Trials@uspto.gov
`Tel: 571-272-7822
`
`
`
`Paper 78
`Entered: July 19, 2022
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`LIQUIDIA TECHNOLOGIES, INC.,
`Petitioner,
`
`v.
`
`UNITED THERAPEUTICS CORPORATION,
`Patent Owner.
`
`
`IPR2021-00406
`Patent 10,716,793 B2
`
`
`
`
`
`
`
`
`
`
`
`
`Before ERICA A. FRANKLIN, CHRISTOPHER M. KAISER,
`and DAVID COTTA, Administrative Patent Judges.
`
`KAISER, Administrative Patent Judge.
`
`
`
`
`JUDGMENT
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`35 U.S.C. § 318(a)
`
`
`
`
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`

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`IPR2021-00406
`Patent 10,716,793 B2
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`
`INTRODUCTION
`
`A. Background
`Liquidia Technologies, Inc. (“Petitioner”) filed a Petition (Paper 2,
`“Pet.”) requesting an inter partes review of claims 1–8 of U.S. Patent
`No. 10,716,793 B2 (Ex. 1001, “the ’793 patent”). United Therapeutics
`Corporation (“Patent Owner”) filed a Preliminary Response. Paper 13
`(“Prelim. Resp.”).
`On August 11, 2021, we instituted inter partes review of claims 1–8
`of the ’793 patent on all grounds set forth in the Petition. Paper 18 (“Inst.
`Dec.”). After institution of trial, Patent Owner filed a Response (Paper 29,
`“PO Resp.”), Petitioner filed a Reply (Paper 44), and Patent Owner filed a
`Sur-Reply (Paper 55). In addition, both parties filed Motions to Exclude
`Evidence (Papers 65 and 66), Oppositions to their respective opponents’
`Motions to Exclude (Papers 68 and 69), and Replies in support of their own
`Motions to Exclude (Papers 71 and 72). At the request of both parties, we
`held an oral hearing, the transcript of which has been entered into the record.
`Paper 77 (“Tr.”).
`We have jurisdiction under 35 U.S.C. § 6. This is a Final Written
`Decision under 35 U.S.C. § 318(a) as to the patentability of the challenged
`claims of the ’793 patent. For the reasons discussed below, we determine
`Petitioner has established by a preponderance of the evidence that each of
`claims 1–8 of the ’793 patent is unpatentable.
`
`B. Related Matters
`The parties identify United Therapeutics Corporation v. Liquidia
`Technologies, Inc., 1:20-cv-00755-RGA (D. Del.) (“the District Court
`proceeding”), as a related matter. Pet. 1; Paper 3, 1.
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`C. The Asserted Grounds of Unpatentability
`Petitioner contends that claims 1–8 of the ’793 patent are unpatentable
`based on the following grounds (Pet. 30–68):1
`Claim(s) Challenged 35 U.S.C. §2
`1–8
`103(a)
`1–8
`103(a)
`1
`102(a)
`1, 3, 8
`103(a)
`1, 3
`102(a)
`
`Reference(s)/Basis
`’212 patent,3 Voswinckel JESC,4
`Voswinckel JAHA5
`’212 patent, Voswinckel JESC
`Ghofrani6
`Voswinckel JAHA, Ghofrani
`Voswinckel 20067
`
`
`1 Petitioner also relies on declarations from Nicholas Hill, M.D., and Igor
`Gonda, Ph.D. Exs. 1002, 1004, 1106, 1107.
`2 The ’793 patent claims a priority date of May 15, 2006, and Petitioner
`“assumes the relevant priority date . . . is May 15, 2006.” Pet. 12; Ex. 1001,
`code (60). Accordingly, patentability is governed by the versions of
`35 U.S.C. §§ 102 and 103 preceding the amendments in the Leahy-Smith
`America Invents Act (“AIA”), Pub. L. No. 112–29, 125 Stat. 284 (2011).
`3 US 6,521,212 B1, issued Feb. 18, 2003 (Ex. 1006) (alleged to be prior art
`under 35 U.S.C. §§ 102(a), (b), (e)).
`4 Voswinckel, R., et al., Inhaled treprostinil is a potent pulmonary
`vasodilator in severe pulmonary hypertension, 25 EUROPEAN HEART J. 22
`(2004) (Ex. 1007) (alleged to be prior art under 35 U.S.C. § 102(b)).
`5 Robert Voswinckel, et al., Inhaled Treprostinil Sodium (TRE) For the
`Treatment of Pulmonary Hypertension, in Abstracts from the 2004 Scientific
`Sessions of the American Heart Association, 110 CIRCULATION III-295 (Oct.
`26, 2004) (Ex. 1008) (alleged to be prior art under 35 U.S.C. § 102(b)).
`6 Hossein Ardeschir Ghofrani, et al., Neue Therapieoptionen in der
`Behandlung der pulmonalarteriellen Hypertonie, 30 HERZ 296–302 (June
`2005) (Ex. 1010) (alleged to be prior art under 35 U.S.C. § 102(a)). We rely
`on the English translation that follows the German original article as part of
`Ex. 1010.
`7 Robert Voswinckel, et al., Inhaled Treprostinil for Treatment of Chronic
`Pulmonary Arterial Hypertension, 144 ANNALS OF INTERNAL MEDICINE
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`IPR2021-00406
`Patent 10,716,793 B2
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`
`Claim(s) Challenged 35 U.S.C. §2
`2, 4–8
`103(a)
`
`Reference(s)/Basis
`Voswinckel 2006, ’212 patent
`
`D. The ’793 Patent
`The ’793 patent, titled “Treprostinil Administration by Inhalation,”
`issued on July 21, 2020. Ex. 1001, codes (45), (54). The patent “relates to
`methods and kits for therapeutic treatment and, more particularly, to
`therapeutic methods involving administering treprostinil using a metered
`dose inhaler and related kits.” Id. at 1:20–23.
`Treprostinil “is a prostacyclin analogue” that may be used to treat
`pulmonary hypertension. Id. at 5:37–41. According to the ’793 patent, it
`was previously known to administer treprostinil by intravenous,
`subcutaneous, or inhalation routes to treat any of several conditions,
`including pulmonary hypertension. Id. at 5:42–58.
`The ’793 patent relates to the administration of treprostinil in high
`concentrations over a short inhalation time. Id. at 16:61–63, 17:44–46. This
`method of administration is described as reducing pulmonary vascular
`resistance and pulmonary artery pressure, as well as increasing cardiac
`output. Id. at 16:32–42, Fig. 10.
`
`E. Illustrative Claim
`Claims 1–8 of the ’793 patent are challenged. Claim 1 is independent
`and illustrative; it recites:
`1. A method of treating pulmonary hypertension
`comprising administering by inhalation to a human
`suffering from pulmonary hypertension a
`therapeutically effective single event dose of a
`
`149–50 (January 2006) (Ex. 1009) (alleged to be prior art under 35 U.S.C.
`§ 102(a)).
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`formulation comprising treprostinil or a
`pharmaceutically acceptable salt thereof with an
`inhalation device, wherein the therapeutically
`effective single event dose comprises from 15
`micrograms to 90 micrograms of treprostinil or a
`pharmaceutically acceptable salt thereof delivered
`in 1 to 3 breaths.
`Ex. 1001, 18:23–31.
`
`ANALYSIS
`
`A. Claim Construction
`In an inter partes review, we construe a claim in an unexpired patent
`“in accordance with the ordinary and customary meaning of such claim as
`understood by one of ordinary skill in the art and the prosecution history
`pertaining to the patent.” 37 C.F.R. § 42.100(b) (2020). “[T]he ordinary
`and customary meaning of a claim term 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.” Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed. Cir. 2005)
`(en banc). “Importantly, the person of ordinary skill in the art is deemed to
`read the claim term not only in the context of the particular claim in which
`the disputed term appears, but in the context of the entire patent, including
`the specification.” Id.
`Neither party presents any terms for construction. Pet. 12–13
`(“Petitioner does not believe construction of any claim term is required”);
`PO Resp. 7 (not proposing construction of any terms). Accordingly, we
`determine that no express construction of any claim term is necessary in
`order to decide whether to institute trial. Nidec Motor Corp. v. Zhongshan
`Broad Ocean Motor Co., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (citing Vivid
`Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)
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`(“[O]nly those terms need be construed that are in controversy, and only to
`the extent necessary to resolve the controversy.”)).
`
`B. Asserted Obviousness over ’212 Patent, Voswinckel JESC, and
`Voswinckel JAHA
`Petitioner argues that claims 1–8 would have been obvious over the
`combination of the ’212 patent, Voswinckel JESC, and Voswinckel JAHA.
`Pet. 30–46. Patent Owner argues that Petitioner fails to show that
`Voswinckel JESC and Voswinckel JAHA are prior art to the ’793 patent.
`PO Resp. 11–18. Patent Owner also argues that Petitioner fails to show that
`this combination of references teaches or suggest all the limitations of any of
`the challenged claims. PO Resp. 18–22, 38–40. In addition, Patent Owner
`also argues that Petitioner fails to show that a person of ordinary skill in the
`art would have had a reason to combine the teachings of these references.
`Id. at 23–38.
`
`’212 Patent
`1.
`The ’212 patent teaches “[a] method of delivering benzindene
`prostaglandins to a patient by inhalation.” Ex. 1006, code (57). In
`particular, the ’212 patent teaches the use of “[a] benzindene prostaglandin
`known as UT-15,” which “has unexpectedly superior results when
`administered by inhalation compared to parenterally administered UT-15 in
`sheep with induced pulmonary hypertension.” Id. There is evidence in the
`present record that “UT-15” was also known as “Remodulin” or “treprostinil
`sodium.” Ex. 1035, 582. According to the ’212 patent, the UT-15 may be
`delivered either as droplets formed “from a solution or liquid containing the
`active ingredient(s)” via a nebulizer, or as a solid-phase powder via an
`inhaler. Ex. 1006, 5:30–41.
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`According to the ’212 patent, this method may be used to “treat[]
`pulmonary hypertension in a mammal.” Id. at 14:9–12. Moreover, the ’212
`patent teaches “medical use” of its method in a “human.” Id. at 7:4–5. The
`necessary dose to achieve “a particular therapeutic purpose will, of course,
`depend upon the specific circumstances of the patient being treated and the
`magnitude of the effect desired by the patient’s doctor. Titration to effect
`may be used to determine proper dosage.” Id. at 6:66–7:3. “[A]erosolized
`UT-15 has a greater potency as compared to intravascularly administered
`UT-15,” so the ’212 patent teaches delivering “only a fraction (10–50%) of
`the dosage delivered intravascularly” when using its inhalation delivery
`method. Id. at 8:8–12. Even at “high doses,” however, the ’212 patent
`teaches a lack of “significant non-lung effects, i.e., heart rate, cardiac
`output.” Id. at 10:51–54.
`
`2. Voswinckel JESC
`Voswinckel JESC discusses a study to investigate “the acute
`hemodynamic response to inhaled treprostinil.” Ex. 1007, 7. Of the 29
`patients in the study, eight were administered a placebo, groups of six
`patients each were administered 16, 32, and 48 μg/mL solutions of
`treprostinil, and three patients were administered a solution containing 64
`μg/mL of treprostinil. Id. Each administration used an “OptiNeb ultrasound
`nebulizer, [made by] Nebu-Tec, Germany” for six minutes. Id. For each
`patient, various measurements were taken before administration of the
`treprostinil and at 0, 15, 30, 60, 90, 120, 150, and 180 minutes after
`administration. Id. According to Voswinckel JESC, “[t]reprostinil
`inhalation results in a significant long-lasting pulmonary vasodilatation,”
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`and, “at a concentration of 16 μg/mL, near maximal pulmonary
`vasodilatation is achieved without adverse effects.” Id.
`
`3. Voswinckel JAHA
`Voswinckel JAHA discusses a study of 17 patients with “severe
`pulmonary hypertension” who received treprostinil inhalations. Ex. 1008, 3.
`These inhalations each involved “3 single breaths” using a “pulsed
`OptiNeb® ultrasound nebulizer” and a “600 μg/mL” treprostinil solution.
`Id. In addition, “[t]wo patients with idiopathic PAH received compassionate
`treatment with 4 inhalations of TRE per day after the acute test” and were
`“treated for more than 3 months.” Id. According to Voswinckel JAHA,
`“inhalation resulted in a sustained, highly pulmonary selective vasodilatation
`over 120 minutes,” showing “strong pulmonary selective vasodilatory
`efficacy with a long duration of effect following single acute dosing,” and
`“[t]olerability is excellent even at high drug concentrations and short
`inhalation times (3 breaths).” Id.
`
`4. Prior-Art Status of Voswinckel JESC and Voswinckel JAHA
`In arguing that claims 1–8 would have been obvious, Petitioner relies
`on Voswinckel JESC and Voswinckel JAHA, but Patent Owner argues that
`Petitioner fails to show sufficiently that either of these references qualifies as
`a “printed publication.” PO Resp. 11–18.
`Only “prior art consisting of patents or printed publications” may
`form “the basis of” an inter partes review. 35 U.S.C. § 311(b). Neither
`Voswinckel JESC nor Voswinckel JAHA is a patent, so Petitioner may not
`rely on these references unless they are “printed publications.” Id. Public
`accessibility is the “touchstone in determining whether a reference
`constitutes a printed publication,” and a reference is considered publicly
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`accessible only if it was “disseminated or otherwise made available to the
`extent that persons interested and ordinarily skilled in the subject matter or
`art exercising reasonable diligence, can locate it.” Kyocera Wireless Corp.
`v. Int’l Trade Comm’n, 545 F.3d 1340, 1350 (Fed. Cir. 2008) (quoting SRI
`Int’l, Inc. v. Internet Sec. Sys. Inc., 511 F.3d 1186, 1194 (Fed. Cir. 2008); In
`re Hall, 781 F.2d 897, 898–99 (Fed. Cir. 1986)).
`Patent Owner argues that, because Petitioner relies on Voswinckel
`JESC and Voswinckel JAHA having been “stored in libraries, public
`accessibility requires that the reference be both available at the library and
`sufficiently indexed or catalogued by the priority date.” PO Resp. 12 (citing
`Blue Calypso, LLC v. Groupon, Inc., 815 F.3d 1331, 1348 (Fed. Cir. 2016);
`In re Klopfenstein, 380 F.3d 1345, 1349 (Fed. Cir. 2004)). According to
`Patent Owner, Petitioner fails to show sufficiently either of these
`requirements. Id. at 12–18.
`But Petitioner does not rely solely on availability in libraries to show
`the prior-art status of Voswinckel JESC and Voswinckel JAHA. Instead,
`Petitioner also argues that “Voswinckel JESC is an abstract presented at the
`European Society of Cardiology (JESC) Congress,” that Voswinckel JAHA
`“was publicly presented at the 2004 Scientific Sessions of the American
`Heart Association,” and that both references were cited in other documents
`dating from before the priority date of the ’793 patent whose public
`accessibility is not at issue. Pet. 22; Reply 3–4, 6–8.
`Patent Owner objects that Petitioner’s public-presentation and
`citation-in-other-references arguments are untimely because they should
`have been, but were not, presented in the Petition. Sur-Reply 2–3. We
`disagree. First, the argument that Voswinckel JESC was presented publicly
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`appears in the Petition. Pet. 22. Second, although other of Petitioner’s
`arguments appear for the first time in the Reply, they are not untimely.
`Reply 3–4, 6–8.
`Petitioner is permitted a “limited opportunit[y]” to present new
`evidence in or with its Reply, as long as that new evidence is “responsive to
`the prior briefing” and does not constitute “changing theories after filing
`[the] petition.” Hulu, LLC v. Sound View Innovations, LLC, IPR2018-
`01039, Paper 29, at 14–15 (PTAB Dec. 20, 2019) (precedential). Here, both
`of the arguments that Patent Owner alleges are new—the argument that
`Voswinckel JESC and Voswinckel JAHA were presented publicly and the
`argument that these references were cited in other publicly available
`references—respond to Patent Owner’s argument in the Patent Owner
`Response that Voswinckel JESC and Voswinckel JAHA were not publicly
`accessible. PO Resp. 11–18. The argument that Voswinckel JESC was
`publicly presented is not a change in theory from the Petition, because
`Petitioner presented this argument in the Petition. Pet. 22. As to both
`Voswinckel JESC and Voswinckel JAHA, Petitioner’s Reply evidence
`showing citation to the references in other publicly accessible documents is
`merely additional evidence supporting Petitioner’s original theory that a
`person of ordinary skill in the art could have located the references.
`Accordingly, we find that the following arguments made by Petitioner are
`not untimely: (1) that Voswinckel JESC was presented publicly, (2) that
`Voswinckel JESC was referenced in a publicly accessible document, and (3)
`that Voswinckel JAHA was referenced in a publicly accessible document.
`Given the evidence supporting Petitioner’s timely arguments, we are
`persuaded that Petitioner has shown by a preponderance of the evidence that
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`Voswinckel JESC and Voswinckel JAHA were publicly accessible. “[T]he
`presence of a ‘research aid’ can . . . establish public accessibility” of a
`reference if that research aid “provide[s] a skilled artisan with a sufficiently
`definite roadmap leading to” the reference by “provid[ing] enough details
`[to] determine that an interested party is reasonably certain to arrive at the
`destination: the potentially invalidating reference.” Blue Calypso, LLC v.
`Groupon, Inc., 815 F.3d 1331, 1350 (Fed. Cir. 2016).
`Here, Petitioner directs us to research aids for finding both
`Voswinckel JESC and Voswinckel JAHA: a “June 2005 Ghofrani article in
`the journal Herz” for the former, and “a March 2005 article authored by
`Roxana Sulica et al. in the Expert Review of Cardiovascular Therapy” for
`the latter. Reply 3, 7 (citing Ex. 1010, 298, 301; Ex. 1104, 359). The
`Ghofrani article cites Voswinckel JESC as providing a solution to patients
`experiencing “pain at the injection site” by replacing injected treprostinil for
`“pulmonary arterial hypertension” with “inhaled treprostinil.” Ex. 1010,
`298 (citing reference 6), 301 (defining reference 6 as Voswinckel JESC).
`The Ghofrani article also discusses the study reported in Voswinckel JESC,
`summarizing both the “major reduction in pulmonary selective pressure and
`resistance” and the lack of “adverse effects” described in Voswinckel JESC.
`Id. The Sulica article cites to Voswinckel JAHA, explaining that the
`reference reports that “inhaled treprostinil demonstrated substantial
`pulmonary vasodilatory efficacy in acute administration, as well as
`symptomatic and functional benefit in chronic use in a small number of PAH
`patients.” Ex. 1104, 351, 359. Thus, both the Ghofrani article and the
`Sulica article provide roadmaps directing a person of ordinary skill in the art
`looking for successful studies discussing the use of inhaled treprostinil in
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`pulmonary arterial hypertension straight to Voswinckel JESC or Voswinckel
`JAHA. Because these articles provide these roadmaps, they are “research
`aid[s]” that “establish [the] public accessibility” of Voswinckel JESC and
`Voswinckel JAHA. Blue Calypso, 815 F.3d at 1350.
`
`5. Analysis
`Petitioner argues that the combination of the ’212 patent, Voswinckel
`JESC, and Voswinckel JAHA teaches or suggests the subject matter of
`claims 1–8 and that a person of ordinary skill in the art would have had a
`reason to combine the teachings of these references with a reasonable
`expectation of success. Pet. 30–46. Patent Owner argues that this
`combination of references fails to teach or suggest delivering a dose of
`treprostinil within the dose range of the challenged claims in a single dosing
`event of one to three breaths. Prelim. Resp. 42–55.
`
`a. Claim 1
`(1) “A method of treating pulmonary hypertension
`comprising administering by inhalation to a
`human suffering from pulmonary hypertension
`a therapeutically effective single event dose of a
`formulation comprising treprostinil or a
`pharmaceutically acceptable salt thereof”
`Claim 1 recites “[a] method of treating pulmonary hypertension
`comprising administering by inhalation to a human suffering from
`pulmonary hypertension a therapeutically effective single event dose of a
`formulation comprising treprostinil or a pharmaceutically acceptable salt
`thereof.” Ex. 1001, 18:23–27. Petitioner argues that the ’212 patent,
`Voswinckel JESC, and Voswinckel JAHA each teach or suggest this
`limitation. Pet. 35–37. Patent Owner does not dispute this argument.
`PO Resp. 10–40.
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`The ’212 patent teaches treating pulmonary hypertension via
`inhalation of a benzindene prostaglandin called UT-15, which was also
`known as “treprostinil sodium.” Ex. 1006, code (57) (identifying
`“benzindene prostaglandin” as “UT-15”), 2:66–3:5 (“This invention relates
`to . . . a method of treating pulmonary hypertension by administering an
`effective amount of a benzindene prostaglandin to a mammal in need thereof
`by inhalation.”); Ex. 1035, 582 (“UT-15” also known as “treprostinil
`sodium”). Voswinckel JAHA teaches treating “patients with severe
`pulmonary hypertension” with “Inhaled Treprostinil Sodium (TRE)” with
`“3 single breaths” of “TRE solution 600 μg/ml,” resulting in “strong
`pulmonary selective vasodilatory efficacy with a long duration of effect
`following single acute dosing.” Ex. 1008, 3. Voswinckel JESC describes
`“the acute hemodynamic response to inhaled treprostinil” following the
`administration to patients of nebulized treprostinil solution in concentrations
`of 16, 32, 48, and 64 μg/ml for six minutes, resulting in “significant long-
`lasting pulmonary vasodilatation” without “adverse effects.” Ex. 1007, 7.
`Accordingly, Petitioner has shown by a preponderance of the evidence
`that the ’212 patent, Voswinckel JESC, and Voswinckel JAHA each teach or
`suggest this portion of claim 1.
`
`(2) “With an inhalation device”
`Next, claim 1 recites “with an inhalation device.” Ex. 1001,
`18:27–28. Petitioner argues that the ’212 patent, Voswinckel JESC, and
`Voswinckel JAHA each teach or suggest this limitation. Pet. 37. Patent
`Owner does not dispute this argument. PO Resp. 10–40. The ’212 patent
`teaches the use in its inhalation method of “a nebulizer, inhaler, atomizer or
`aerosolizer” to “form[] droplets from a solution or liquid containing the
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`active ingredient(s).” Ex. 1006, 5:30–32. Both Voswinckel JESC and
`Voswinckel JAHA teach the use of a “nebulizer” in their inhalation
`methods. Ex. 1007, 7 (“OptiNeb ultrasound nebulizer”); Ex. 1008, 3 (“the
`pulsed OptiNeb® ultrasound nebulizer”). Dr. Hill testifies that a person of
`ordinary skill in the art would have understood “that nebulizers and inhalers
`are inhalation devices.” Ex. 1002 ¶ 94. Accordingly, Petitioner has shown
`by a preponderance of the evidence that the ’212 patent, Voswinckel JESC,
`and Voswinckel JAHA each teach or suggest this limitation of claim 1.
`
`(3) “Wherein the therapeutically effective single
`event dose comprises from 15 micrograms to 90
`micrograms of treprostinil or a
`pharmaceutically acceptable salt thereof”
`Claim 1 recites “wherein the therapeutically effective single event
`dose comprises from 15 micrograms to 90 micrograms of treprostinil or a
`pharmaceutically acceptable salt thereof.” Ex. 1001, 18:28–30. Petitioner
`argues that the combination of the ’212 patent and Voswinckel JESC teaches
`or suggests this limitation. Pet. 37–40. Patent Owner disagrees. PO
`Resp. 18–38.
`Petitioner calculates the dose that the prior art teaches delivering by
`inhalation in three separate ways: (1) relying on Voswinckel JESC’s solution
`concentrations and solution volumes taught by Ex. 1037, (2) relying on
`Voswinckel JESC’s solution concentrations and solution volumes normally
`delivered according to the testimony of Petitioner’s declarants, and
`(3) relying on the ’212 patent’s conversion from an intravascular treprostinil
`dose to an equivalent inhaled dose. Pet. 22–24, 38–39. According to
`Petitioner, each of these three calculation methods results in a teaching of a
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`therapeutically effective single event dose comprising from 15 micrograms
`to 90 micrograms of treprostinil. Id.
`We agree with Patent Owner that Petitioner’s first and third
`calculation methods do not demonstrate that the prior art taught or suggested
`a therapeutically effective single event dose comprising from 15 micrograms
`to 90 micrograms of treprostinil, and we do not discuss these calculations
`any further. The preponderance of the evidence, however, supports
`Petitioner’s argument that its second calculation demonstrates that the prior
`art taught or suggested a therapeutically effective single event dose
`comprising from 15 micrograms to 90 micrograms of treprostinil.
`Voswinckel JESC teaches that “patients inhaled solvent solution
`(placebo) (n=8) or treprostinil for 6 min (OptiNeb ultrasound nebulizer,
`Nebu-tec, Germany) in concentrations of 16, 32, 48, and 64 μg/ml (n=6, 6,
`6, and 3 patients).” Ex. 1007, 7. Although this teaching shows
`administration to patients of inhaled solutions with particular concentrations
`of treprostinil, it does not disclose the amount of solution administered,
`which is necessary in order to calculate the amount of treprostinil
`administered. Id. Petitioner directs us to the testimony of its declarants,
`Dr. Nicholas Hill and Dr. Igor Gonda, to understand how a person of
`ordinary skill in the art would have interpreted Voswinckel JESC’s
`disclosure. Pet. 23 (citing Ex. 1002 ¶ 65; Ex. 1004 ¶ 56). Dr. Gonda
`testifies that “in May 2006 . . . nebulizers conventionally deliver[ed]
`between 1 and 5 mL” of solution. Ex. 1004 ¶ 56. Relying on Dr. Gonda’s
`testimony as well as his own experience, Dr. Hill testifies that a person of
`ordinary skill in the art in 2006 would have understood that “nebulizers . . .
`nebulize (i.e. aerosolize liquid) at least” 1 mL of solution. Ex. 1002 ¶ 65.
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`Multiplying Voswinckel JESC’s 16, 32, 48, or 64 micrograms of treprostinil
`per milliliter of solution by the 1 to 5 milliliters of solution in the testimony
`of Drs. Hill and Gonda, a person of ordinary skill in the art would have
`interpreted Voswinckel JESC as teaching the delivery of 16–80, 32–160,
`48–240, or 64–320 micrograms of treprostinil. Each of those four dose
`ranges has at least one endpoint that falls within the 15–90 microgram
`claimed range.
`Patent Owner argues that this evidence is insufficient to show that the
`combination of the ’212 patent, Voswinckel JESC, and Voswinckel JAHA
`teaches or suggests a therapeutically effective single event dose comprising
`from 15 micrograms to 90 micrograms of treprostinil. Specifically, Patent
`Owner argues that the volume of solution that Drs. Hill and Gonda testify
`was typically used in nebulizers is “the fill volume,” or the amount of
`solution loaded into a nebulizer to be nebulized, which cannot be used with
`the concentrations in Voswinckel JESC to arrive at the amount of treprostinil
`actually delivered to a patient. PO Resp. 30–31. This is because “there is no
`guarantee that the entire fill volume would be completely nebulized in” the
`time period over which Voswinckel JESC teaches delivering its dose of
`treprostinil. Id. at 30. In addition, Patent Owner argues that there were
`other factors that might have caused less than all the solution nebulized by a
`nebulizer to be actually delivered to the patient, none of which Petitioner
`accounts for. Id. at 31–32.
`Petitioner “presented evidence that nebulizers at the time typically
`involved fill volumes of 1-5mL.” Reply 10–11. To the extent that
`something less than the entire fill volume was delivered to the patient, either
`because it was not nebulized or because other factors resulted in the
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`nebulized solution not reaching the mouthpiece, the preponderance of the
`evidence still supports the actual delivered solution volume being at least
`one milliliter. Dr. Hill testifies that the “at least 1 mL” of solution he
`discusses is the volume that “nebulizers at the time were known to
`nebulize,” not the amount of liquid loaded into the nebulizer. Ex. 1002 ¶ 65.
`Patent Owner’s declarant, Dr. Aaron Waxman, testifies that standard
`nebulizers had fill volumes of “3 to 5 [milliliters]” and that he had never
`administered a dose as low as one milliliter to a patient. Ex. 1108,
`153:1–22; 156:12–16.
`Thus, Voswinckel JESC teaches delivering solution with a treprostinil
`concentration of 16, 32, 48, or 64 micrograms per milliliter, and the
`preponderance of the evidence supports a finding that a person of ordinary
`skill in the art would have understood the volume of solution delivered in
`Voswinckel JESC to be at least one milliliter. Accordingly, Petitioner has
`shown by a preponderance of the evidence that Voswinckel JESC teaches or
`suggests a therapeutically effective single event dose comprising from 15
`micrograms to 90 micrograms of treprostinil.
`
`(4) “Delivered in 1 to 3 breaths”
`Claim 1 recites “delivered in 1 to 3 breaths.” Ex. 1001, 18:31.
`Petitioner argues that Voswinckel JAHA teaches or suggests this limitation.
`Pet. 40–41. Patent Owner does not dispute this teaching of Voswinckel
`JAHA. PO Resp. 10–40.
`Voswinckel JAHA teaches delivering to patients “a TRE inhalation by
`use of the pulsed OptiNeb® ultrasound nebulizer (3 single breaths, TRE
`solution 600 μg/ml).” Ex. 1008, 3. It also reports that “[t]olerability is
`excellent even at high drug concentrations and short inhalation times (3
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`breaths).” Id. Accordingly, Petitioner has shown by a preponderance of the
`evidence that Voswinckel JAHA teaches or suggests this limitation of
`claim 1.
`
`b. Reason to Combine with a Reasonable Expectation
`of Success
`As discussed above, Petitioner has shown sufficiently on the present
`record that the combination of the ’212 patent, Voswinckel JESC, and
`Voswinckel JAHA teaches or suggests every limitation of claim 1. This
`alone is not sufficient to show that the challenged claims would have been
`obvious; Petitioner also must show that a person of ordinary skill would
`have had a reason to combine the teachings of the references and would have
`had a reasonable expectation of success in doing so.
`Petitioner argues that a person of ordinary skill in the art would have
`had a reason to combine the teachings of the ’212 patent, Voswinckel JESC,
`and Voswinckel JAHA. Pet. 30–34. Patent Owner argues that a person of
`ordinary skill in the art would have had “serious concerns about side effects”
`that would have persuaded them not to combine the teachings of the ’212
`patent, Voswinckel JESC, and Voswinckel JAHA. PO Resp. 37–38.
`The ’212 patent teaches the use of inhaled treprostinil sodium for the
`treatment of pulmonary hypertension at doses between 10 and 50 percent of
`the doses needed for intravascular delivery. Ex. 1006, code (57), 6:1–2,
`8:8–12. According to the ’212 patent, the inhaled treprostinil sodium is used
`in sheep, which are a model for pulmonary hypertension in humans. Id.
`at 9:14–27. Dr. Hill testifies that, based on these teachings, a person of
`ordinary skill in the art would have looked for further information regarding
`“experimentation [with] inhaled treprostinil in humans.” Ex. 1002 ¶ 78. On
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`the present record, such information can be found in Voswinckel JESC,
`which reports on a study in which humans with pulmonary hypertension
`inhaled treprostinil and experienced “significant long-lasting pulmonary
`vasodilatation . . . without adverse effects.” Ex. 1007, 7.
`Dr. Hill testifies that, based on the teachings of these references a
`person of ordinary skill would reasonably have expected that treprostinil
`could safely and effectively treat pulmonary hypertension in humans.
`Ex. 1002 ¶ 79. Dr. Hill also testifies that a person of ordinary skill in the art
`“would have been motivated to further decrease the 6 minute administration
`time in Voswinckel JESC.” Ex. 1002 ¶ 80. Specifically, Dr. Hill testifies
`that patients often did not adhere to “inhalation therapy for respiratory
`diseases,” that “[p]oor adherence to medication was known to correlate with
`worse outcomes,” and that “reducing administration time or the number of
`breaths required for therapy [was known to] improve adherence rates.” Id.
`(citing Ex. 1002 ¶¶ 36–37; Ex. 1030, 63; Ex. 1032, 179–80; Ex. 1077, 4).
`Voswinckel JAHA teaches administering treprostinil in three breaths using a
`high concentrat