`571-272-7822
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` Paper 7
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`Date: October 13, 2020
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`____________
`
`IPR2020-00770
`Patent 9,604,901 B2
`____________
`
`
`
`Before ERICA A. FRANKLIN, ZHENYU YANG, and
`JOHN E. SCHNEIDER, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Granting Institution of Inter Partes Review
`35 U.S.C. § 314
`
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`INTRODUCTION
`Liquidia Technologies, Inc. (“Petitioner”) filed a Petition (Paper 1
`(“Pet.”)), seeking an inter partes review of claims 1–9 of U.S. Patent
`No. 9,604,901 B2 (Ex. 1001, “the ’901 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). On April 24, 2018,
`the Supreme Court held that a decision under § 314 may not institute review
`on fewer than all claims challenged in the petition. SAS Inst., Inc. v. Iancu,
`138 S. Ct. 1348, 1355–56 (2018). In addition, the Federal Circuit has
`interpreted the statute to require “a simple yes-or-no institution choice
`respecting a petition, embracing all challenges included in the petition.” PGS
`Geophysical AS v. Iancu, 891 F.3d 1354, 1360 (Fed. Cir. 2018).
`For the reasons provided below, we determine Petitioner has satisfied
`the threshold requirement set forth in 35 U.S.C. § 314(a). Thus, based on the
`information presented, we institute an inter partes review of claims 1–9 of
`the ’901 patent.
`
`Related Matters
`Patent Owner asserted the ’901 patent against Petitioner in United
`Therapeutics Corporation v. Liquidia Technologies, Inc., Case No. 1:20-cv-
`00755 (D. Del.). Paper 5, 1.
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`Petitioner filed IPR2020-00769, challenging the claims of U.S. Patent
`No. 9,593,066, a patent in the same family as the ’901 patent. Id. Together
`with this Decision, we concurrently issue a decision in that case, denying the
`Petition. IPR2020-00769, Paper 7.
`U.S. Patent No. 8,497,393 (Ex. 1004, “the ’393 patent”) is a parent of
`the ’901 patent. Ex. 1001, Code (63). The ’393 patent was the subject of
`SteadyMed Ltd. v. United Therapeutics Corp., IPR2016-00006 (“the ’393
`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 ’901 Patent
`The ’901 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.
`
`
`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.
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`According to the ’901 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 ’901 patent discloses “a process for the preparation of a
`compound having formula IV, or a hydrate, solvate, or pharmaceutically
`acceptable salt thereof.” Id. at 8:44–46. Petitioner represents that Formula IV
`is treprostinil. Pet. 11; Ex. 1002 ¶ 30. Formula IV has the following
`structure:
`
`
`The figure above shows the structure of Formula IV. Ex. 1001, 8:48–
`
`63.
`
`The process of the ’901 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 8:65–9:48. Structure V, formula VI, and the salt formed in step (c)
`have the following structures:
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`The figures above show the structures of structure V, formula VI, and
`the salt formed in step (c). Id. at 9:1–28, 9:33–45. The ’901 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 9:49–50.
`According to the ’901 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
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`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 16:66–17:12, see also id. at 6:4–18 (the same).
`Illustrative Claim
`Claim 1 is the only independent claim. With the Certificate of
`Correction incorporated, it is reproduced below:
`A pharmaceutical batch consisting of treprostinil or a salt
`1.
`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.
`Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability:
`Claims Challenged 35 U.S.C. §
`References
`1–9
`103
`Phares2
`1–9
`103
`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).
`
`
`2 PCT Application No. WO 2005/007081 A9, published Jan. 27, 2005
`(Ex. 1008).
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`ANALYSIS
`Discretionary Denial under 35 U.S.C. § 325(d)
`Patent Owner asks us to exercise our discretion and deny the
`Petitioner under § 325(d). Prelim. Resp. 12–29. Although it is undisputed
`that the Office considered both Phares and Moriarty during the prosecution
`of the ’901 patent, we find that the examiner erred in evaluating these
`references. Thus, we decline to deny the Petitioner under § 325(d).
`To better explain how we reach this conclusion, it is necessary to
`review the ’393 IPR and the prosecution history of the ’901 patent.
`The ’393 IPR
`The ’393 patent is a parent of the ’901 patent. Ex. 1001, Code (63).
`Claim 9 of the ’393 patent recites:
`9. A product comprising a compound of formula IV
`
`
`or a pharmaceutically acceptable salt thereof, wherein said
`product is prepared by a process comprising
`(a) alkylating a compound of structure V with an alkylating agent
`to produce a compound of formula VI,
`
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`(b) hydrolyzing the product of formula VI of step (a) with a base,
`(c) contacting the product of step [(b)] with a base B to form a
`salt of formula IVs, and
`
`
`(d) optionally reacting the salt formed in step (c) with an acid to
`form the compound of formula IV.
`Formula IV of the ’393 patent is the same as that of the ’901 patent,
`and shows the structure of treprostinil. See the ’393 Dec. 24 (“Claim 9 . . . is
`drawn to a product comprising the specific treprostinil compound.”).
`The petition for the ’393 IPR challenged claims 1–5, 7–9, 11–14, and
`16–20 of the ’393 patent as anticipated by Phares, and as obvious over
`Moriarty and Phares. Id. at 7. It also challenged claims 6, 10, 15, 21, and 22
`as obvious over Moriarty, Phares, and additional prior art. Id. On March 31,
`2017, the Board held that the petitioner prevailed in all asserted grounds, and
`that claims 1–22 of the ’393 patent are unpatentable. Id. at 44, 67, 84, 90.
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`The Prosecution of the ’901 Patent
`During the prosecution of the ’901 patent, the applicant submitted the
`petition for the ’393 IPR in an IDS. Ex. 1006, 127. Thereafter, the examiner
`issued an office action, rejecting then pending claims 1–3, 6, 8, and 9 as
`anticipated by Moriarty. Id. at 118. The examiner found that those claims are
`product-by-process claims and stated
`[E]ven though product-by-process claims are limited by and
`defined by the process, determination of patentability is based on
`the product itself. The patentability of a product does not depend
`on its method of production. If the product in the product-by-
`process claim is the same or obvious from the product of the prior
`art, the claim is unpatentable even though the prior art product
`was made by a different process.
` Id. at 119 (quoting In re Thorpe, 777 F.2d 695, 698 (Fed. Cir. 1985)).
`The examiner found that
`Moriarty et al disclose[s] a method for preparing treprostinil.
`Said method comprises the steps of: (a) alkylation of benzindene
`triol and (b) hydrolysis of the product of step (a) . . . . 441 g of
`treprostinil (a therapeutically effective amount) was prepared at
`99.7% purity. Moriarty also discloses removing impurities via
`extraction and further purification via crystallization. Although
`the method of Moriarty and the steps recited in the instant claims
`are not identical, the product obtained is the same.
`Id. at 118–19.
`The examiner also rejected then pending claims 10–12 as obvious
`over Moriarty and Phares. Id. at 120. The examiner acknowledged that
`Moriarty fails to teach the “preparation of a diethanolamine salt of
`treprostinil” and the “preparation of a pharmaceutical product comprising
`diethanolamine salt.” Id. The examiner, however, found “Phares et al
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`teach[es] preparation of treprostinil diethanolamine by dissolving treprostinil
`acid and treating it with diethanolamine.” Id. at 121.
`According to the examiner,
`One skilled in the art practicing the invention of Phares would
`have found it obvious to prepare a diethanolamine salt of
`treprostinil prepared by the method of Moriarty. Moriarty
`discloses a method for preparing a treprostinil acid which is a
`needed starting material for the process of Phares. The resulting
`salt would meet the limitations directed to pharmaceutical
`product because treprostinil diethanolamine is the sole claimed
`component of the claimed pharmaceutical product.
`One skilled in the art would have found it obvious to prepare a
`pharmaceutical product from the treprostinil diethanolamine salt
`of Phares prepared from the treprostinil free acid that has been
`obtained by the process of Moriarty.
`
`Id.
`
`In response to the rejections, the applicant cancelled then pending
`claims 2 and 3, and amended other claims. Id. at 96–97. Most significantly,
`the applicant amended claim 1 as follows:
` (Currently Amended) A pharmaceutical batch comprising
`1.
`consisting of treprostinil or a salt thereof and impurities resulting
`from prepared by (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.
`Id. at 96.
`The applicant also submitted “Patent Owner’s Response and expert
`declarations from Dr. Williams and [Dr.] Ruffolo” from the ’393 IPR. Id. at
`10
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`98. Relying on the expert declarations, the applicant argued that “a
`pharmaceutical batch produced according to steps (a)-(e) of claim l is
`different from the product produced by the process described in Moriarty
`2004” because “the processes result in products having different impurity
`profiles, and in fact, the pharmaceutical batch of claim 1 has higher average
`purity.” Id. at 99. The applicant highlighted that
`As noted in the Patent Owner’s [’393] IPR Response, the
`differences between claim 1’s pharmaceutical batch and a
`product produced according to the process of Moriarty were
`significant enough to result in FDA’s acceptance of a new purity
`specification for the commercial product, thus proving that the
`products are not the same in the eyes of the FDA.
`Id. As a result, the applicant requested that the examiner withdraw the
`anticipation rejection. Id.
`Regarding the obviousness rejection, the applicant contended that “the
`differences in the resulting products, as explained above, would not have
`been expected based on the prior art.” Id. According to the applicant, “it
`would not have been obvious to use the salt formation step of Phares to
`decrease amounts of stereoisomer impurities of treprostinil” and an
`ordinarily skilled artisan “would have had no reasonable expectation of
`success in removing any undesired treprostinil stereoisomer impurities by
`salt formation and subsequent regeneration of the free acid.” Id. at 99–100.
`The applicant again emphasized that “even small changes in impurity are
`important to FDA.” Id. at 100. Thus, according to the applicant, “FDA’s
`decision to adopt a new purity specification for the resulting product further
`establishes unobviousness of the presently claimed invention.” Id.
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`Thereafter, the examiner withdrew the anticipation and the
`obviousness rejections “in view of applicants’ arguments, amendments and
`the accompanying declarations.” Id. at 87. And after the applicant filed a
`terminal disclaimer to overcome a double-patenting rejection (id. at 73–75),
`the examiner allowed claims 1, 6, and 8–14 (id. at 62), and they issued as the
`challenged claims 1–9. The ’901 patent issued on March 28, 2017, three
`days before the Board issued the ’393 Decision.
`Section 325(d) Analysis
`
`Under § 325(d),
`In determining whether to institute or order a proceeding under
`. . . chapter 31, the Director may take into account whether, and
`reject the petition or request because, the same or substantially
`the same prior art or arguments previously were presented to the
`Office.
`In evaluating whether to exercise our discretion under § 325(d), we
`weigh the following non-exclusive factors (“BD factors”):
`(a) the similarities and material differences between the asserted
`art and the prior art involved during examination;
`(b) the cumulative nature of the asserted art and the prior art
`evaluated during examination;
`(c) the extent to which the asserted art was evaluated during
`examination, including whether the prior art was the basis for
`rejection;
`(d) the extent of the overlap between the arguments made during
`examination and the manner in which Petitioner relies on the
`prior art or Patent Owner distinguishes the prior art;
`(e) whether Petitioner has pointed out sufficiently how the
`Examiner erred in its evaluation of the asserted prior art; and
`(f) the extent to which additional evidence and facts presented in
`the Petition warrant reconsideration of prior art or arguments.
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`Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586,
`Paper 8 at 17–18 (PTAB Dec. 15, 2017) (precedential as to § III.C.5, first
`paragraph).
`Factors (a), (b), and (d) relate to whether the art and arguments
`presented in the petition are the same or substantially the same as those
`previously presented to the Office. Advanced Bionics, LLC v. Med-El
`Electromedizinishe Gerӓte GmbH, IPR2019-01469, Paper 6 at 10 (PTAB
`Feb. 13, 2020) (precedential). Factors (c), (e), and (f) “relate to whether the
`petitioner has demonstrated a material error by the Office” in its prior
`consideration of that art or arguments. Id.
`In this case, it is undisputed that the examiner considered both
`Moriarty and Phares during the prosecution of the ’901 patent. Pet. 4.
`Petitioner contends that “the Examiner relied upon statements from the
`Patent Owner supported by documents submitted during the ’393 IPR as
`grounds for allowance of the ’901 patent claims.” Id. at 5. According to
`Petitioner, the examiner “erred in discounting the arguments set forth by the
`petitioner and its expert in the ’393 IPR.” Id. Patent Owner contends that
`Petitioner “fails to identify any error the Office committed beyond merely
`disagreeing with the result.” Prelim. Resp. 12. We find Petitioner’s
`arguments more persuasive.
`As discussed above, during the prosecution of the ’901 patent, the
`examiner rejected the claims as anticipated by Phares, and obvious over
`Moriarty and Phares. Ex. 1006, 118–21. Relying on its expert testimony in
`the ’393 IPR, the applicant overcame those rejections by arguing that “the
`pharmaceutical batch of claim 1 has higher average purity” than the product
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`produced by the process described in Moriarty. Id. at 98–100. The applicant
`emphasized that “the products are not the same in the eyes of the FDA,”
`because “even small changes in impurity are important to FDA.” Id.
`A “higher average purity,” however, is not a claim limitation. This is
`true despite that the challenged claims recite a “pharmaceutical batch” or a
`“pharmaceutical product.” As the ’901 patent acknowledges, before its
`priority date, treprostinil had been prepared as described in Moriarty
`(Ex. 1001, 1:28–32), and used as the active ingredient in Remodulin (id. at
`1:27). In our view, to gain FDA approval, the product produced by the
`process of Moriarty must have met the requirement of a “pharmaceutical
`batch” or a “pharmaceutical product,” as defined by Patent Owner. Indeed,
`the Board previously found “batches of Moriarty treprostinil satisfy the 98%
`minimum purity requirement for treprostinil approved by the FDA . . . and
`could be sold to the public.” The ’393 Dec. 62.
`Moreover, Example 6 of the ’901 patent compares the processes for
`preparing treprostinil according to Moriarty and a working example of the
`process disclosed in the ’901 patent. Ex. 1001, 15:25–16:65; see also Prelim.
`Resp. 61 (“The ‘former process’ in example 6 of the ’901 patent is
`essentially the same as [Petitioner] Liquidia’s Moriarty reference.”).
`Example 6 reports a purity of ~99.0% for Moriarty treprostinil, and a purity
`of 99.9% for treprostinil prepared according to the claimed invention.
`Ex. 1001, 16:64; see also Ex. 1009, 13 (Moriarty reporting the purity of its
`product as 99.7%). The ’901 patent states that in one embodiment, the purity
`of treprostinil “is at least 90.0%, 95.0%, 99.0%, 99.5%.” Ex. 1001, 9:49–50.
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`Thus, treprostinil prepared according to Moriarty, whether it is ~99.0% or
`99.7%, meets the purity requirement specified in the ’901 patent.
`For these reasons, we agree with Petitioner that the examiner erred in
`relying on the applicant’s argument on the improved purity profile to allow
`the challenged claims. We, thus, decline to deny the Petition under § 325(d).
`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).
`Petitioner argues that no construction of claim terms is required and
`“[a]ll terms should be given their plain and ordinary meaning in the art” at
`the priority date of the ’901 patent. Pet. 18–19.
`Patent Owner proposes that we construe terms “pharmaceutical
`batch,” “pharmaceutical product,” and “a salt treprostinil.” Prelim. Resp. 8–
`11. Citing the FDA’s definition of “batch” (id. at 9 (citing 21 C.F.R. § 210.3
`(April 1, 2007 ed.))), Patent Owner argues that
`The POSA viewing the ’901 patent claims in light of the ’901
`patent specification would have understood claim 1’s
`‘pharmaceutical batch’ to be 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,
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`wherein the uniform character and quality is such that it still
`contains impurities resulting from the method by which it is
`produced.
`Id. at 9 (citing Ex. 2002 ¶ 121). Patent Owner asserts that a “pharmaceutical
`product” is “a chemical composition suitable for pharmaceutical use.” Id. at
`10 (citing Ex. 2002 ¶¶ 105–116). Patent Owner also contends that “‘a salt
`treprostinil’ is a printing error for ‘a salt of treprostinil.’” Id. at 11 (citing
`Ex. 2002 ¶ 128). Based on the current record, and for purposes of this
`Decision, we generally agree with Patent Owner’s proposed constructions of
`these terms because they are supported by relevant evidence. For precision,
`however, we construe the term “pharmaceutical product” to mean “a
`chemical composition manufactured for pharmaceutical use.”
`Patent Owner also proposes that we construe the terms
`“storing”/“storage.” Id. at 10–11. Claims 6 and 7 require “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.” Patent Owner contends that an
`ordinarily skilled artisan would have “understood these terms to require
`stability of the material being stored in a batch q[]u[a]ntity in the context of
`commercial pharmaceutical man[u]facturing.” Id. at 10 (citing Ex. 2002
`¶¶ 123–124).
`The ’901 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
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`for a sufficient period of time to be useful for the purposes
`detailed herein.
`Ex. 1001, 5:4–10.
`Thus, according to Patent Owner, we should construe 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.”
`Prelim. Resp. 11 (citing Ex. 2002 ¶ 127). Based on the current record, we
`find Patent Owner’s argument persuasive, and for purposes of this Decision,
`adopt its proposed construction of “storing”/“storage.”
`On this record and for purposes of this Decision, we see no need to
`construe any other term expressly. See Wellman, Inc. v. Eastman Chem. Co.,
`642 F.3d 1355, 1361 (Fed. Cir. 2011) (stating that claim terms need only be
`construed to the extent necessary to resolve the controversy).
`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:
`
`
`3 For Moriarty, the parties cite to the pagination added by Petitioner. For
`consistency, we do the same.
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`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)
`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
`
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`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.
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`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:
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`
`
`The figure above shows the structure of treprostinil. Id. at 8.
`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:
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`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:
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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.”).
`Level of Ordinary Skill
`In determining the skill level, we consider various factors including
`“type of problems encountered in the art; prior art solutions to those
`problems; rapidity with which innovations are made; sophistication of the
`technology; and educational level of active workers in the field.” Custom
`Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir.
`1986).
`Petitioner argues that an ordinarily skilled artisan “would hold a
`master’s degree or Ph.D. in medicinal or organic chemistry, or a closely
`related field,” or would have “a bachelor’s degree and at least five years of
`practical experience in medicinal or organic chemistry.” Pet. 25.
`Patent Owner disagrees. Prelim. Resp. 55–57. Patent Owner argues
`that “the claims contemplate batch-scale synthesis.” Id. at 55. According to
`Patent Owner, “scaling up is a separate and difficult process.” Id. at 56.
`Thus, Patent Owner concludes that an ordinarily skilled artisan “would have
`been an industrial chemist or chemical engineer with experience in
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`pharmaceutical production, familiar with controlling for polymorphs and
`realizing highly pure products at batch scales as the challenged claims
`require.” Id.
`At this stage, even if we assume Patent Owner is correct about the
`level of ordinary skill in the art, we find Petitioner’s evidence and arguments
`sufficient to demonstrate a reasonable likelihood of establishing
`unpatentability of the challenged claims. Accordingly, for purposes of this
`Decision, we need not resolve Patent Owner’s dispute regarding the level of
`ordinary skill in the art, which is an issue well-suited for resolution after
`development of a full record during trial.
`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.”).
`Obviousness over Phares and Moriarty
`Petitioner argues that claims 1–9 of the ’901 patent would have been
`obvious over Moriarty and Phares. Pet. 49–75. Based on this record, we
`determine Petitioner has established a reasonable likelihood that it would
`prevail in showing the obviousness of at least claims 1–5, 8, and 9.
`Claims 1–5, 8, and 9
`Regarding claim 1, Petitioner argues that 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
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`composition” (id. at 33). Petitioner nevertheless argues that the combination
`of Moriarty Phares teaches or suggests each limitation.5
`Petitioner points out that Moriarty describes synthesizing treprostinil
`via the stereoselective intramolecular Pauson-Khand cyclization, and Phares
`teaches forming treprostinil diethanolamine salt having the same structure as
`disclosed in the ’901 patent. Id. at 53–55. According to Petitioner, “[t]he
`combination of Moriarty and Phares discloses the same process steps and
`product of the ’901 patent and as such, the combination of these references
`would disclose a purity of at least equal purity to that claimed in the ’901
`patent.” Id. at 56. In addition, Phares teaches “the pharmaceutical
`acceptability.” Id. at 29 (citing Ex. 1008, 22). Thus, Petitioner concludes
`“Moriarty in combination with Phares disclose a pharmaceutical batch
`consisting of treprostinil or a salt thereof and impurities,” as recited in
`challenged claim 1. Id. at 56.
`Petitioner refers to Moriarty for teaching alkylating benzindene triol
`34 to yield nitrile 35, and hydrolyzing of nitrile 35 to yield treprostinil. Id. at
`57–59 (citing Ex. 1009, 6, 8, 13). Petitioner contends that Moriarty teaches
`steps (a) and (b) of challenged claim 1.
`Acknowledging that step (c), “the step of reacting treprostinil with a
`base to form a sal