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.
`____________
`
`IPR2020-00770
`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
`
`
`
`
`
`
`
`
`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.
`____________
`
`IPR2020-00770
`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
`
`
`
`
`
`
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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.
`
`2
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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.
`
`3
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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:
`
`4
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`
`
`
`
`
`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
`5
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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).
`
`6
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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,
`
`
`
`7
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`
`(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.
`
`8
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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
`
`9
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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.
`
`11
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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.
`12
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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
`
`13
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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.
`
`14
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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,
`15
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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
`
`16
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`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.
`
`17
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`
`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
`
`
`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.
`18
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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.
`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:
`
`19
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`
`
`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:
`
`
`
`20
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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
`
`21
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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
`
`22
`
`
`
`IPR2020-00770
`Patent 9,604,901 B2
`
`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
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
