Petitioner Liquidia
`Technologies, Inc.
`
`Oral Argument
`Demonstratives
`
`June 23, 2021
`Liquidia Technologies, Inc. v. United
`Therapeutics Corp.,
`IPR2020-00770
`
`U.S. Patent No. 9,604,901
`
`attorney advertisement
`Copyright © Cooley LLP, 3175 Hanover Street, Palo Alto, CA 94304. The content of this packet is an introduction to Cooley LLP’s
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`capabilities and is not intended, by itself, to provide legal advice or create an attorney-client relationship. Prior results do not
`guarantee future outcome.
`
`Liquidia's Exhibit No. 1055
`IPR2020-00770 - Page 001
`
`
`Technologies, Inc.
`
`Oral Argument
`Demonstratives
`
`June 23, 2021
`Liquidia Technologies, Inc. v. United
`Therapeutics Corp.,
`IPR2020-00770
`
`U.S. Patent No. 9,604,901
`
`attorney advertisement
`Copyright © Cooley LLP, 3175 Hanover Street, Palo Alto, CA 94304. The content of this packet is an introduction to Cooley LLP’s
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`capabilities and is not intended, by itself, to provide legal advice or create an attorney-client relationship. Prior results do not
`guarantee future outcome.
`
`Liquidia's Exhibit No. 1055
`IPR2020-00770 - Page 001
`
`
`
`“a second computer system distinct
`Overview of the Claims
`from the first computer system”
`
`Product by Process Claims
`Claim 1
`A pharmaceutical batch consisting of treprostinil
`or a salt thereof and impurities resulting from
`(a) alkylating a benzindene triol, (b) hydrolyzing
`the product of step (a) to form a solution
`comprising treprostinil, (c) contacting the
`solution comprising treprostinil from step (b)
`with a base to form a salt of treprostinil, (d)
`isolating the salt of treprostinil, and (e)
`optionally reacting the salt of treprostinil with
`an acid to form treprostinil, and
`
`wherein the pharmaceutical batch contains at
`least 2.9 g of treprostinil or its salt.
`Claims 2-5 depend from it.
`
`Method Claims
`Claim 6
`A method of preparing a pharmaceutical
`product from a pharmaceutical batch as claimed
`in claim 1, comprising storing a pharmaceutical
`batch of a salt of treprostinil as claimed in claim
`1 at ambient temperature, and preparing a
`pharmaceutical product from the
`pharmaceutical batch after storage.
`
`Method Claims
`Claim 8
`A method of preparing a pharmaceutical batch
`as claimed in claim 1, comprising (a) alkylating a
`benzindene triol, (b) hydrolyzing the product of
`step (a) to form a solution comprising
`treprostinil, (c) contacting the solution
`comprising treprostinil from step (b) with a base
`to form a salt of treprostinil, (d) isolating the
`salt of treprostinil, and (e) optionally reacting
`the salt of treprostinil with an acid to form
`treprostinil.
`
`Claim 7 depends from it.
`
`Claim 9 depends from it.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1001, 17:24-18:30; Petition, 8, 15, 19, 24
`2
`
`
`
`The Claims of the ’901 Patent are Product-by-Process Claims
`“a second computer system distinct
`from the first computer system”
`• Process limitations are not accorded any weight for determining validity.
`•
`In determining validity of a product-by-process claim, the focus is on the product and
`not on the process of making it (Amgen Inc. v. F. Hoffman-La Roche Ltd., 580 F.3d 1340,
`1369 (Fed. Cir. 2009).
`• The process claim elements do nothing to impart structural or functional differences in
`the claimed treprostinil or salt thereof, and thus, do not patentably limit the claimed
`pharmaceutical composition.
`• The Examiner withdrew the rejection based on product-by-process limitations because
`Patent Owner argued that the resulting products of the ’901 had different impurity
`profiles.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 8, 15, 17, 19, 24, 33; Institution Decision, 9, 22-23, 30-31
`3
`
`
`
`Person of Ordinary
`Skill in the Art
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`Person of Ordinary Skill in the Art
`from the first computer system”
`
`“Instead, for purposes of this Decision, we find that the
`level of ordinary skill in the art is reflected by the prior art,
`including Phares and Moriarty. See In re GPAC Inc., 57
`F.3d 1573, 1579 (Fed. Cir. 1995) (‘The person of ordinary
`skill in the art is a hypothetical person who is presumed to
`know the relevant prior art.’).”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Institution Decision, 22
`5
`
`
`
`“a second computer system distinct
`Person of Ordinary Skill in the Art
`from the first computer system”
`
`Liquidia
`
`Proposed Definition
`A POSA “would hold a master’s degree
`or Ph.D. in medicinal or organic
`chemistry, or a closely related field” or
`“a bachelor’s degree and at least five
`years of practical experience in
`medicinal or organic chemistry.”
`
`UTC
`
`Proposed Definition
`
`A POSA would have been “an
`industrial chemist or chemical
`engineer with experience in
`pharmaceutical manufacturing.”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 25; POPR, 56; POR, 23
`6
`
`
`
`Claims Not Directed to Commercial- or
`Claim 1:
`Industrial-Scale Synthesis
`the second computer is “distinct” and “independent”
`
`•
`“Commercial/Industrial/Large-Scale” absent from the claims.
`• Multi-kilogram quantities are not claimed: claims only require 2.9 grams of
`treprostinil or its salt.
`• UTC’s expert, Dr. Pinal, agrees that:
`•
`The terms “commercial,” “commercialization,” “high-scale,” “plant,” “large-scale
`manufacture,” and “industrial scale” do not appear in the claims. (EX1018, 105:21-106:21,
`117:5-20.)
`
`•
`
`Claims cover non-commercialized products, such as those used in clinical trials. (EX1018,
`110:13-112:8.)
`
`•
`
`The claims only require basic organic chemistry steps of alkylation,
`hydrolysis and salt formation.
`
`’901 Patent, Claim 1
`
`A pharmaceutical batch consisting of
`treprostinil or a salt thereof and impurities
`resulting from (a) alkylating a benzindene
`triol, (b) hydrolyzing the product of step (a)
`to form a solution comprising treprostinil,
`(c) contacting the solution comprising
`treprostinil from step (b) with a base to
`form a salt of treprostinil, (d) isolating the
`salt of
`treprostinil, and (e) optionally
`reacting the salt of treprostinil with an acid
`to form treprostinil, and
`
`batch
`pharmaceutical
`the
`wherein
`contains at least 2.9 g of treprostinil or its
`salt.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 8-9; EX1001, 17:24-18:2; EX1018, 105:21-106:21, 117:5-20, 110:13-112:8
`7
`
`
`
`Prior Art “Former Process”
`Claim 1:
`(Moriarty) is “Commercial-Scale”
`the second computer is “distinct” and “independent”
`
`Moriarty discloses production of 441g of treprostinil free acid
`
`(EX1009, 13; Petition, 15, 39, 63-64)
`
`•
`
`Board already found in the ’393 IPR that “Former Process” of Example 6 is the “process for preparing treprostinil
`according to Moriarty,” and that UTC used the Moriarty process to make commercial batches of treprostinil.
`(EX1005, 17-18, 34, 38.)
`• UTC and its experts have repeatedly admitted this fact. (IPR2020-00769, Paper 6, at 66 (P.T.A.B. July 14, 2020);
`EX2034, 209:9-210:7; EX2025, ¶89.)
`
`•
`
`’901 patent discloses production of 535 grams of treprostinil in Example 6. (EX1001, 16:60-61 (Example 6, Step
`No. 51.)
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 9
`8
`
`
`
`Dr. Winkler qualifies as a POSA under the Board’s and
`“a second computer system distinct
`either party’s proposed definition
`from the first computer system”
`
`Liquidia’s Proposed POSA
`“a master’s degree or Ph.D. in medicinal or
`organic chemistry, or a closely related field”
`or “a bachelor’s degree and at least five
`years of practical experience in medicinal or
`organic chemistry”
`M.A., M.Phil., Ph.D., Chemistry, Columbia
`University
`
`UTC’s Proposed POSA
`“an industrial chemist or chemical engineer
`with experience in pharmaceutical
`manufacturing”
`
`•
`
`•
`
`•
`
`Extensive experience consulting for
`process chemistry groups of
`pharmaceutical companies, including
`Bristol Myers Squibb
`Lab produces >2.9 g quantities of anti-
`cancer compounds
`Co-founder of company that developed
`and scaled-up API drug production
`
`Board
`“reflected by the
`prior art”
`Qualified as expert
`in ’393 IPR involving
`the same prior art
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Institution Decision, 21-22; Reply, 9-10; EX1017, ¶¶7-14, 18, 27; EX1003;
`EX2026, 24:13-25:18, 26:5-16, 27:5-21, 29:23-30:21
`
`9
`
`
`
`Claim Construction
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Claim 1:
`Terms At Issue
`the second computer is “distinct” and “independent”
`
`A salt treprostinil
`(not disputed)
`
`Pharmaceutical
`Product
`(not disputed)
`
`Pharmaceutical Batch
`(Disputed)
`
`contacting the solution comprising
`treprostinil from step (b) with a
`base to form a salt of treprostinil
`(Motion to Strike, Paper 29)
`
`Storing / Storage
`(Disputed)
`(Motion to Strike, Paper 29)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 18-19; POPR, 6-11; POR, 8-12; Reply, 3-8; Paper 29
`11
`
`
`
`“pharmaceutical batch”
`
`(claims 1-4, 6, and 8)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`“pharmaceutical batch”
`from the first computer system”
`UTC
`Liquidia
`
`Proposed Definition (Petition, 18; Reply, 5)
`
`Proposed Definition (POPR, 8-9; POR, 9-10)
`
`Plain and Ordinary Meaning:
`“pharmaceutical batch made according to the process recited
`in steps (a)-(d) and optionally (e), wherein no purification steps
`appear between alkylation and salt formation.”
`
`“[A] specific quantity of treprostinil (or its salt) that is intended
`to have uniform character and quality, within specified limits,
`and is produced according to a single manufacturing order
`during the same cycle of manufacture, wherein the uniform
`character and quality is such that it still contains impurities
`resulting from the method by which it is produced.”
`Also, “requires storage stability” (POR, 9; Sur-Reply, 10-11)
`
`Under either construction, Moriarty discloses a “pharmaceutical batch” of 441g. (Institution Decision, 26-27.)
`UTC’s expert, Dr. Pinal, confirmed this fact, testifying that:
`• Moriarty is “almost identical” to the “Former Process” listed in Example 6 of the ’901 Patent; and that
`•
`The term “batch” used to describe the “Former Process” and “Process According to the Invention” in Example 6 means a
`“pharmaceutical batch” to a POSA.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 18; POPR, 8-9; Institution Decision, 26-27; POR, 9-10; Reply, 5;
`Sur-Reply, 10-11; EX1018, 89:4-9, 90:14-92:9
`
`13
`
`
`
`UTC’s Construction Improperly Imports
`Claim 1:
`FDA Regulations and Other Claim Terms
`the second computer is “distinct” and “independent”
`
`Importation of FDA Regulation 21 C.F.R. § 210.3(b)(2) Creates More Ambiguity than Clarity.
`
`•
`
`21 C.F.R. § 210.3(b)(2) is not referenced anywhere in the claims, specification, or prosecution
`history.
`• UTC’s importation of § 210.3(b)(2) introduces several vague terms that themselves require
`construction.
`• “Uniform character and quality,” “single manufacturing order,” and “same cycle of
`manufacture” are not defined.
`
`Importation of “Storage” Limitations renders the “storing/storage” terms superfluous.
`
`District Court rejected importation of these limitations. (Paper 38, 4-5; EX1053, 28:3-15.)
`Reply, 4, 6; Paper 38, 5
`14
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`The Plain and Ordinary Meaning Does Not Include
`Claim 1:
`Purification Between Alkylation and Salt Formation
`the second computer is “distinct” and “independent”
`
`’901 Patent (EX1001, claim 1)
`
`’901 Patent (EX1001, claim 8)
`
`’901 Patent (EX1001,
`claims 1, 8)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`The process steps recited in independent claims 1 and 8 do not include purification steps.
`
`Reply, 5; EX1001, claims 1, 8
`15
`
`
`
`’901 Patent Emphasizes Claimed “Pharmaceutical Batch”
`Claim 1:
`Made Without Intermediate Purification Step
`the second computer is “distinct” and “independent”
`
`“The quality of treprostinil produced according
`to this invention is excellent. The purification
`of benzindene nitrile by column
`chromatography is eliminated.”
`(EX1001, 16:66-17:1.)
`Q: [T]he present invention excludes column
`chromatography, correct?
`A: Yes.
`- Dr. Pinal (EX1018, 79:9-11).
`
`’901 Patent (EX1001)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 5; EX1001, 16:66-17:1 (Example 6); EX1018, 79:9-11
`16
`
`
`
`Claim 1:
`Liquidia is Simply Agreeing with UTC’s Position
`in This and Previous IPRs
`the second computer is “distinct” and “independent”
`• UTC distinguished Moriarty based on the exclusion of the purification step in the ’393 IPR POR and here.
`POR, 58
`’393 IPR
`
`• UTC argued for a different POSA definition based on caution in eliminating purification step from Moriarty.
`POPR, 56
`POR, 25
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX2007, 3928-29; POPR 56, POR, 25, 58; Reply, 5
`17
`
`
`
`“contacting the solution
`comprising treprostinil from
`step (b) with a base to form a
`salt of treprostinil”
`
`(claims 1, 8)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`“contacting the solution comprising treprostinil from step (b) with a
`base to form a salt of treprostinil”
`from the first computer system”
`
`UTC’s original construction lined up with Liquidia’s
`plain and ordinary meaning application
`
`• Only at issue because UTC attempts to withdraw this
`construction (Sur-Reply, 9-10), but maintains
`arguments based on this construction, i.e., arguing
`that Moriarty and Phares are deficient because both
`disclose isolation of the treprostinil intermediate
`before salt formation.
`
`•
`
`For consistency, Board should either:
`•
`Find exclusion of isolation necessary and reject UTC’s
`withdrawal; OR
`Strike all portions of the POR, Sur-Reply, and UTC’s two
`expert declarations that still rely on the exclusion of
`isolation. (Paper 29, EX1043-1046 (yellow highlighting).)
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`POR, 11; Petition, 37-38, 52, 61, 62; Reply, 15-17, 21-22; Sur-Reply, 9-10; Paper 29; EX1043-1046
`19
`
`
`
`UTC Is Attempting to Withdraw Soundbites But Has
`Claim 1:
`NOT Changed Its Position
`the second computer is “distinct” and “independent”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`POR, 56-57, 67-68; EX1043, 66-67, 77-78
`20
`
`
`
`“storing” / “storage”
`
`(claims 6, 7)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`“a second computer system distinct
`“Stored” / “Storing” / “Storage”
`from the first computer system”
`UTC
`Liquidia
`
`Proposed Definition (Petition, 18-19; Reply, 6-8)
`Plain and Ordinary Meaning – “Any
`method of keeping raw materials,
`chemicals, food products, and energy
`while awaiting use, transportation, or
`consumption”
`
`Proposed Definition (POPR, 10-11; POR, 11-12)
`“[T]o require that the stored material
`possess stability sufficient to allow
`manufacture and which maintains
`integrity for a sufficient period of time
`to be useful for the preparation of a
`pharmaceutical product”
`
`District Court refused to adopt UTC’s construction and found plain and ordinary
`meaning. (EX1053, 98:21-99:10, 112:12-19, 122:21-123:14; EX1054.)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 18-19; POPR, 10-11; POR, 11-12; Reply, 6-8; Paper 38 (citing EX1053, 1054)
`22
`
`
`
`Claim 1:
`Specification Has No Guidance on “Storing” / “Storage;”
`Assumes POSA’s Understanding of Plain and Ordinary Meaning
`the second computer is “distinct” and “independent”
`
`Specification refers to storage only once and
`provides no details, definition or data.
`
`Hawley’s Condensed Chemical
`Dictionary (2007)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1001, 17:4-10; EX1038, 4; Reply, 6-8
`23
`
`
`
`Claim 1:
`Importation of “Stability” Violates Claim Construction Canon
`the second computer is “distinct” and “independent”
`
`The term “stable” is separately defined in the ’901 specification. (EX1001, 5:4-10.)
`
`The term “stable” is recited along with the term “storing” in claim 8 of the related
`’066 Patent, which has an identical specification. (EX2027, 18:38-61.)
`• Omega Engineering v. Raytek Corp., 334 F.3d 1314, 1334 (Fed. Cir. 2003)
`(presumption that “the same claim term in the same patent or related
`patents carries the same construed meaning”).
`
`•
`
`•
`
`UTC’s definition of “storing/storage” is essentially the definition of “stable” and renders the terms redundant.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1001, 5:4-10; EX2027, 18:38-61; Reply, 7
`24
`
`
`
`“a second computer system distinct
`Motion to Strike Issue
`from the first computer system”
`UTC’s Expert and Counsel Have Asserted in District Court
`That Little to No Storage is Sufficient
`
`UTC’s Counsel at Markman Hearing
`(EX1053, 115:18-24)
`
`UTC’s district court expert, Dr. Ruffolo
`(EX2034, 171:10-172:4)
`For consistency, all portions of the POR, Sur-Reply, and UTC’s two expert declarations that fault the prior
`art for not disclosing actual storage should be stricken. (Paper 29, EX1043-1046 (orange highlighting).)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Paper 29; EX1043-1046; Paper 38, 7; EX1053, 115:18-24
`25
`
`
`
`Ground 2: Moriarty in
`view of Phares (§ 103)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Overview of Moriarty
`“a second computer system distinct
`from the first computer system”
`• Moriarty discloses the same
`treprostinil as the ’901 Patent.
`• Moriarty discloses the equivalent
`alkylation reaction to the ’901
`Patent.
`• Alkylation product 35 is hydrolyzed
`with a base, followed by acidification
`to yield Treprostinil.
`• Moriarty teaches synthesizing 441 g
`of Treprostinil.
`
`(EX1009, 3)
`
`(EX1001, 11:50-65)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 50; Institution Decision, 18; EX1001, 11:50-65; EX1009, 3, 6, 13; EX1002, ¶147
`27
`
`Alkylation Reaction
`
`
`
`Overview of Ground 2
`“a second computer system distinct
`from the first computer system”
`• UTC does not address dependent claims 2-5 and 8-9.
`• The claims of the ’901 Patent are Product-by-Process Claims.
`• UTC is precluded from disputing motivation to combine Moriarty and Phares.
`• A POSA would have formed the salt of Phares with a reasonable expectation of success.
`• Elimination of intermediate isolation and crystallization steps of Moriarty would have
`been obvious.
`• The combination of Moriarty and Phares would necessarily have impurities resulting
`from the claimed steps.
`• A POSA would have had a reasonable expectation that treprostinil diethanolamine salt
`could be stored at ambient temperature.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`28
`
`
`
`UTC is Precluded From
`Disputing the Motivation to
`Combine Moriarty and Phares
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`Issue Preclusion Applies
`“a second computer system distinct
`from the first computer system”
`• Fully and fairly tried in a previous action involving substantially similar claims and
`adversely resolved against UTC. (EX1005; EX1017, ¶¶ 63-67.)
`• Claims need not be identical.
`•
`Identity of the issues is the relevant inquiry.
`
`“Our precedent does not limit collateral estoppel to patent claims
`that are identical. Rather, it is the identity of the issues that were
`litigated that determines whether collateral estoppel should apply.”
`
`Ohio Willow Wood Co. v. Alps S., 735 F.3d 1333, 1342 (Fed. Cir. 2013)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`EX1017, ¶¶ 63-67; Reply, 10-12
`30
`
`
`
`Issue Preclusion Applies
`“a second computer system distinct
`from the first computer system”
`• UTC’s shifting claim construction negates their argument regarding
`issue preclusion (“…each claim of the ‘901 patent requires that
`treprostinil not be isolated before forming a salt, whereas Phares and
`Moriarty both teach isolating treprostinil, and the ‘393 claims did not
`exclude isolating treprostinil.”)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`POR, 53; Reply, 10-12; EX1017, ¶68
`31
`
`
`
`Issue Preclusion Applies
`“a second computer system distinct
`from the first computer system”
`• The ’393 and ’901 Claims are substantially similar for purposes of
`motivation to combine Moriarty and Phares.
`• The only differences are “impurities resulting from [the process steps]”
`and “wherein the pharmaceutical batch contains at least 2.9 g of
`treprostinil or its salt.” (See chart comparing claims; EX1017, ¶68.)
`• The differences are not excluded by the ’393 Patent.
`• Differences are disclosed by proposed combination.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`POR, 53; Reply, 10-12; EX1017, ¶68
`32
`
`
`
`A POSA Would Have Been
`Motivated to Combine
`Moriarty and Phares
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`•
`
`Motivation to Form the Treprostinil Diethanolamine Salt
`“a second computer system distinct
`from the first computer system”
`If isolation before salt formation is allowed by the claims, the Board previously
`determined that a POSA would be motivated to combine Moriarty and Phares.
`•
`If isolation before salt formation is excluded by the claims:
`• Phares starts where Moriarty ends.
`• Phares teaches the preparation of treprostinil diethanolamine and is directed to
`improving treprostinil – Moriarty was a well-known way to make Treprostinil.
`• Bioavailability increase based on Phares (21-25% vs. less than 10% in Moriarty).
`• Safety of diethanolamine salt which exhibited a “safety profile…consistent with the
`reported safety profile and product labeling of[FDA-approved] Remodulin (treprostinil
`sodium) and other prostacyclin analogs.”
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 16, 37-38; Reply, 12-14; EX1008, 2, 83 (cites are to bottom center page numbers)
`34
`
`
`
`Elimination of Isolation and Crystallization of
`“a second computer system distinct
`Moriarty Would have been Obvious
`from the first computer system”
`• Elimination of isolation promotes synthetic efficiency and reduces production cost.
`• Board rejected UTC’s arguments and accepted efficiency motivation in ’393 IPR.
`• Crystallization not necessary if isolation of crude treprostinil is eliminated during salt
`formation.
`• Eliminating crystallization avoids the formation of white needles that create
`manufacturing difficulties.
`• Formation of carboxylate salt by adding a base to a neutral carboxylic acid is a standard
`procedure.
`• Contrary to UTC’s position, the claims do not require “late-stage” or “large-scale”
`manufacturing.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 51-53; Reply, 15-17; EX1005, 47; EX1017, ¶¶140-144
`35
`
`
`
`Moriarty + Phares Necessarily Results in a Pharmaceutical Batch
`“a second computer system distinct
`Having Impurities Resulting From the Claimed Steps
`from the first computer system”
`• No need for “identical impurities”.
`• Claims do not require any specific type of impurity.
`• Both Dr. Winkler and Dr. Pinal agree that all reactions form impurities.
`
`(EX2026, 105:22-24)
`
`(EX1018, 55:19-58:17)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 31-32, 56; Reply, 17-18; EX1018, 54:11-55:18; 67:3-68:2; EX2026, 105:13-106:2
`36
`
`
`
`Ground 1: Phares (§ 103)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`•
`
`•
`
`•
`
`•
`
`Overview of Phares
`“a second computer system distinct
`from the first computer system”
`Phares discloses the chemical structure of treprostinil,
`which was known at the time (e.g., Moriarty was already
`commercially used to make Remodulin).
`Phares teaches compounds, including treprostinil and
`derivatives thereof, “and methods for inducing prostacyclin-
`like effects in a subject or patient.”
`Phares teaches that “[a] preferred embodiment of the
`present invention is the diethanolamine salt of treprostinil,”
`and depicts the structure of the diethanolamine salt of
`treprostinil.
`Phares teaches the synthesis of (-)-treprostinil, the
`enantiomer of (+)-treprostinil. Specifically, Phares teaches
`the following reaction procedure (to the right), depicting
`the reaction procedure for the conversion of 11b to 2.
`Phares describe it as: “(l) i. ClCH2CN, K2CO3. ii, KOH, CH3OH,
`reflux. 83% (2 steps).”
`
`Treprostinil
`Diethanolamine
`
`Treprostinil
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Institution Decision, 18-22; EX1008, 8-9, 39-40, 96
`38
`
`Conversion ‘L’ from Compound 11b to 2
`
`
`
`Phares discloses, but does not require, isolation
`of treprostinil prior to salt formation
`
`Phares discloses making diethanolamine salt
`from treprostinil free acid. (EX1008, 24.)
`
`•
`
`UTC has waffled about whether isolation before salt formation is allowed by the ’901 claims. (Sur-Reply, 9-10; Paper 29.)
`•
`If isolation before salt formation is allowed by the claims, Phares teaches “dissolving” the treprostinil free acid for use of
`isolated treprostinil to make a salt.
`If isolation before salt formation is excluded by the claims:
`• A POSA would have been motivated by synthetic efficiency and found it obvious to save the step of intermediate
`isolation and avoid having to redissolve the acid before contacting with a base to form the salt. (Petition, 37; EX1002,
`¶91-92; Reply, 21; EX1017, ¶¶101-110.)
`• Removal of the isolation step prior to salt formation does not change a “critical step,” as relevant to the ’901 claims.
`• UTC argues “various impurities from previous synthetic steps could remain following salt formation.” (POR, 29-34.)
`• But the ’901 Patent claims require impurities resulting from the claimed process steps. (EX1001, claim 1; POR, 35
`(subsection titled, “Claim 1 requires a pharmaceutical batch consisting of treprostinil and impurities”).)
`• Thus, any alleged concern about the resulting purity (or presence of impurities) of the resulting treprostinil salt is
`immaterial to the obviousness of the challenged claims.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 37-38; Reply, 21-22
`39
`
`
`
`Phares’s Diethanolomine Salt Contains Impurities Resulting
`from Claim Steps (a)-(d)
`• Neither the claims nor specification identify any specific “type” of impurity
`possessed by the claimed pharmaceutical batch, only “impurities resulting
`from” the process steps. (EX1001, claim 1; EX1018, 54:11-55:18; 67:3-12.)
`As UTC’s expert agrees, no specific solvents, reagents (other than
`diethanolamine in claim 7), or reaction conditions are claimed.
`
`•
`
`(EX1018, 53:6-55:18)
`
`(EX1018, 67:3-12)
`
`• Both experts agree that impurities will necessarily result from the claimed process steps (a)-(d).
`• Pinal: “[W]e can say that, as a rule, chemical reactions produce some impurities.” (EX1018, 58:13-14.)
`• Winkler: “[I]n basically all chemical reactions, one observes impurities. I know of no exceptions to that.”
`(EX2026, 105:13-106:2.)
`Phares discloses alkylation, hydrolysis, and salt formation the resulting salt will necessarily have
`impurities from those steps.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 22-23; EX1017, ¶¶92-96
`40
`
`
`
`A POSA reading Phares would understand synthesis of both
`enantiomeric forms of treprostinil
`Phares discloses that synthesis of (+)-treprostinil was already well-known, and
`that its sodium salt was FDA-approved as Remodulin. (EX1008, 8-9.)
`
`Phares explains that in some of its disclosed “compounds are derivatives of (-)-treprostinil, the
`enantiomer of (+)-treprostinil,” and because synthesis of (-)-treprostinil was less well-known, Phares
`provides the details. (EX1008, 9, 40.)
`
`Phares discloses alkylation and hydrolysis to convert an enantiomer of benzidine triol (compound
`11b) the enantiomer of treprostinil (compound 2):
`
`•
`
`•
`
`•
`
`Phares describe the “2-step” process “l” as:
`i. ClCH2CN, K2CO3 Alkylation
`ii. KOH, CH3OH, reflux. 83% Hydrolysis
`
`• A POSA would understand the steps and reagents to be identical for benzidine triol (+) treprostinil
`because the disclosed reagents are achiral.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 23-24; EX1008, 8-9, 40; EX1017, ¶¶76-91
`41
`
`
`
`Phares discloses 1 gram quantities, and scaling up
`“a second computer system distinct
`would have been obvious
`from the first computer system”
`Phares teaches a reaction of ~1 gram-scale quantities of treprostinil (for the preparation of the
`corresponding methyl ester). (EX1008, 18, 22.)
`Scaling up by factor of 3 is common sense in the field. (EX1002, ¶102.)
`• Undergraduate chemistry courses and laboratories routinely synthesize quantities of 2.9 grams or
`more. (EX1017, ¶¶111-114.)
`
`POSA is presumed to have knowledge of the art (In re Rouffet, 149 F.3d 1350, 1357 (Fed. Cir. 1998)), and
`the art disclosed 441 gram-scale of treprostinil used to make the Remodulin that Phares discusses.
`(EX1009, 13; EX1008, 2.)
`
`•
`
`•
`
`•
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 39; EX1002, ¶102; EX1017, ¶¶111-114; Reply, 24-25
`42
`
`
`
`Phares renders claims 2-5 and 8-9 obvious
`
`Claim
`
`Phares’ Disclosure
`
`2. The pharmaceutical batch of claim 1, which has been dried
`under vacuum.
`3. A pharmaceutical product comprising a therapeutically
`effective amount of treprostinil from a pharmaceutical batch
`as claimed in claim 1.
`4. A pharmaceutical product comprising a therapeutically
`effective amount of a salt treprostinil from a pharmaceutical
`batch as claimed in claim 1.
`5. The product of claim 4, wherein the salt is the
`diethanolamine salt of treprostinil.
`8. A method of preparing a pharmaceutical batch as claimed
`in claim 1 . . .
`9. A method as claimed in claim 8, wherein the salt of
`treprostinil is a diethanolamine salt.
`
`Undisputed: drying under vacuum was standard organic
`chemistry practice for the isolation of a solid in 2007.
`Phares defines “therapeutically effective dose” (EX1008,
`48, 51) and discloses safe and tolerated administration of
`treprostinil diethanolamine salt in clinical studies
`(EX1008, 82-85).
`
`Undisputed: Phares discloses formation of
`diethanolamine salt. (EX1008, 22.)
`Same issues as claim 1.
`
`Undisputed: Phares discloses formation of
`diethanolamine salt. (EX1008, 22.)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 40-43,45-48; Reply, 25-26
`43
`
`
`
`Claims 6 and 7
`(Grounds 1 and 2)
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`
`
`POSA Would Have a Reasonable Expectation That Treprostinil
`“a second computer system distinct
`Diethanolamine Salt Could be Stored at Ambient Temperature
`from the first computer system”
`• The only reference to storage in the ’901 Patent:
`
`(EX1001, 17:4-6)
`
`• The ’901 Patent confirms that a POSA would understand that all crude treprostinil salts
`can be stored at ambient temperature, without storage data.
`• A POSA would understand the treprostinil diethanolamine salt described in Phares to
`be storable at room temperature, without storage data.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 43-45; Reply, 18-21; EX1001, 17:4-6; EX1017, ¶¶155, 158
`45
`
`
`
`POSA Would Have a Reasonable Expectation That Treprostinil
`“a second computer system distinct
`Diethanolamine Salt Could be Stored at Ambient Temperature
`from the first computer system”
`Phares discloses the formation of polymorph (Form B) at ambient temperature so, a POSA would reasonably
`expect that Form B could further be stored under the same conditions. (EX1008, 22, 89 (Table 17); EX1017, ¶158.)
`• A POSA would expect that the more “thermodynamically stable” polymorph, Form B, disclosed in Phares could be stored at
`ambient temperatures.
`Regardless, Claims 6 and 7 are not specific to any particular polymorph. Phares discloses two polymorphic forms of treprostinil
`diethanolamine salt, both of which have melting temperatures at over 100°C—well over ambient temperature of ~25°C.
`Phares specifies when special storage conditions are needed. (EX1008, 67.)
`
`•
`
`•
`
`•
`
`• A POSA would have expected a similar disclosure if treprostinil diethanolamine salt required non-ambient temperature storage.
`•
`But Phares does not mention any special storage conditions for the treprostinil diethanolamine salt.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 43-45; Reply, 18-21; EX1008, 22, 67, 89; EX1017, ¶158
`46
`
`
`
`•
`
`POSA Would Have a Reasonable Expectation That Treprostinil
`“a second computer system distinct
`Diethanolamine Salt Could be Stored at Ambient Temperature
`from the first computer system”
`To the extent “stability” is read into “storability,” UTC’s expert Dr. Pinal explains that the claimed
`pharmaceutical batch derives such stability from the presence of impurities resulting from the claimed
`steps. (EX2025, ¶91.)
`• The Phares salt and the treprostinil salt formed by the combination of Moriarty and Phares have the
`same impurities as the salt of claims 6 and 7.
`• A POSA would thus have understood the prior art salts to have the same storability.
`• UTC’s expert and counsel have asserted in district court that little (“one day”) to no storage is sufficient
`to fall under the scope of claims 6 and 7. (See Slide 25.)
`• Under this understanding, a POSA need only find obvious that Phares’s salt is storable for as little
`as “one day,” without any actual storage data.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Petition, 43-45; Reply, 18-21; EX2025, ¶91; EX1017, ¶¶149, 153
`47
`
`
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