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`Patent 8,497,393
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`Patent Owner Preliminary Response
`
`this salt should then be converted back to the free acid (6g, there is no suggestion
`
`of using the salt formation as a purification method).
`
`As discussed above, the impurities in representative examples of Moriarty
`
`include two different stereoisomers of treprostinil free acid. Ege suggests that a
`
`“carboxylate salt formation and regeneration of the neutral carboxylic acid” step
`
`would not remove these compounds from the product. Thus, a POSA looking to
`
`make the free acid product of claims 6, 10, 15, and 21, such as treprostinil free
`
`acid, would have understood Moriarty, Phares, and Ege to suggest simply making
`
`the treprostinil free acid product of Moriarty, and not undergoing the additional
`
`time and expense of a “carboxylate salt formation and regeneration of the neutral
`
`carboxylic acid” step because Ege actually teaches away from the usefulness of
`
`this step.
`
`Petitioner provides no additional evidence to augment or strengthen the
`
`position taken in the Petition by adding E ge. Although Petitioner submitted the
`
`Winkler declaration with the Petition, the only declaratory “evidence” relied upon
`
`in the Petition for claims 6, 15, and 21 is the conclusory statements made in
`
`paragraphs 84, 86, and 88, which are entitled to little or no weight. See 37 CPR.
`
`§ 42.65(a) (“Expert testimony that does not disclose the underlying facts or data on
`
`which the opinion is based is entitled to little or no weight”).
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`In sum, even though Phares discloses fonnin g a salt from treprostinil free
`
`acid, and Ege generally discusses that carboxylate salt formation was known in the
`
`art, there would have been no motivation or expectation of success in using these
`
`teachings on the already-formed free acid disclosed in Moriarty, and Petitioner has
`
`failed to establish that a POSA would have carried out steps necessary to
`
`inherently obtain the claimed products. Thus, Petitioner fails to establish a
`
`reasonable likelihood that claims 6, 10, 15 and 21 are unpatentable as obvious.
`
`2.
`
`Petitioner fails to provide a motivation to combine
`Moriarty, Phares and Ege or an expectation of success for
`obtaining the salt product of claim 22
`
`As noted above, claim 22 recites a salt form of a compound of Formula (I)
`
`that has been purified through the salt-formation step (0) followed by the acid-
`
`forrnation step (d). In essence, this claim requires a salt product of the free acid
`
`that has a novel purity profile, as discussed above.
`
`For the reasons outlined above, Petitioner has failed to establish that a POSA
`
`would have had a motivation or a reasonable expectation that subjecting a free acid
`
`compound such as treprostinil to a “carboxylate salt formation and regeneration of
`
`the neutral carboxylic acid” step, which was shown by Patth Owner (and
`
`evidenced by the FDA’s actions) to produce a significantly different final product.
`
`Petitioner has likewise failed to show that a POSA would be motivated to then turn
`
`around and make a salt of the significantly different final product. Again,
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`Petitioner provides no additional evidence to augment or strengthen the position
`
`taken in the Petition, and instead cites to the conclusory statements made in
`
`paragraphs 84, 86 and 88 of the Winkler declaration.
`
`C. Moriarty in View of Kawakami with Ege
`
`Much like the first alternative for Ground 3, the second alternative 7 over
`
`Moriarty, Kawakami and Ege — fails to establish a reasonable likelihood that
`
`claims 6, 10, 15, 21, and 22 are unpatentable as obvious.
`
`1.
`
`Petitioner fails to provide a motivation to combine
`Moriarty, Kawakami and Ege or an expectation of success
`for obtaining the free-acid product of claims 6, 10, 15, and
`21
`
`As noted throughout this Preliminary Response, the treprostinil free acid in
`
`Moriarty has a different purity profile than treprostinil free acid encompassed by
`
`the present claims. This difference in product was so significant that FDA changed
`
`its protocol for analyzing treprostinil free acid once this new product was
`
`introduced. See, supra, Section II.
`
`Kawakami allegedly discloses purification of a compound containing a
`
`carboxylic acid by forming the acid addition salt and then reformin g the carboxylic
`
`acid. Petition, pg. 53. Kawakami allegedly discloses that the resulting product is
`
`of “fairly high purity.” Id. Petitioner, however, fails to establish that a POSA
`
`would reasonably expect the teachings of Kawakami to extend to the products in
`
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`Moriarty. Specifically, Petitioner offers no evidence that a POSA would expect
`
`that the purification of a particular compound in Kawakami to a “fairly high
`
`purity” would suggest that the products in Moriarty (containing structurally
`
`unrelated stereoisomers of treprostinil free acid and other impurities) could be
`
`purified using the same process. Again, despite submitting the Winkler declaration
`
`with the Petition, the only “evidence” relied upon in the Petition for claims 6, 15,
`
`and 21 is the conclusory statements made in paragraphs 84, 86, and 88. This
`
`provides no evidence as to why Kawakami (separation of E/Z isomers of an
`
`alkene) would be applicable to the products in Moriarty or why Ege does not
`
`directly teach away from Petitioner’s conclusion.
`
`2.
`
`Petitioner fails to provide a motivation to combine
`Moriarty, Kawakami, and Ege or an expectation of success
`for obtaining the salt product of claim 22
`
`As noted above, claim 22 recites a salt form of a compound of Formula (I)
`
`that has been purified through the salt-formation step (0) followed by the acid-
`
`formation step (d). In essence, this claim requires a salt product of the free acid
`
`that has a novel purity profile, as discussed above.
`
`For the reasons outlined above, Petitioner has failed to establish that a POSA
`
`would have had a motivation or a reasonable expectation that subjecting a free acid
`
`compound such as treprostinil to a “carboxylate salt formation and regeneration of
`
`the neutral carboxylic acid” step, which was shown by Patent Owner (and
`
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`
`evidenced by FDA’s actions) to produce a significantly different final product.
`
`Petitioner has likewise failed to show that a POSA would be motivated to then turn
`
`around and make a salt of the significantly different final product. Again,
`
`Petitioner provides no additional evidence to augment or strengthen the position
`
`taken in the Petition, and instead cites to the conclusory statements made in
`
`paragraphs 84, 86 and 88 of the Winkler declaration.
`
`D.
`
`Petitioner provides no evidence that the product of the ’393 patent
`would be “inherently produced”
`
`Petitioners attempt to create a new legal theory out of whole cloth by
`
`alleging that a hypothetical combination of prior art references would inherently
`
`create the same product as the ’393 patent. Specifically, Petitioner has not asserted
`
`that the free acid and salt products of claims 6, 10, 15 , 21, and 22 would have been
`
`obvious from the product in Moriarty, Phares/Kawakami, and Ege.5 instead,
`
`Petitioner asserts an inherency position whereby it would have been obvious to
`
`conduct the salt-formation step (0) followed by the acid-formation step (d) (and a
`
`further salt-formation step for the purposes of claim 22), and the resulting product
`
`would have inherently been the same as that which is claimed.
`
`5 Indeed, Patent Owner established during prosecution that the free acid and salt
`
`products of claims 6, 10, 15, 21, and 22 were patentably distinct from the products
`
`in Moriarty and Phares. Ex. 1002.
`
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`
`Petitioner has set forth an inherency rationale that “a [POSA] would want to
`
`form the treprostinil diethanolamine salt, purify it, and then convert it back to its
`
`free form (i.e., treprostinil) in order to obtain excellent crystallinity and increased
`
`purity.” Petition, p. 54. Basically, Petitioner’s rationale relies on the inherent
`
`production of the claimed product flowing from the assertion that it would have
`
`been obvious to conduct the salt-formation step (0) followed by the acid-formation
`
`step (d) (and a further salt-formation step for the purposes of claim 22). This
`
`position, however, has no basis in law as inherency stems from what must
`
`necessarily be present in the prtor art, not what might possibly be present based on
`
`an alleged obviousness combination. See, e. g., Atlas Powder Co. v. [reco Inc, 190
`
`F.3d 1342, 1345-46 (Fed. Cir. 1999). As discussed for anticipation, Petitioner
`
`failed to provide a shred of evidence that any prior art reference contained any
`
`specific impurity profile or impurity level, much less that any prior art reference
`
`necessarily matched the impurity profile or impurity level of the ’393 patent. For
`
`obviousness, Petitioner asserts that new hypothetical products made by combining
`
`prior art references would also result in the same treprostinil products claimed in
`
`the ”393 patent. This argument however, has absolutely no evidentiary support or
`
`legal support. For these additional reasons, the petition for IPR should be denied
`
`should be denied with respect to Ground 3.
`
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`XIII. SECONDARY CONSIDERATIONS WOULD REBUT ANY
`
`POSSIBLE CASE OF OBVIOUSNESS
`
`Petitioner has not established a primafacz’e case of obviousness. Thus,
`
`Patent Owner is not obligated to provide evidence of objective indicia of non-
`
`obviousness. Nonetheless, objective indicia of non-obviousness confirm that the
`
`”393 patent would not have been obvious and, in fact, represents a surprising
`
`solution to the problem of minimizing impurities and providing a safer and purer
`
`treprostinil product.
`
`A.
`
`Long-felt unmet need
`
`At the time of the invention, there was a long-felt need to have a more
`
`efficient synthesis to produce treprostinil in a more pure form and in a cost-
`
`effective manner. Treprostinil has five chiral centers resulting in 32 possible
`
`diastereomers, so the potential for diastereomeric impurities is high, only the
`
`treprostinil stereoisomer has the desired pharmaceutical effect. EX. 2013, at pp. 11,
`
`11. 18-25, pp. 15,11. l-pp. 16,11. 8, pp. 19,11. 14-25. Treprostinil is also avery
`
`potent drug so any diastereomeric impurities would also potentially be potent and
`
`could potentially have deleterious effects. Id. Thus, there was a desire to reduce the
`
`amount of impurities as much as possible and the product of the ”393 patent further
`
`reduces impurities over the previous treprostinil products made by the prior art.
`
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`B.
`
`Unexpected results
`
`Patent Owner Preliminary Response
`
`The results of the claimed inventions in the ’393 were unexpected. The use
`
`of a salt form of treprostinil to further purify the treprostinil acid in a cheaper and
`
`better way than the previously used methods of purification was an unexpected
`
`result. Moreover, it was unexpected that the salt purification step reduced not only
`
`diastereomeric impurities, but also non-acidic impurities as well. See, supra,
`
`Section XI.B. 1. Thus, a person of skill in the art would not have expected the
`
`results of the ’393 patent to be so successful.
`
`C.
`
`Commercial Success
`
`The ’393 patent is used in the current production of Remodulin® and has
`
`reduced the amount of solvents and purification steps used to make Remodulin®
`
`and has thereby reduced the cost of making Remodulin® and increased efficiency.
`
`Ex. 2006, pp. 64-66. Remodulin is a commercially successful product that
`
`competes well against other alternatives such as Flolan. The commercial success
`
`of Remodulin® is reflected in its total revenue and relevant market share.
`
`Specifically, Remodulin® generated approximately $553.7 million, $491.2 million
`
`and $458.0 million in revenues for the years ended December 31, 2014, 2013 and
`
`20l2, respectively. Ex. 20l6, p. 6.
`
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`D.
`
`Copying
`
`Patent Owner Preliminary Response
`
`The non-obviousness of the ’393 patent is evidenced by the actions of
`
`several generic pharmaceutical companies Who have attempted to copy
`
`13.
`Remodulin® and Tyvasofl. See, e.g., United Therapeutics Corp. v. Sandoz, Inc,
`
`Civil Action No. 3: l4-cv-05499-PGS-LHG (D.N.J. 2014); United Nterapeutics
`
`Corp. v. Teva Pharma, Civil Action No. 3:14-cv-05498-PGS—LHG (D.N.J. 2014);
`
`United Therapeutics Corp. v. Watson Laboratories, Inc, Civil Action No. lS-cv-
`
`5723 (DNJ. 20 I 5). Treprostinil is marketed under the trade names Remodulin®
`
`for infusion and Tyvaso® for inhalation. The ’393 patent product and process is
`
`currently used in the production of Remodulin® and Tyvaso®. See, supra, Section
`
`II.
`
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`XIV. CONCLUSION
`
`Patent Owner Preliminary Response
`
`For the foregoing reasons, SteadyMed’s Petition should be denied. The
`
`issues raised have already been addressed by the Office, so denying the Petition is
`
`appropriate under 35 U.S.C. § 325(d). Even if the Board does not exercise its
`
`discretion, the Petition should be denied because Petitioner has failed to
`
`demonstrate a likelihood of success 011 the merits.
`
`Date:
`
`
`Jan. 14 2016
`
`Respectfully submitted,
`
`/ Stephen B. Maebius/
`Stephen B. Maebius
`Reg. No. 35,264
`
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`CERTIFICATE OF SERVICE
`
`The undersigned hereby certifies that a copy of the foregoing Patent Owner
`
`Preliminary Response was served on counsel of record for Petitioner on January
`
`14, 2016 by delivering a copy Via email to Stuart Pollack and Lisa Haile (the
`
`counsel of record for the Petitioner) at the following address:
`
`Steadwneddl—"R @dE a 3i errcom
`
`
`
`Date:
`
`Jan. 14: 2016
`
`signature:
`
`/Stephen B. Maebius/
`Stephen B. Maebius
`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`Paper
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`STEADYIVIED LTD.
`
`Petitioner
`
`V.
`
`UNITED THERAPEUTICS CORPORATION
`
`Patent Owner
`
`US. Patent No. 8,497,393
`
`Issue Date: Jul. 30, 2013
`
`Title: PROCESS TO PREPARE TREPROSTINIL, THE ACTIVE
`INGREDIENT IN REMODULIN®
`
`Case IPR2016-00006
`
`Patent Owner’s Exhibit List
`
`Mail Stop “PA TENT BOARD”
`Patent Trial and Appeal Board
`US. Patent and Trademark Office
`
`PO. BOX 1450
`
`Alexandria, VA 22313-1450
`
`4825-0169—9884.1
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`lPR2016-OOOO6
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`Patent 8,497,393
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`Patent Owner Docket No. 080618-1601
`
`Exhibit Description
`Ex #
`
`
`November 19, 2015 Conference Call Before the Panel
`2001
`
`
`2002
`
`Rernodulin Label
`
`FDA Approval Letter
`2003
`
`
`Process Validation Report: (Protocol No.: “VAL 00131”)
`
`Process Optimization Report
`2005
`
`
`UTC Letter of January 2009 to FDA
`
`2007
`
`US Patent No. 8,242,305, the ”305 patent
`
`2008
`
`US. Provisional Patent Application No. 61/014,232
`
`2009
`
`US. Patent No. 8,748,657, the ’657 patent
`
`The ’657 patent prosecution history
`2010
`
`
`Zumdahl, Chemistry, pp. A25, A36 (1986)
`
`
`
`Brown, et al., Chemistry: The Central Science, pp. G-2, G-lO (9th ed.
`
`2012
`
`- 2003)
`
`2013
`
`Trial testimony of Dr. Williams and Dr. Aristoff
`
`Suchocki, et al., Conceptual Chemistry, p. G—6 (2001)
`
`US. Patent No. 4,668,814, the ’8l4 patent
`20 l 5
`
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`IPR2016-00006
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`Patent 8,497,393
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`
`2016
`
`UTC Form 10K 2014 Annual Report
`
`Respectfully submitted,
`
`Date: Jan. 14 2016
`
`/Stephen B. Maebius/
`Stephen B. Maebius
`Registration N 0. 35,264
`Counsel for Patent Owner
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`Attorney Docket No. 080618-1601
`
`CERTIFICATE OF SERVICE
`
`The undersigned hereby certifies that a copy of the foregoing Patent
`
`Owner’s Exhibit List and a copy of each listed exhibit except for Exhibit Nos.
`
`2003-2006 (which are filed under seal) were served on counsel of record for the
`
`Petitioner on Jan. 14, 2016 by delivering a copy Via email to Stuart Pollack and
`
`Lisa Haile (the counsel of record for the Petitioner) at the following address:
`
`Steadymed—IPR@dlapipercom.
`
`
`Date: Jan. 14 2016
`
`/Step_hen B. Maebius/
`Stephen B. Maebius
`Registration No. 35,264
`Counsel for Patent Owner
`
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`REMODULIN safely and effectively. See full prescribing information for
`REMODULIN.
`
`REMOD U LIN,” (treprostinil) Injection, for subcutaneous or intravenous
`11 se
`Initial U.S. Approval: May 2002
`————————————————————————————RECENT MAJOR CHANGES--------------------------
`
`12’2014
`Dosage and Administration (2.1, 2.5)
`----------------------------INDICATIONS AND USAGE
`Remodulin is a prostacyclin vasodilator indicated for:
`Treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to
`diminish symptoms associated with exercise. Studies establishing
`effectiveness included patients with NYHA Functional Class II-IV
`symptoms and etiologies of idiopathic or heritable PAH (58%), PAH
`associated with congenital systemic-to-pulmonary shunts (23%), or PAH
`associated with connective tissue diseases ( 19%) (1.1)
`Patients who require transition from Flolan:), to reduce the rate of
`clinical deterioration The risks and benefits of each drrrg shorrld be
`carefully considered prior to transition. (12)
`----------------------DOSAGE AND ADMINISTRATION-----------------------
`
`PAH in patients with NYHA Class II-IV symptoms:
`Initial dose for patients new to prostaeyclin infusion therapy: 1.25
`ng/kg/min; increase based on clinical response (increments of 1.25
`ng/kg/min per week for the first 4 weeks of treatment, later 2.5
`ng/kg/min per week). Avoid abrupt cessation. (2.2, 2.3)
`Mild to moderate hepatic insufficiency: Decrease initial dose to 0.625
`ng/kg/min.
`Severe hepatic insufficiency: No studies performed (2.4)
`Transition from Flolan:
`Increase the Remodulin dose gradually as the Flolan dose is decreased, based
`on constant observation of response. (2.6)
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1. INDICATIONS AND USAGE
`1.1 Pulmonary Arterial Hypertension
`1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from
`Flolan®
`2 DOSAGE AND ADMINISTRATION
`2.1 General
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`2.3 Dosage Adjustments
`2.4 Patients with Hepatic Insufficiency
`2.5 Administration
`2.6 Patients Requiring Transition from Flolan
`3 DOSAGE FORIVIS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARN IN GS AN D PRECAU TION S
`5.1 Risk of Catheter-Related Bloodstream Infection
`5.2 Worsening PAH upon Abrupt Withdrawal or Sudden Large Dose
`Reduction
`5.3 Patients with Hepatic or Renal Insufficiency
`5.4 Effect of Other Drugs on Treprostinil
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`6.2 Po st-Mar‘keting Experience
`7 DRUG INTERACTIONS
`7:1 Antihypertensive Agents or Other Vasodilators
`7.2 Anticoagulants
`
`Administration:
`Continuous subcutaneous infusion (undiluted) is the preferred mode. Use
`intravenous (IV) infusion (dilution required) if subcutaneous infusion is not
`tolerated. (2.1, 2.5)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`Remodulin is supplied in 20 mL vials containing 20, 50, 100, or 200 mg
`of treprostinil (1, 2.5, 5 or 10 mg/mL). (3)
`-------------------------------CONTRAINDICATIONS------------------------------
`None
`
`
`--WARNINGS AND PRECAUTIONS----
`For intravenous infusion use an indwelling central venous catheter. This
`route is associated with the risk of blood stream infections (BSIs) and
`sepsis. which may be fatal. (5.1)
`Do not abnrptly lower the dose or withdraw dosing. (5.2)
`
`----ADVERSE REACTIONS---
`Most common adverse reactions (incidence >3%) reported rn clrrucal studres
`with Remodulin: subcutaneous infusion site pain and reaction, headache,
`diarrhea, nausea, jaw pain, vasodilatation, edema, and hypotension. (6.1)
`
`To report SUSPECTED ADVERSE REACTIONS, contact United
`Therapeutics Corp. at 1—866—458—6479 or contact FDA at 1-800—FDA—1088
`or wwwfdagov/medwatch.
`------------------------------DRUG INTERACTIONS-------------------------------
`Blood pressure lowering drugs (e g., diuretics, antihypertensive agents,
`orvasodilators): Risk of increased reduction in blood pressure (7.1)
`Remodulin inhibits platelet aggregation. Potential for increased risk of
`bleeding, particularly among patients on anticoagulants. (7.2)
`Remodulin dosage adjustment may be necessary if inhibitors or inducers
`of CYP2C8 are added or withdrawn. (7.6)
`See 17 for PATIENT COUNSELING INFORMATION,
`
`Revised: 12/2014
`
`7,3 Bosentan
`7.4 Sildenafil
`7.5 Effect of Treprostinil on Qltochrome P450 Enzymes
`7,6 Effect of cytochrome P450 Inhibitors and Inducers on Treprostinil
`7,7 Effect of Other Drugs on Treprostinil
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8,2 Labor and Delivery
`8,3 Nursing Mothers
`8,4 Pediatric Use
`8.5 Geriatric Use
`8,6 Patients with Hepatic Insufficiency
`8,7 Patients with Renal Insufficiency
`10 OVERDOSAGE
`11 DESCRIPTION
`12 CLINICAL PHARIVIACOLOCY
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`12.3 Pharmacokinetics
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis. Mutagcnesis, Impairment of Fertility
`14 CLINICAL STUDIES
`14.1 Clinical Trials in Pulmonary Arterial Hypertension (PAH)
`l4.2 Flolan-To-Remodulin Transition Sturdy
`16 HOW SUPPLIED / STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the full prescribing information are not
`listed.
`
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`FULL PRESCRIBING INFORMATION
`
`1. INDICATIONS AND USAGE
`
`1.1 Pulmonary Arterial Hypertension
`
`Remodulin is indicated for the treatment of pulmonary arterial hypertension (PAH) (WI-IO Group
`1) to diminish symptoms associated with exercise. Studies establishing effectiveness included
`patients with NYHA Functional Class II-IV symptoms and etiologies of idiopathic or heritable PAH
`(58%), PAH associated with congenital systemic-to-pulmonary shunts (23%), or PAH associated
`with connective tissue diseases (19%) [see Clinical Studies (14.1)].
`
`It may be administered as a continuous subcutaneous infusion or continuous intravenous (IV)
`infusion; however, because of the risks associated with chronic indwelling central venous
`catheters, including serious blood stream infections (BSIs), reserve continuous intravenous
`infusion for patients who are intolerant ofthe subcutaneous route, or in whom these risks are
`considered warranted [see Warnings and Precautions 5.1].
`
`1.2 Pulmonary Arterial Hypertension in Patients Requiring Transition from Flolan®
`
`In patients with pulmonary arterial hypertension requiring transition from Flolan (epoprostenol
`sodium), Remodulin is indicated to diminish the rate of clinical deterioration. Considerthe risks
`and benefits of each drug prior to transition.
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 General
`
`Remodulin can be administered without further dilution for subcutaneous administration, or
`diluted for intravenous infusion with Sterile Diluent for Remodulin or similar approved high-pH
`glycine diluent (e.g. Sterile Diluent for Flolan or Sterile Diluent for Epoprostenol Sodium), Sterile
`Water for Injection, or 0.9% Sodium Chloride Injection priorto administration. See Table 1 below
`for storage and administration time limits forthe different diluents.
`
`Table 1. Selection Of Diluent
`
`Storage limits
`Administration limits
`See section 16
`72 hours at 37°C
`
`refrigerated
`
`Sterile Diluent for Remodulin
`Sterile Diluent for Flolan
`Sterile Diluent for Epoprostenol Sodium
`Sterile water for injection
`0.9% Sodium Chloride for injection
`
`14 days at room
`temperature
`
`4 hours at room
`temperature or
`24 hours
`
`48 hours at 40 °C
`
`48 hours at 40°C
`
`2.2 Initial Dose for Patients New to Prostacyclin Infusion Therapy
`
`Remodulin is indicated for subcutaneous (SC) or intravenous (IV) use only as a continuous
`infusion. Remodulin is preferably infused subcutaneously, but can be administered by a central
`intravenous line ifthe subcutaneous route is not tolerated, because of severe site pain or
`reaction. The infusion rate is initiated at 1.25 ng/kg/min. Ifthis initial dose cannot be tolerated
`because of systemic effects, reduce the infusion rate to 0.625 ng/kg/min.
`
`2
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`lPR2016-00006
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`2.3 Dosage Adjustments
`
`The goal of chronic dosage adjustments is to establish a dose at which PAH symptoms are
`improved, while minimizing excessive pharmacologic effects of Remodulin (headache, nausea,
`emesis, restlessness, anxiety and infusion site pain or reaction).
`
`The infusion rate should be increased in increments of 1.25 ng/kg/min per week for the first four
`weeks of treatment and then 2.5 ng/kg/min per week for the remaining duration of infusion,
`depending on clinical response. Dosage adjustments may be undertaken more often iftolerated.
`Avoid abrupt cessation of infusion [see Warnings and Precautions (5.4)]. Restarting a Remodulin
`infusion within a few hours after an interruption can be done using the same dose rate.
`Interruptions for longer periods may require the dose of Remodulin to be re-titrated.
`
`2.4 Patients with Hepatic Insufficiency
`
`In patients with mild or moderate hepatic insufficiency, decrease the initial dose of Remodulin to
`0.625 ng/kg/min ideal body weight. Remodulin has not been studied in patients with severe
`hepatic insufficiency [see Warnings and Precautions (5.3), Use In Specific Populations (8.6) and
`Clinical Pharmacology (72.3)].
`
`2.5 Administration
`
`Inspect parenteral drug products for particulate matter and discoloration prior to administration
`whenever solution and container permit. If either particulate matter or discoloration is noted, do
`not use.
`
`Subcutaneous Infusion
`
`Remodulin is administered subcutaneously by continuous infusion without further dilution, via a
`subcutaneous catheter, using an infusion pump designed for subcutaneous drug delivery. To
`avoid potential interruptions in drug delivery, the patient must have immediate access to a backup
`infusion pump and subcutaneous infusion sets. The ambulatory infusion pump used to administer
`Remodulin should: (1) be small and lightweight, (2) be adjustable to approximately 0.002 mL/hr,
`(3) have occlusion/no delivery, low battery, programming error and motor malfunction alarms,
`(4) have delivery accuracy of i6% or better and (5) be positive pressure driven. The reservoir
`should be made of polyvinyl chloride, polypropylene or glass.
`
`Remodulin is administered subcutaneously by continuous infusion at a calculated subcutaneous
`infusion rate (mL/hr) based on a patient’s dose (ng/kg/min), weight (kg), and the vial strength
`(mg/mL) of Remodulin being used. During use, a single reservoir (syringe) of undiluted
`Remodulin can be administered up to 72 hours at 37°C. The subcutaneous infusion rate is
`calculated using the following formula:
`
`Subcutaneous
`Infusion Rate
`
`=
`
`Dose (ng/kg/min)
`
`x Weight (kg)
`
`x
`
`0.000%"
`
`(mL/hr)
`
`Remodulin Vial Strength (mg/mL)
`
`*Conversion factor of 0.00006 = 60 min/hour X 0.000001 mg/ng
`
`Example calculations for Subcutaneous Infusion are as follows:
`
`Example 1:
`
`3
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`For a 60 kg person at the recommended initial dose of 1.25 ng/kg/min using the 1 mg/mL
`Remodulin, the infusion rate would be calculated as follows:
`
`.
`
`
`
`
`mg m
`
`
`
`=—1'25”g/kg/m'” 1" [GE kg x 0'00“";
`
`= 0.005 mL/hr
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`Example 2:
`
`For a 65 kg person at a dose of 40 ng/kg/min using the 5 mg/mL Remodulin, the infusion
`rate would be calculated as follows:
`
`Subcutaneous
`Infusion Rate
`(mL/hr)
`
`=
`
`40 ng/kg/min
`
`65 kg
`x
`5 mg/mL
`
`x
`
`0.00006
`
`= 0.031 mL/hr
`
`lntrave nous Infusion
`
`Diluted Remodulin is administered intravenously by continuous infusion via a surgically placed
`indwelling central venous catheter using an infusion pump designed for intravenous drug delivery.
`If clinically necessary, a temporary peripheral intravenous cannula, preferably placed in a large
`vein, may be used for short term administration of Remodulin. Use of a peripheral intravenous
`infusion for more than a few hours may be associated with an increased risk of thrombophlebitis.
`To avoid potential interruptions in drug delivery, the patient must have immediate access to a
`backup infusion pump and infusion sets. The ambulatory infusion pump used to administer
`Remodulin should: (1) be small and lightweight, (2) have occlusion/no delivery, low battery,
`programming error and motor malfunction alarms, (3) have delivery accuracy of i6% or better of
`the hourly dose, and (4) be positive pressure driven. The reservoir should be made of polyvinyl
`chloride, polypropylene or glass.
`
`Infusion sets with an in-Iine 0.22 or 0.2 micron pore size filter should be used.
`
`Diluted Remodulin has been shown to be stable at ambient temperature when stored for up to 14
`days using high-pH glycine diluent at concentrations as low as 0.004 mg/mL (4,000 ng/mL).
`
`Select the intravenous infusion rate to allow for a desired infusion period length of up to 48 hours
`between system changeovers. Typical intravenous infusion system reservoirs have volumes of 50
`or 100 mL. With this selected intravenous infusion rate (mL/hr) and the patient’s dose (ng/kg/min)
`and weight (kg), the diluted intravenous Remodulin concentration (mg/mL) can be calculated
`using the following formula:
`
`Step 1
`
`Diluted
`Intravenous
`Remodulin
`concentration
`(mg/mL)
`
`Effie.
`("9 g m'”)
`
`=
`
`-
`x Wight
`( 9)
`Intravenous Infusion Rate
`(mL/hr)
`
`0.00006
`
`The volume of Remodulin Injection needed to make the required diluted intravenous Remodulin
`concentration for the given reservoir size can then be calculated using the following formula:
`
`4
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`UT Ex. 2002
`SteadyMed v. United Therapeutics
`lPR2016—00006
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`lPR2020-00770
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`United Therapeutics EX2007
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`

`SteQ 2
`
`Volume of
`Remodulin
`Injection
`(mL)
`
`=
`
`Diluted Intravenous
`Remodulin
`Concentration
`(mg/mL)
`Remodulin Vial
`Strength
`(mg/mL)
`
`'
`ngflgldolzfimggfufigffnd
`Reservoir
`(mL)
`
`The calculated volume of Remodulin Injection is then added to the reservoir along with the
`sufficient volume ofdiluent to achieve the desired total volume in the reservoir.
`
`Example calculations for Intravenous Infusion are as follows:
`
`Example 3:
`
`For a 60 kg person at a dose of 5 ng/kg/min, with a pr