Trials@uspto.gov
`571-272-7822
`
` Paper 7
`
`Date: October 13, 2020
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`____________
`
`IPR2020-00769
`Patent 9,593,066 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`571-272-7822
`
` Paper 7
`
`Date: October 13, 2020
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`____________
`
`IPR2020-00769
`Patent 9,593,066 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`IPR2020-00769
`Patent 9,593,066 B2
`
`
`INTRODUCTION
`Liquidia Technologies, Inc. (“Petitioner”) filed a Petition (Paper 1
`(“Pet.”)), seeking an inter partes review of claims 1–10 of U.S. Patent
`No. 9,593,066 B2 (Ex. 1001, “the ’066 patent”). United Therapeutics
`Corporation (“Patent Owner”) filed a Preliminary Response (Paper 6
`(“Prelim. Resp.”)).
`We have authority under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a).
`For the reasons provided below, we determine Petitioner has not
`demonstrated a reasonable likelihood that it would prevail with respect to at
`least one of the claims challenged in the Petition. Accordingly, we deny
`institution of an inter partes review.
`Related Matters
`Patent Owner asserted the ’066 patent against Petitioner in United
`Therapeutics Corporation v. Liquidia Technologies, Inc., Case No. 1:20-cv-
`00755 (D. Del.). Paper 5, 1.
`Petitioner filed IPR2020-00770, challenging the claims of U.S. Patent
`No. 9,604,901, a patent in the same family as the ’066 patent. Id. Together
`with this Decision, we concurrently issue a decision in that case, instituting
`an inter partes review. IPR2020-00770, Paper 7.
`U.S. Patent No. 8,497,393 (Ex. 1004, “the ’393 patent”) is a parent of
`the ’901 patent. Ex. 1001, Code (60). The ’393 patent was the subject of
`SteadyMed Ltd. v. United Therapeutics Corp., IPR2016-00006 (“the ’393
`
`2
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`
`
`IPR2020-00769
`Patent 9,593,066 B2
`
`IPR”). In that case, the Board held that claims 1–22 of the ’393 patent are
`unpatentable (IPR2016-00006, Paper 82 (PTAB March 31, 2017) (“the ’393
`Decision” or “the ’393 Dec.”), and the Federal Circuit affirmed (United
`Therapeutics Corp. v. SteadyMed Ltd., 702 Fed.App’x. 990 (Fed. Cir.
`2017)).
`
`The ’066 Patent
`The ’066 patent relates to “an improved process to convert benzindene
`triol to treprostinil via salts of treprostinil and to purify treprostinil.”
`Ex. 1001, Abstract.
`Treprostinil was a known, useful pharmaceutical compound. Id. at
`1:35–65, see also id. at 27 (“Treprostinil [is] the active ingredient in
`Remodulin®.”). Before the ’901 patent, treprostinil had been prepared as
`described in Moriarty1 and other prior-art references. Id. at 1:28–32.
`According to the ’066 patent, because treprostinil is “of great importance
`from a medicinal point of view, a need exists for an efficient process to
`synthesize th[is] compound[] on a large scale suitable for commercial
`production.” Id. at 1:66–2:3.
`The ’066 patent discloses “a process for the preparation of a
`compound having formula IV, or a hydrate, solvate, or pharmaceutically
`acceptable salt thereof.” Id. at 8:20–22. Petitioner represents that Formula IV
`
`
`1 Moriarty et al., The Intramolecular Asymmetric Pauson-Khand Cyclization
`as a Novel and General Stereoselective Route to Benzindene Prostacyclins:
`Synthesis of UT-15 (Treprostinil), 69 J. ORG. CHEM. 1890–1902 (2004)
`(Ex. 1009). Moriarty is one of the two prior-art references asserted in this
`proceeding.
`
`3
`
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`IPR2020-00769
`Patent 9,593,066 B2
`
`is treprostinil. Pet. 33; Ex. 1002 ¶ 31. Formula IV has the following
`structure:
`
`
`The figure above shows the structure of Formula IV. Id. at 8:25–37.
`The process of the ’066 patent comprises
`alkylating a compound of structure V with an alkylating
`(a)
`agent such as ClCH2CN to produce a compound of formula VI,
`hydrolyzing the product of step (a) with a base such as
`(b)
`KOH,
`contacting the product of step (b) with a base B such as
`(c)
`diethanolamine to for a salt of the following structure, and
`reacting the salt from step (b) with an acid such as HCl to
`(d)
`form the compound of formula IV.
`Id. at 8:40–9:21. Structure V, formula VI, and the salt formed in step (c)
`have the following structures:
`
`
`
`4
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`IPR2020-00769
`Patent 9,593,066 B2
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`
`
`
`
`The figures above show the structures of structure V, formula VI, and
`the salt formed in step (c). Id. at 8:45–65, 9:8–18. The ’066 patent states that
`“[i]n one embodiment, the purity of compound of formula IV is at least
`90.0%, 95.0%, 99.0%, 99.5%.” Id. at 9:23–24.
`According to the ’066 patent:
`The quality of treprostinil produced according to this invention
`is excellent. The purification of benzindene nitrile by column
`chromatography is eliminated. The impurities carried over from
`intermediate steps (i.e. alkylation of triol and hydrolysis of
`benzindene nitrile) are removed during the carbon treatment and
`the salt formation step. Additional advantages of this process are:
`(a) crude treprostinil salts can be stored as raw material at
`ambient temperature and can be converted to treprostinil by
`simple acidification with diluted hydrochloric acid, and (b) the
`treprostinil salts can be synthesized from the solution of
`treprostinil without isolation. This process provides better
`quality of final product as well as saves significant amount of
`solvents and manpower in purification of intermediates.
`Id. at 17:27–40, see also id. at 5:57–6:3 (the same).
`5
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`IPR2020-00769
`Patent 9,593,066 B2
`
`
`Illustrative Claims
`Claims 1 and 8 are independent, and are reproduced below:
`A pharmaceutical composition comprising treprostinil or
`1.
`a pharmaceutically acceptable salt thereof, said composition
`prepared by a process comprising providing a starting batch of
`treprostinil having one or more impurities resulting from prior
`alkylation and hydrolysis steps, forming a salt of treprostinil by
`combining the starting batch and a base, isolating the treprostinil
`salt, and preparing a pharmaceutical composition comprising
`treprostinil or a pharmaceutically acceptable salt thereof from the
`isolated treprostinil salt, whereby a level of one or more
`impurities found in the starting batch of treprostinil is lower in
`the pharmaceutical composition, and wherein said alkylation is
`alkylation of benzindene triol.
`A process of preparing a pharmaceutical product
`8.
`comprising treprostinil or a pharmaceutically acceptable salt
`thereof, comprising alkylating a triol intermediate of the formula:
`
`
`hydrolyzing the resulting compound to form treprostinil, forming
`a salt of treprostinil stable at ambient temperature, storing the
`treprostinil salt at ambient temperature, and preparing a
`pharmaceutical product from the treprostinil salt after storage,
`wherein the pharmaceutical product comprises treprostinil or a
`pharmaceutically acceptable salt thereof.
`
`6
`
`
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`IPR2020-00769
`Patent 9,593,066 B2
`
`
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability:
`Claims Challenged 35 U.S.C. §
`References
`1–7
`103(a)
`Phares2
`8–10
`102(b)
`Phares
`1–9
`103(a)
`Moriarty, Phares
`In support of their respective positions, Petitioner relies on the
`Declaration of Jeffrey D. Winkler, Ph.D. (Ex. 1002), and Patent Owner
`relies on the Declaration of Rodolfo Pinal, Ph.D. (Ex. 2002).
`ANALYSIS
`Claim Construction
`In an inter partes review, we construe a claim term “using the same
`claim construction standard that would be used to construe the claim in a
`civil action under 35 U.S.C. [§] 282(b).” 37 C.F.R. § 42.100(b). Under that
`standard, the words of a claim “are generally given their ordinary and
`customary meaning,” which is “the meaning that the term would have to a
`person of ordinary skill in the art in question at the time of the invention, i.e.,
`as of the effective filing date of the patent application.” Phillips v. AWH
`Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc).
`The parties proposes the construction of several terms. Pet. 17–18;
`Prelim. Resp. 5–9. Claim terms need only be construed to the extent
`necessary to resolve the controversy. Wellman, Inc. v. Eastman Chem. Co.,
`642 F.3d 1355, 1361 (Fed. Cir. 2011). For purposes of this Decision, we
`
`
`2 PCT Application No. WO 2005/007081 A9, published Jan. 27, 2005
`(Ex. 1008).
`
`7
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`IPR2020-00769
`Patent 9,593,066 B2
`
`discuss Patent Owner’s proposed construction of
`“stored”/“storing”/“storage.” Prelim. Resp. 8–9.
`Claim 6 recites the pharmaceutical composition of claim 1, “wherein
`the isolated salt is stored at ambient temperature.” Claims 8–10 require
`“forming a salt of treprostinil stable at ambient temperature, storing the
`treprostinil salt at ambient temperature, and preparing a pharmaceutical
`product from the treprostinil salt after storage.” Patent Owner contends that
`an ordinarily skilled artisan would have “understood these terms to require
`stability of the material being stored.” Id. at 8 (citing Ex. 2002 ¶¶ 123–124).
`The ’066 patent states:
`Combinations of substituents and variables envisioned by this
`invention are only those that result in the formation of stable
`compounds. The term “stable”, as used herein, refers to
`compounds which possess stability sufficient
`to allow
`manufacture and which maintains the integrity of the compound
`for a sufficient period of time to be useful for the purposes
`detailed herein.
`Ex. 1001, 4:57–63.
`Thus, according to Patent Owner, we should construe the terms
`“stored”/“storing”/“storage” to “require that the stored material possesses
`stability sufficient to allow manufacture and which maintains integrity for a
`sufficient period of time to be useful for the preparation of a pharmaceutical
`composition or a pharmaceutical product.” Prelim. Resp. 9 (citing Ex. 2002
`¶ 126). Based on the current record, we find Patent Owner’s argument
`persuasive, and for purposes of this Decision, adopt its proposed
`construction of “stored”/“storing”/“storage.”
`
`8
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`IPR2020-00769
`Patent 9,593,066 B2
`
`
`Prior Art Disclosures
`Moriarty
`Moriarty describes synthesizing treprostinil “via the stereoselective
`intramolecular Pauson-Khand cyclization.” Ex. 1009, 1.3 Formula 7 of
`Moriarty is reproduced below:
`
`
`Id. at 3. Formula 7 of Moriarty depicts the chemical structure of treprostinil.
`Id.
`
`An excerpt of Scheme 4 of Moriarty is reproduced below:
`
`
`Id. at 6. The excerpted portion of Scheme 4 of Moriarty illustrates that
`“[t]riol 34 was alkylated at the phenolic hydroxyl group with use of
`chloroacetonitrile in refluxing acetone with potassium carbonate (34 → 35)
`
`
`3 For Moriarty, the parties cite to the pagination added by Petitioner. For
`consistency, we do the same.
`
`9
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`IPR2020-00769
`Patent 9,593,066 B2
`
`and nitrile 35 was hydrolyzed with ethanolic potassium hydroxide to yield
`UT-15 (7),” treprostinil. Id. at 8.
`
`Phares
`Phares teaches compounds, including treprostinil and derivatives
`thereof, “and methods for inducing prostacyclin-like effects in a subject or
`patient.” Ex. 1008, 8.4 “Treprostinil is a chemically stable analog of
`prostacyclin, and as such is a potent vasodilator and inhibitor of platelet
`aggregation.” Id. Phares states that “[t]he compounds provided herein can be
`formulated into pharmaceutical formulations and medicaments that are
`useful in the methods of the invention.” Id., see also id. at 48 (“providing for
`compositions which may be prepared by mixing one or more compounds of
`the instant invention, or pharmaceutically acceptable salts thereof, with
`pharmaceutically acceptable carriers, excipients, binders, diluents or the like,
`to treat or ameliorate a variety of disorders related vasoconstriction and/or
`platelet aggregation”).
`The chemical structure of treprostinil, as shown in Phares, is
`reproduced below:
`
`
`
`The figure above shows the structure of treprostinil. Id. at 8.
`
`4 For Phares, the parties cite to the original page numbers of the exhibits, and
`not the pagination added by Petitioner. For consistency, we do the same.
`10
`
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`IPR2020-00769
`Patent 9,593,066 B2
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`
`Phares teaches that “[a] preferred embodiment of the present
`invention is the diethanolamine salt of treprostinil.” Id. at 9. The structure of
`the diethanolamine salt of treprostinil, as shown in Phares, is reproduced
`below:
`
`
`The figure above shows the structure of treprostinil diethanolamine salt. Id.
`at 96 (claim 49).
`Phares teaches two crystalline forms of treprostinil diethanolamine
`salt, the metastable Form A and the thermodynamically more stable Form B.
`Id. at 85. Phares states that “[a] particularly preferred embodiment of the
`present invention is form B of treprostinil diethanolamine.” Id. at 9.
`Phares teaches the synthesis of (-)-treprostinil, the enantiomer of (+)-
`treprostinil. Id. at 39–40. Specifically, Phares teaches the following reaction
`procedure:
`
`11
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`IPR2020-00769
`Patent 9,593,066 B2
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`
`
`Id. at 40. The figure above shows the reaction procedure for the conversion
`of 11b to 2. Id. Phares describe it as: “(l) i. ClCH2CN, K2CO3. ii, KOH,
`CH3OH, reflux. 83% (2 steps).” Id.
`Phares further teaches that “the enantiomer of the commercial drug
`(+)-treprostinil was synthesized using the stereoselective intramolecular
`Pauson Khand reaction as a key step and Mitsunobu inversion of the side-
`chain hydroxyl group.” Id., see also id. at 39 (“Enantiomers of these
`compounds . . . can be synthesized using reagents and synthons of
`enantiomeric chirality of the above reagents.”).
`Obviousness over Phares
`Petitioner argues that claims 1–7 of the ’066 patent would have been
`obvious over Phares. Pet. 30–45. Based on this record, we determine
`Petitioner has not established a reasonable likelihood that it would prevail in
`this assertion.
`Regarding claim 1, Petitioner argues that it is a product-by-process
`claim (id. at 19), “[t]he remaining 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” (id. at 33). Petitioner nevertheless argues that Phares teaches
`or suggests the process. Id. at 33–38.
`
`12
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`IPR2020-00769
`Patent 9,593,066 B2
`
`
`Regarding the whereby clause reciting “a level of one or more
`impurities found in the starting batch of treprostinil is lower in the
`pharmaceutical composition,” Petitioner points out that Phares discloses two
`crystalline forms of treprostinil diethanolamine salt, Form A and Form B. Id.
`at 38 (citing Ex. 1008 at 85–89). Petitioner observes that “Form A has an
`endotherm at 103 °C and Form B has an endotherm at 107 °C.” Id. at 38–39
`(citing Ex. 1008, 87). According to Petitioner, “[a] form exhibiting a higher
`endotherm temperature is inherently compatible with a higher purity.” Thus,
`Petitioner concludes that “the higher melting point of Form B is consistent
`and compatible with a higher degree of purity in Form B in comparison with
`Form A based on these endotherm temperatures.” Id. at 39. Petitioner further
`observes that “Form A is utilized as the starting material for formation of
`Form B.” Id. As such, Petitioner contends that Phares teaches the whereby
`clause. We are not persuaded by this argument.
`As Patent Owner points out, claim 1 recites a starting batch that is of
`treprostinil, and not a salt. Prelim. Resp. 57 (citing Ex. 1001, claim 1).
`Indeed, claim 1 recites “a starting batch of treprostinil,” in contrast to
`“forming a salt of treprostinil by combining the starting batch and a base.”
`As Petitioner recognizes, both Form A and Form B are of treprostinil
`diethanolamine salt. Pet. 38. Thus, even though Form B is made from Form
`A (Ex. 1008, 85), and even if, as Petitioner argues, Form B has “a higher
`degree of purity” than Form A (Pet. 39), it does not suggest “a level of one
`or more impurities found in the starting batch of treprostinil is lower in the
`pharmaceutical composition,” as claim 1 requires.
`
`13
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`IPR2020-00769
`Patent 9,593,066 B2
`
`
`As a result, Petitioner has not sufficiently demonstrated the
`obviousness of claims 1–7 over Phares.
`Anticipation by Phares
`Petitioner argues that Phares anticipates claims 8–10 of the ’066
`patent. Pet. 45–54. Based on this record, we determine Petitioner has not
`established a reasonable likelihood that it would prevail in this assertion.
`Claims 8–10 require “forming a salt of treprostinil stable at ambient
`temperature, storing the treprostinil salt at ambient temperature, and
`preparing a pharmaceutical product from the treprostinil salt after storage.”
`As discussed above, we adopt Patent Owner’s proposed construction for the
`terms “storing”/“storage” to “require that the stored material possesses
`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.” Supra at 8. Petitioner argues that Phares teaches Form B is stable
`at ambient temperature and therefore could be stored at ambient temperature.
`Pet. 44, 48. We are not persuaded by this argument.
`Phares teaches two crystalline forms of treprostinil diethanolamine
`salt, Form A and Form B. Ex. 1008, 85. Phares states that Form B appears to
`be “thermodynamically more stable” than the “metastable” Form A. Id. at
`85, 89. Phares reaches this conclusion after performing inter-conversion
`experiments in two different solvents, using Forms A and B material. Id. at
`89. In isopropanol, Phares reports full conversion from Form A to Form B at
`ambient temperature after 7 days. Id. Dr. Winkler, Petitioner’s expert,
`testifies that this “inherently teaches that Form B is stable at ambient
`temperature and therefore could be stored at ambient temperature.” Ex. 1002
`
`14
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`IPR2020-00769
`Patent 9,593,066 B2
`
`¶ 109. Dr. Winkler, however, does not provide a sufficient explanation or
`cite any support for this conclusory statement.
`On the other hand, Dr. Pinal, Patent Owner’s expert, testifies that
`Form B being more stable than Form A does not imply Form B is, itself,
`stable. Ex. 2002 ¶ 225. Patent Owner contends that “Phares discusses the
`relative thermodynamic stability of Form A and Form B, but does not
`discuss what happens to Form B after storage.” Prelim. Resp. 53 (arguing
`that Form A converting to Form B “says nothing about how long [Form B]
`can be stored and maintain purity”). Based on the current record, we find
`Patent Owner’s argument more persuasive. Petitioner and Dr. Winkler have
`not shown that Phares describes or suggests Form B as reaching a stability
`sufficient for storage, as construed in this proceeding.
`As a result, Petitioner has not sufficiently demonstrated that Phares
`anticipates claims 8–10.
`Obviousness over Moriarty and Phares
`Petitioner argues that claims 1–10 of the ’066 patent would have been
`obvious over Moriarty and Phares. Pet. 54–71.
`For the whereby clause of claim 1, Petitioner relies on the same
`evidence and argument as presented in the obviousness ground over Phares
`alone. See Pet. 61. For the same reason explained above, we are not
`persuaded. See supra at 13.
`For claims 8–10, Petitioner relies on the same evidence and argument
`as presented in the anticipation ground. See Pet. 70. For the same reason
`explained above, we are not persuaded. See supra at 14–15.
`
`15
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`IPR2020-00769
`Patent 9,593,066 B2
`
`
`In sum, Petitioner has not sufficiently demonstrated the obviousness
`of claims 1–10 over Moriarty and Phares.
`CONCLUSION
`For the reasons explained above, we determine that Petitioner has not
`established a reasonable likelihood that it would prevail in showing that at
`least one of the challenged claims is unpatentable.
`ORDER
`In consideration of the foregoing, it is hereby:
`ORDERED that the Petition is denied, and we do not institute inter
`partes review of any claim of the ’066 patent based on the ground asserted
`in the Petition.
`
`
`
`
`
`
`16
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`IPR2020-00769
`Patent 9,593,066 B2
`
`FOR PETITIONER:
`
`Ivor Elrifi
`Erik Milch
`COOLEY LLP
`ielrifi@cooley.com
`emilch@cooley.com
`
`
`FOR PATENT OWNER:
`
`Stephen B. Maebius
`George Quillin
`Daniel R. Shelton
`Foley & Lardner LLP
`smaebius@foley.com
`gquillin@foley.com
`dshelton@foley.com
`
`Shaun R. Snader
`United Therapeutics Corp.
`ssnader@unither.com
`
`Douglas Carsten
`Richard Torczon
`Wilson, Sonsini, Goodrich & Rosati
`dcarsten@wsgr.com
`rtorczon@wsgr.com
`
`17
`
`
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