I 1111111111111111 1111111111 1111111111 111111111111111 IIIII IIIIII IIII IIII IIII
`US010716793B2
`
`c12) United States Patent
`Olschewski et al.
`
`US 10,716,793 B2
`(IO) Patent No.:
`(45) Date of Patent:
`*Jul. 21, 2020
`
`(54) TREPROSTINIL ADMINISTRATION BY
`INHALATION
`
`(71) Applicant: United Therapeutics Corporation,
`Silver Spring, MD (US)
`
`(72)
`
`Inventors: Horst Olschewski, Graz (AT); Robert
`Roscigno, Chapel Hill, NC (US); Lewis
`J. Rubin, LaJolla, CA (US); Thomas
`Schmehl, Giessen (DE); Werner
`Seeger, Giessen (DE); Carl Sterritt,
`Weybridge (GB); Robert Voswinckel,
`Giessen (DE)
`
`(73) Assignee: United Therapeutics Corporation,
`Silver Spring, MD (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 16/778,662
`
`(22) Filed:
`
`Jan. 31, 2020
`
`(65)
`
`Prior Publication Data
`
`US 2020/0171044 Al
`
`Jun. 4, 2020
`
`(60)
`
`Related U.S. Application Data
`
`Continuation of application No. 16/536,954, filed on
`Aug. 9, 2019, which is a continuation of application
`No. 15/011,999, filed on Feb. 1, 2016, now Pat. No.
`10,376,525, which is a division of application No.
`13/469,854, filed on May 11, 2012, now Pat. No.
`9,339,507, which is a division of application No.
`12/591,200, filed on Nov. 12, 2009, now Pat. No.
`9,358,240, which is a continuation of application No.
`11/748,205, filed on May 14, 2007, now abandoned.
`
`(60)
`
`Provisional application No. 60/800,016, filed on May
`15, 2006.
`
`(51)
`
`(52)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`A61K 311557
`A61K 9/00
`A61K 31/192
`U.S. Cl.
`CPC ............ A61K 311557 (2013.01); A61K 9/008
`(2013.01); A61K 9/0078 (2013.01); A61K
`31/192 (2013.01)
`
`( 58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
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`
`Primary Examiner -
`Jeffrey S Lundgren
`Assistant Examiner - Michael J Schmitt
`(74) Attorney, Agent, or Firm - Foley & Lardner LLP
`
`(57)
`
`ABSTRACT
`
`Treprostinil can be administered using a metered dose
`inhaler. Such administration provides a greater degree of
`autonomy to patients. Also disclosed are kits that include a
`metered dose inhaler containing a pharmaceutical formula(cid:173)
`tion containing treprostinil.
`
`8 Claims, 12 Drawing Sheets
`
`Liquidia's Exhibit 1001
`Page 1
`
`

`

`US 10,716,793 B2
`Page 2
`
`(56)
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`Liquidia's Exhibit 1001
`Page 2
`
`

`

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`Liquidia's Exhibit 1001
`Page 3
`
`

`

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`
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`
`* cited by examiner
`
`Liquidia's Exhibit 1001
`Page 4
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 1 of 12
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`US 10,716,793 B2
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`Page 5
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`Liquidia's Exhibit 1001
`Page 6
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 3 of 12
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`US 10,716,793 B2
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`Liquidia's Exhibit 1001
`Page 7
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 4 of 12
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`US 10,716,793 B2
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`Liquidia's Exhibit 1001
`Page 8
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 5 of 12
`
`US 10,716,793 B2
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`Liquidia's Exhibit 1001
`Page 9
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 6 of 12
`
`US 10,716,793 B2
`
`FIGURE 6
`
`a
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`Liquidia's Exhibit 1001
`Page 10
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 7 of 12
`
`US 10,716,793 B2
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`Liquidia's Exhibit 1001
`Page 11
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 8 of 12
`
`US 10,716,793 B2
`
`FIGURE 8
`
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`Liquidia's Exhibit 1001
`Page 12
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 9 of 12
`
`US 10,716,793 B2
`
`FIGURE 9
`
`PVR
`
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`Liquidia's Exhibit 1001
`Page 13
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 10 of 12
`
`US 10,716,793 B2
`
`FIGURE 10
`
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`Liquidia's Exhibit 1001
`Page 14
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 11 of 12
`
`US 10,716,793 B2
`
`....
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`Liquidia's Exhibit 1001
`Page 15
`
`

`

`U.S. Patent
`
`Jul. 21, 2020
`
`Sheet 12 of 12
`
`US 10,716,793 B2
`
`---
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`Liquidia's Exhibit 1001
`Page 16
`
`

`

`US 10,716,793 B2
`
`1
`TREPROSTINIL ADMINISTRATION BY
`INHALATION
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`2
`pulmonary arterial hypertension tend to comprise a recog(cid:173)
`nizable entity of about 40% of patients cared for in large
`specialized pulmonary hypertension centers. Approximately
`65% of the most commonly afflicted are female and young
`5 adults, though it has occurred in children and patients over
`50. Life expectancy from the time of diagnosis is short
`without specific treatment, about 3 to 5 years, though
`occasional reports of spontaneous remission and longer
`survival are to be expected given the nature of the diagnostic
`10 process. Generally, however, disease progress is inexorable
`via syncope and right heart failure and death is quite often
`sudden.
`Pulmonary hypertension refers to a condition associated
`with an elevation of pulmonary arterial pressure (PAP) over
`normal levels. In humans, a typical mean PAP is approxi(cid:173)
`mately 12-15 mm Hg. Pulmonary hypertension, on the other
`hand, can be defined as mean PAP above 25 mmHg, assessed
`by right heart catheter measurement. Pulmonary arterial
`pressure may reach systemic pressure levels or even exceed
`20 these in severe forms of pulmonary hypertension. When the
`PAP markedly increases due to pulmonary venous conges(cid:173)
`tion, i.e. in left heart failure or valve dysfunction, plasma can
`escape from the capillaries into the lung interstitium and
`alveoli. Fluid buildup in the lung (pulmonary edema) can
`25 result, with an associated decrease in lung function that can
`in some cases be fatal. Pulmonary edema, however, is not a
`feature of even severe pulmonary hypertension due to pul(cid:173)
`monary vascular changes in all other entities of this disease.
`Pulmonary hypertension may either be acute or chronic.
`30 Acute pulmonary hypertension is often a potentially revers(cid:173)
`ible phenomenon generally attributable to constriction of the
`smooth muscle of the pulmonary blood vessels, which may
`be triggered by such conditions as hypoxia (as in high(cid:173)
`altitude sickness), acidosis, inflammation, or pulmonary
`35 embolism. Chronic pulmonary hypertension is characterized
`by major structural changes in the pulmonary vasculature,
`which result in a decreased cross-sectional area of the
`pulmonary blood vessels. This may be caused by, for
`example, chronic hypoxia, thromboembolism, collagen vas-
`40 cular diseases, pulmonary hypercirculation due to left-to(cid:173)
`right shunt, HIV infection, portal hypertension or a combi(cid:173)
`nation of genetic mutation and unknown causes as in
`idiopathic pulmonary arterial hypertension.
`Pulmonary hypertension has been implicated in several
`45 life-threatening clinical conditions, such as adult respiratory
`distress syndrome ("ARDS") and persistent pulmonary
`hypertension of the newborn ("PPHN"). Zapol et al., Acute
`Respiratory Failure, p. 241-273, Marcel Dekker, New York
`(1985); Peckham, J. Ped. 93:1005 (1978). PPHN, a disorder
`50 that primarily affects full-term infants, is characterized by
`elevated pulmonary vascular resistance, pulmonary arterial
`hypertension, and right-to-left shunting of blood through the
`patent ductus arteriosus and foramen ovale of the newbom's
`heart. Mortality rates range from 12-50%. Fox, Pediatrics
`55 59:205 (1977); Dworetz, Pediatri