just 18 specifically identified
`isotonic agents
`
`Flink (Ex.1004), 47-48 (claims
`5, 13 & 14) (annotated)
`
`Pet. 30-34; Reply 9-12;
`Ex. 1002 ¶¶157-168 ; Ex. 1106 ¶¶14-23
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`16
`
`Flink (Ex.1004), 19-20 (annotated)
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Flink’s Danish Priority Applications
`
`Ex.1108, 11; Ex.1109, 12; Ex.1110, 12; Ex.1111, 11 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`17
`
`Ex.1112, 12; Ex.1113, 11 (annotated)
`
`Reply 9-10
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Tessier Testimony
`
`Q: So the person skilled in the art reading [Flink at 8:33-19:9] would understand that
`propylene glycol could be used in the formulations disclosed in this patent as an
`isotonicity agent, is that right?
`
`DR. TESSIER: I view this differently, so I would answer, no. And I’m going to explain
`why. So I would view the way that this is written in this sentence, in the context of the
`entire paragraph.
`So the way that I understand this is that in the second sentence, it says, “in a
`further embodiment of the invention, the isotonic agents selected from the group
`consisting of,” and then there’s groups there that are given, so things like salts or
`polyhydric alcohols, or so on.
`And so I would view that as propylene glycol is an example of a
`polyhydric alcohol, but if I wanted to know what the particular chemicals, not groups of
`chemicals, but particular chemicals that are being recommended as isotonicity agents,
`I’d read the next paragraph, where they actually give specific chemicals. And in that list,
`I do not see propylene glycol, and nor do I see it in the preferred embodiments, which
`are even more narrow. So I would disagree.
`
`Ex.1077, 82:1-83:4 (objection omitted) (emphasis added)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`18
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Dr. Tessier’s Analysis of Flink’s Claim 14
`
`Q: So let me make sure I understand your position. You do -- it is your person
`that a person of skill in the art, looking at claim 14, would understand isotonicity -
`- or isotonic agent to include propylene glycol, is that correct?
`
`DR. TESSIER: Again, this is not something I considered in my declaration, the
`scope of the Flink claims. But if we’re now talking about the scope of the Flink
`claims, and what the claim 14 covers, there is no limitation to which isotonic
`agent one uses.
`. . . .
`
`Ex.1077, 86:16-87:6 (objection omitted)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`19
`
`
`
`Claim 14 of Flink Anticipates Claim 1
`Propylene Glycol Ranges
`
`Flink (Ex.1004), claims 13 & 14 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`20
`
`Flink (Ex.1004), 20 (annotated)
`
`Pet. 34-35; Reply 10-11;
`Ex. 1002 ¶¶170-171; Ex. 1106 ¶¶19-23
`
`
`
`Flink’s U.S. Counterpart
`Flink Becomes the ’618 Patent
`
`Ex.1107, 1, claims 1, 6 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`21
`
`Reply 7-8
`
`
`
`Flink’s U.S. Counterpart
`Orange Book Listing for Victoza
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`22
`
`Ex.1117, 1, 3 (annotated)
`
`Reply 7-8
`
`
`
`Flink’s U.S. Counterpart
`Novo Nordisk Asserts the ’618 Patent
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`23
`
`Ex.1118, 1, 3 (annotated)
`
`Reply 7-8
`
`
`
`WM Wrigley Jr. Co. v. Cadbury Adams USA LLC
`683 F.3d 1356 (Fed. Cir. 2012)
`
`The challenged claim:
`
`The prior art:
`• The prior art disclosed WS-23 as
`1 of 3 optional cooling agents
`• The prior art disclosed menthol as
`1 of 23 flavoring agents
`
`The prior art anticipated claim 34
`
`Pet. 31-33, 51
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`24
`
`
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.
`780 F.3d 1376 (Fed. Cir. 2015)
`
`“However, a reference can anticipate a claim even if it
`‘d[oes] 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.”
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376, 1381 (Fed. Cir. 2015) (citation omitted)
`
`“Grab’s express “contemplat[ion]” of PVD coatings is
`sufficient evidence that a reasonable mind could find that
`a person of skill in the art, reading Grab’s claim 5, would
`immediately envisage applying a PVD coating.”
`
`Kennametal, Inc. v. Ingersoll Cutting Tool Co.,
`780 F.3d 1376, 1383 (Fed. Cir. 2015)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`25
`
`Pet. 31-33
`
`
`
`Perricone v. Medicis Pharm. Corp.
`432 F.3d 1368 (Fed. Cir. 2005)
`
`“With respect to its skin benefit ingredient, Pereira discloses
`‘from 0.01 to 20% by weight of a skin benefit ingredient chosen
`from: ... Ascorbyl palmitate [and] Tocopherol [i.e., Vitamin E] ....’
`In addition to those two identified ingredients, Pereira lists an
`additional twelve ingredients. In total, Pereira teaches a total of
`fourteen skin benefit ingredients. This court rejects the
`notion that one of these ingredients cannot anticipate
`because it appears without special emphasis in a longer
`list. To the contrary, the disclosure is prior art to the extent
`of its enabling disclosure. See Hewlett–Packard Co. v.
`Mustek Sys., Inc., 340 F.3d 1314, 1324 n.6 (Fed. Cir. 2003)
`(‘The anticipation analysis asks solely whether the prior art
`reference discloses and enables the claimed invention, and not
`how the prior art characterizes that disclosure or whether
`alternatives are also disclosed.’) (citing Celeritas Techs. v.
`Rockwell Int’l Corp., 150 F.3d 1354, 1361 (Fed. Cir. 1998)).”
`
`Perricone v. Medicis Pharm. Corp.,
`432 F.3d 1368, 1376 (Fed. Cir. 2005)
`(emphasis added) (citations omitted)
`
`Pet. 32; Reply 9-10
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`26
`
`
`
`Flink Anticipates Claims 1-15
`
`• Concerns about the use of propylene glycol as an isotonic agent,
`while incorrect, do not avoid anticipation
`
`• Broad disclosures in the prior art do not avoid anticipation
`
`• The ’833 patent’s claims do not require physical or chemical
`stability, efficacy or isotonicity
`
`• Unexpected results do not avoid anticipation
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`27
`
`Pet. 27-39; Reply 7-14, 22-26;
`Ex. 1002 ¶¶148-187; Ex. 1106 ¶¶14-72, 104-112
`
`
`
`Flink is Enabled
`
`“Gleave’s claims are to compositions of matter—oligonucleotides—
`and therefore a reference satisfies the enablement requirement
`of § 102(b) by showing that one of skill in the art would know how
`to make the relevant sequences disclosed in Wraight. Thus, the fact
`that Wraight provides ‘no understanding of which of the targets would
`be useful’ is of no import, because Gleave admits that it is well within
`the skill of an ordinary person in the art
`to make any
`oligodeoxynucleotide sequence. As such, Wraight
`is an enabling
`disclosure
`sufficient
`to
`anticipate
`Gleave’s
`invention
`under § 102(b).”
`
`In re Gleave,
`560 F.3d 1331, 1335–36 (Fed. Cir. 2009)
`(emphasis added) (citations omitted)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`Reply 13-14; Ex. 1106 ¶¶29-31
`
`
`
`Flink is Enabled
`
`• Flink disclosed a GLP-1 compound formulation with propylene
`glycol as an isotonic agent and disodium phosphate as a buffer
`
`• Efficacy is not required to demonstrate enablement
`
`• An example is not required to demonstrate enablement
`
`• Flink (and the ’833 patent) admit that formulation of GLP-1
`compounds can be done with conventional steps
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`29
`
`Reply 13-14; Ex. 1106 ¶¶29-31
`
`
`
`The Dependent Claims are Anticipated
`
`‘833 patent (Ex.1001), claims 2-4 (annotated)
`
`Flink (Ex.1004), claim 14 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`30
`
`Flink (Ex.1004), 20 (annotated)
`
`Pet. 34-39; Ex. 1002 ¶¶170-187
`
`
`
`Ground 2:
`Obviousness of Claims 1-15 By Flink
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`31
`
`
`
`Differences Between the
`’833 Patent Claims and the Prior Art
`
`“Section 103(a) forbids issuance of a patent when ‘the differences between the
`subject matter sought to be patented and the prior art are such that the subject
`matter as a whole would have been obvious at the time the invention was made
`to a person having ordinary skill in the art to which said subject matter pertains.’”
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398, 406 (2007)
`
`Alleged Differences Between Flink’s Claim 14 and
`Claim 1 of the ’833 patent
`1. Flink claim 14’s recitation of an isotonic agent
`2. Flink claim 14’s recitation of a buffer
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`32
`
`Pet. 39-48
`
`
`
`Flink’s Disclosure of GLP-1 Agonist Formulations
`
`‘833 Patent (Ex.1001), claim 1 (annotated)
`
`Pet. 28-31, 40-47; Reply 9-12, 14-18;
`Ex. 1002 ¶¶148-169; Ex. 1106 ¶¶14-27
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`33
`
`Flink (Ex.1004), 47-48 (annotated)
`
`
`
`Flink Discloses the Use of a
`Disodium Phosphate Dihydrate Buffer
`
`‘833 Patent (Ex.1001), claim 1 (annotated)
`
`Pet. 30, 41-42; Reply 11;
`Ex. 1002 ¶¶152-156; Ex. 1106 ¶¶24-28, 58-59
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`34
`
`Flink (Ex.1004), 45 (annotated)
`
`
`
`Prior Art Use of Phosphate Buffers
`
`The POSA understood disodium phosphate
`buffers to be among the most frequently
`employed
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`35
`
`Ex. 1013, 51, 359 (annotated)
`
`Pet. at 30, 40-42, 48; Reply 11; Ex. 1002 ¶¶153
`
`
`
`Flink Discloses the Use of PG as an Isotonic Agent
`
`Propylene glycol is one of just 18 specifically
`identified isotonicity agents
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`36
`
`Flink (Ex.1004), 19-20 (annotated)
`
`Pet. 30-34, 42-44; Reply 9-12, 14-15;
`Ex. 1002 ¶¶157-168; Ex. 1106 ¶¶14-23
`
`
`
`The Use of Isotonic Agents was Well-Known
`
`Flink (Ex.1004), 20 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`37
`
`Pet. 19-23; Reply at 15-17;
`Ex. 1002 ¶¶58, 68-80; Ex. 1106 ¶¶33-42
`
`
`
`The POSA Was Motivated to Use Propylene Glycol
`
`•
`•
`
`•
`
`Flink’s claim 14 requires an isotonic agent
`Flink expressly taught that propylene glycol is an
`isotonic agent that can be used in the claimed
`formulation
`The POSA understood propylene glycol’s beneficial
`properties:
`Propylene glycol was a known tonicity adjuster
`Propylene glycol was a widely-used, acceptable and safe
`excipient
`Propylene glycol had known advantages over other agents,
`including mannitol
`• Mannitol is a solid at room temperature and risks precipitation
`upon evaporation
`
`•
`•
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`38
`
`Pet. 19-23; Reply 15-17, 23-24; Ex. 1002 ¶¶68-80, 199-204, 212-213; Ex. 1106 ¶¶33-42,
`108-11; Ex. 2079, 255:12-18; Ex. 1114 at abstract; Ex.1077, 77:21-78:11
`
`
`
`Propylene Glycol Was a Well-Known
`Isotonicity Agent
`
`***
`
`Ex. 1080 (1996 Japanese Pharmaceutical Excipients Directory), 3 (annotated)
`
`Ex. 1127 (1996 Merck Index), 3, 10 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`39
`
`Ex. 1106 ¶¶36
`
`
`
`Propylene Glycol Was a Well-Known
`Isotonicity Agent
`
`Ex. 1025 (PCT/US99/02554), 28:24-27 (annotated)
`
`Ex. 1063 (U.S. Patent No. 4,425,346), 4:21-33 (annotated)
`
`Ex. 1065 (U.S. Patent No.6,440,460), 7:47-52 (annotated)
`
`Ex. 1081 (EP 0 037 043), 2:49-57 (annotated)
`
`Ex. 1082 (U.S. Patent No. 5,686,411), 8:15-20 (annotated)
`
`Ex. 1064 (U.S. Patent No. 6,207,684), 4:61-65 (annotated)
`
`Ex. 1002 ¶¶69, 109-110, 141-146, 158; Ex. 1106 ¶36
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`40
`
`
`
`Propylene Glycol Was a Known Tonicity Adjuster
`
`Ex.2022, ¶57 (annotated)
`
`Pet. 19-23; Reply 15-18;
`Ex. 1002 ¶¶68-80; Ex. 1106 ¶¶33-42
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`41
`
`
`
`The POSA Can Determine the
`Amount of Propylene Glycol
`
`‘833 patent (Ex.1001) claim 1
`
`The claims do not require the pharmaceutical
`formulation to be isotonic
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`42
`
`Pet. 44-47; Ex. 1002 ¶¶163-168; Ex. 1106 ¶¶54-57
`
`
`
`Determining the Amount of Propylene Glycol
`
`Q: And each of those isotonic agents that I listed have an amount that was used.
`Was that amount calculated by the sodium chloride equivalent like we discussed in
`Exhibit 2053?
`MS. ENGELUND:
`don’t remember.
`Q: Was there another way that you determined the initial amount to test of each
`isotonic agent other than the sodium chloride equivalent?
`MS. ENGELUND: No, I don’t remember we used any other approach, and that
`calculation would be a natural choice to start with, or to use.
`
`I don’t exactly remember for all of them whether this is the case. I
`
`Ex.1078, 108:19-109:14 (objections omitted) (emphasis added)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`43
`
`Pet. 44-47; Ex. 1002 ¶¶163-168; Ex. 1106 ¶¶54-57
`
`
`
`Calculating the Amount of Propylene Glycol
`Remington’s
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`44
`
`Ex.1013, 307, 313 (annotated)
`
`Pet. 44-47; Ex. 1002 ¶¶163-168; Ex. 1106 ¶¶54-57
`
`
`
`Calculating the Amount of Propylene Glycol
`Remington’s
`
`Ex.1013, 311 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`45
`
`Pet. 44-47; Ex. 1002 ¶¶163-168; Ex. 1106 ¶¶54-57
`
`
`
`Calculating the Amount of Propylene Glycol
`Remington’s
`
`Ex.1013, 314-320 (Appendix A) (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`46
`
`Pet. 44-47; Ex. 1002 ¶¶163-168; Ex. 1106 ¶¶54-57
`
`
`
`Hemolysis Was Not a Concern
`
`•
`
`• Virtually every active and inactive ingredient has some potential
`side effects
`In vitro testing of propylene glycol does not reflect what occurs in
`vivo
`• Hammarlund is an equilibrium study testing a small amount of
`blood mixed with a large amount of solution
`• Hammarlund states that the study conditions are “not very
`often obtained in the body and hence the danger from
`hemolysis is usually much less than is indicated by in vitro
`studies”
`• Hutak teaches that “[i]n vitro methods cannot be reasonably
`expected to include the material concentrations used in in vivo
`testing. In the later situation, anatomical and physiological
`mechanism minimize injury” (Ex. 2034)
`• Other frequently used excipients, like glycerol, had similar
`hemolysis results
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`47
`
`Reply 10, 16-17; Ex. 1106 ¶¶43-53
`
`
`
`Hemolysis Was Not a Concern
`Hammarlund
`
`CITES
`
`Ex.2033, 6 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`48
`
`Reply 10, 16-17; Ex. 1106 ¶¶43-53
`
`
`
`Hemolysis Was Not a Concern
`Hutak
`
`Ex.2034, 19
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`49
`
`Reply 10, 16-17; Ex. 1106 ¶¶41-45
`
`
`
`The POSA Understood Mannitol Precipitation
`
`Q: Okay. Would you agree that it was known in the art before the invention here that
`at high concentrations, mannitol was prone to crystallization?
`
`DR. TESSIER: To the best of my understanding, mannitol has a solubility limit around
`18 percent. And there is a number of references to mannitol solutions crystallizing that
`are greater than that concentration.
`
`And so my understanding of the literature is that mannitol crystallization is associated
`with supersaturated solutions, which as a POSA, is exactly what you’d expect, that
`when you go above the solubility limit, you may or may not get crystallization in a time
`frame that’s relevant, but for mannitol, there are several reports that supersaturated
`solutions were crystallizing in relevant time scales for people to observe.
`
`Q: And kind of a nomenclature question, I guess. When you say supersaturated
`solutions, would that mean a solution that’s above a solubility limit?
`
`DR. TESSIER: That’s right. That’s what I mean by supersaturated.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`50
`
`Ex.1077, 154:8-155:9
`
`
`
`Ground 3:
`Obviousness of Claims 1-31: Flink + Betz
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`51
`
`
`
`Betz is Prior Art
`
`Ex.1005, 1 (annotated)
`
`Pet. 26-27; Reply 26-27;
`Ex. 1005; Ex. 1103; Ex. 1106 ¶¶113-116
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`52
`
`
`
`Betz is Prior Art
`
`July 9, 2002
`U.S. Prov. 60/394,699
`(Ex. 1103) Filing Date
`
`July 8, 2003
`Betz Int’l Filing Date
`
`2002
`
`2003
`
`2004
`
`April 23, 2003
`Alleged RTP Date
`
`November 20, 2003
`Danish Priority Appl.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`53
`
`Pet. 26-27; Reply 26-29; Ex. 1005;
`Ex. 1106 ¶¶113-116; Ex. 1103
`
`
`
`Betz is Prior Art
`
`Ex.1106 ¶¶114-115 (annotated)
`
`Pet. 26-27; Reply 26-27;
`Ex. 1005; Ex. 1103; Ex. 1106 ¶¶113-116
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`54
`
`
`
`Patent Owner Did Not Antedate Betz
`
`Intended Purpose of the Invention
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`55
`
`‘833 Patent (Ex.1001), 1:15-45 (annotated)
`
`Reply 26-27; Ex. 1106 ¶¶113-116
`
`
`
`Patent Owner Did Not Antedate Betz
`
`Only Placebo Formulations Tested for the Intended Purpose
`
`Ex. 2068, 5-6 (citing protocols in Exs. 2053, 2057-2058) (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`56
`
`Reply 26-27; Ex. 1106 ¶¶113-116
`
`
`
`Flink in view of Betz Renders Claims 1-15 Obvious
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`57
`
`
`
`The ’833 Patent’s Disclosure Includes
`hGH Formulations
`
`‘833 patent (Ex.1001), 3:49-4:2 (annotated)
`
`‘833 patent (Ex.1001), 9:58-64 (annotated)
`
`Pet. 49, n.16
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`58
`
`
`
`More Complicated Peptides Inform Formulation of Less
`Complicated Peptides
`
`Ex. 1106 ¶78 (annotated)
`
`• Common problem of active ingredient stability
`• Effects of common excipients in other drug products informs the
`formulation of other drugs
`• hGH and GLP-1 peptides have many similarities
`• More complex chemical and physical systems inform the
`formulation of less complex systems
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`59
`
`Pet. 49, n.16; Reply 18-21;
`Ex. 1002 ¶¶194-196; Ex. 1106 ¶¶78-96
`
`
`
`Flink and Betz Address a Common Problem
`
`Ex. 2022, ¶219 (annotated)
`
`Pet. 51; Reply 19-21;
`Ex. 1002 ¶¶194-196; Ex. 1106 ¶¶49-52
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`60
`
`
`
`The Differences Between the Prior Art and the Claims
`Flink Example 7 versus Claim 1
`
`‘833 Patent (Ex.1001), claim 1 (annotated)
`
`Pet. 48-52; Reply 18-21; Ex. 1002 ¶¶188-204
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`61
`
`Flink (Ex.1004), 45 (annotated)
`
`
`
`Betz Teachings on Propylene Glycol
`
`Betz (Ex.1005), 6 (annotated)
`
`Betz (Ex.1005), 7 (annotated)
`
`Pet. 26-27, 48-52; Reply 18-21;
`Ex. 1002 ¶¶95-96; Ex. 1106 ¶103
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`62
`
`
`
`Decreasing Mannitol and Increasing
`Propylene Glycol
`
`Flink (Ex.1004), 45 (Example 7) (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`63
`
`Betz (Ex. 1005), 17-18 (annotated)
`
`Pet. 26-27, 48-52; Reply 18-21;
`Ex. 1002 ¶¶190-96; Ex. 1106 ¶103
`
`
`
`Flink in view of Betz Renders Claims 16-22 Obvious
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`64
`
`
`
`Claim 16 of the ’833 Patent
`
`16. 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 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.
`
`‘833 patent (Ex.1001), claim 16 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`65
`
`Pet. 7-8, 53-54
`
`
`
`The Formulation Steps in
`the ’833 Patent Are Conventional
`
`‘833 patent (Ex.1001), 12:64-13:29 (annotated)
`
`Pet. 53-54; Reply 14, 21; Ex. 1002 ¶209;
`Ex. 1106 ¶29; Ex. 1005, 16-17
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`66
`
`
`
`Betz’s Formulation Steps
`
`Betz (Ex.1005), 16-17 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`67
`
`Pet. 53-54; Reply 21; Ex. 1002 ¶¶205-209
`
`
`
`Betz’s Bulk hGH Solution Includes Water
`
`Q: So the bulk hGH solution comprises both hGH and a sodium
`phosphate buffer, right?
`DR. FORREST: It comprises both hGH and a sodium phosphate buffer
`solution. It’s important to note the fact that we have 10 millimolars here,
`indicating that we’re discussing a solution.
`Q: Right. So it’s a solution that includes both hGH and a sodium phosphate
`buffer, right?
`DR. FORREST: Well, more precisely, it would be a solution that includes
`hGH sodium phosphate buffer and, of course, water that the sodium
`phosphate buffer would be dissolved in.
`
`Ex.2079, 319:7-23 (emphasis added)
`
`Pet. 53-54; Reply 21; Ex. 1002 ¶¶205-209
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`68
`
`
`
`Flink in view of Betz Renders Claims 23-31 Obvious
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`69
`
`
`
`Claims 23, 26 & 29 of the ’833 Patent
`
`23. 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.
`
`26. 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.
`
`29. 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.
`
`‘833 patent (Ex.1001), claims 23, 26, 29 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`70
`
`Pet. 7-8, 10-11, 54-57; Reply 5-7
`
`
`
`The Preambles of the Claims Are Not Limiting
`
`• Novo offers no evidence from a POSA as to the proper construction
`of the preambles (see generally Exs. 1077, 2022)
`• The Board’s analysis in the Institution Decision is correct (see Paper 12
`7-8)
`• There is no operative difference in the steps of the methods
`claimed in claims 23, 26, and 29 (see generally ’833 patent (Ex. 1001))
`• The district court’s uncertain claim construction decision does not
`control the Board’s construction
`
`Ex.1116, 46:3-8
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`71
`
`Pet. 10-11; Reply 5-7;
`Ex. 1002 ¶¶40, 212-213
`
`
`
`Reduction in Depositions and Clogging
`from Use of Propylene Glycol
`
`• Mannitol was known to cause deposits upon evaporation
`
`• Propylene glycol, a liquid excipient, inherently results in the
`reduction of clogging and the reduction in deposits
`
`• The reduction in clogging and the reduction in deposits necessarily
`results from the use of the formulations expressly taught by Flink
`and made obvious by Flink and/or Betz
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`72
`
`Pet. 21-22; Reply 23-24; Ex. 1002 ¶¶76-79, 199-204, 212-213;
`Ex.1106 ¶¶108-111; Ex. 2079, 255:12-18; Ex. 1114 at abstract
`
`
`
`Secondary Indicia
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`73
`
`
`
`The ’833 Patent’s Testing
`
`‘833 patent (Ex.1001), 16:61-64 (annotated)
`
`‘833 patent (Ex.1001), 17:9-18 (annotated)
`
`‘833 patent (Ex.1001), 17:62-65 (annotated)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`74
`
`
`
`No Unexpected Results
`
`• Propylene glycol was known to be safe and effective
`• Propylene glycol was a known isotonic agent
`• Propylene glycol had known protein stabilizing and antimicrobial
`properties
`• Propylene glycol was considered similar to and a replacement for
`glycerol
`• Propylene glycol was a liquid at room temperature
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`75
`
`Reply 22-26; Ex. 1106 ¶¶104-112
`
`
`
`No Unexpected Results
`
`Difference in Degree Only
`
`‘833 patent (Ex.1001), 18:10-55 (annotated)
`
`Reply 22-26; Ex. 1106 ¶¶104-112
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`76
`
`
`
`No Unexpected Results
`
`Difference in Degree Only
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`77
`
`Ex.2074, 16 (annotated)
`
`Reply 22-26; Ex. 1106 ¶¶104-112
`
`
`
`No Unexpected Results
`
`Evidence Not Commensurate in Scope
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`78
`
`Reply 22-26; Ex. 1106 ¶¶104-112
`
`
`
`CERTIFICATE OF SERVICE
`Pursuant to 37 C.F.R. § 42.6(e), I certify that I caused to be served a true and
`
`correct copy of the foregoing: Petitioners’ Demonstrative Exhibits by email to the
`
`electronic service addresses for Patent Owner and Petitioner Pfiz
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