No. _____
`
`IN THE
`Supreme Court of the United States
`
`
`
`
`LIQUIDIA TECHNOLOGIES, INC.,
`
`
`
`
`
`
`
`Applicant,
`
`v.
`UNITED THERAPEUTICS CORPORATION,
`Respondent.
`
`
`
`
`
`
`APPLICATION FOR AN EXTENSION OF TIME TO FILE A
`PETITION FOR A WRIT OF CERTORIARI TO THE UNITED
`STATES COURT OF APPEALS FOR THE FEDERAL CIRCUIT
`
`SANYA SUKDUANG
`COOLEY LLP
`1299 Pennsylvania Ave., Suite 700
`Washington, DC 20004
`(202) 842-7800
`
`
`
`
`PATRICK J. HAYDEN
`COOLEY LLP
`55 Hudson Yards
`New York, NY 10001
`(212) 479-6000
`
`
`
`
`
`
`KATHLEEN R. HARTNETT
` Counsel of Record
`COOLEY LLP
`3 Embarcadero Center, 20th Floor
`San Francisco, CA 94111
`(415) 693-2000
`khartnett@cooley.com
`
`ADAM S. GERSHENSON
`ALEX ROBLEDO
`COOLEY LLP
`500 Boylston Street
`Boston, MA 02116
`(617) 937-2300
`
`Counsel for Applicant Liquidia Technologies, Inc.
`
`
`
`
`
`

`

`
`
`PARTIES TO THE PROCEEDING AND
`CORPORATE DISCLOSURE STATEMENT
`Applicant Liquidia Technologies, Inc. was defendant in the
`
`1.
`
`district court and appellant before the court of appeals. Liquidia
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`Technologies, Inc. is a wholly owned subsidiary of Liquidia Corporation,
`
`which is a publicly held corporation.
`
`2.
`
`Respondent United Therapeutics Corp. was plaintiff in the
`
`district court and appellee and cross-appellant before the court of
`
`appeals.
`
`
`
`
`
`
`
`
`

`

`
`
`APPLICATION FOR AN EXTENSION OF TIME
`TO THE HONORABLE JOHN G. ROBERTS, JR., CHIEF JUSTICE OF
`THE UNITED STATES AND CIRCUIT JUSTICE FOR THE FEDERAL
`CIRCUIT:
`Pursuant to this Court’s Rules 13.5, 22, and 30.3, Applicant
`
`Liquidia Technologies, Inc. respectfully requests a 30-day extension of
`
`time—to and including January 24, 2024—within which to file a petition
`
`for a writ of certiorari to the United States Court of Appeals for the
`
`Federal Circuit in this case. On September 9, 2022, the district court
`
`entered judgment for Respondent United Therapeutics Corp. as to its
`
`claim against Applicant for induced patent infringement. The district
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`court’s opinion is reported at 624 F. Supp. 3d 436 (D. Del. 2022) and
`
`attached as Exhibit A, and its final judgment is attached as Exhibit B.
`
`On appeal, the Federal Circuit affirmed and entered judgment on July
`
`24, 2023. Its opinion, reported at 74 F.4th 1360 (Fed. Cir. 2023), is
`
`attached as Exhibit C. The court of appeals denied Applicant’s petition
`
`for rehearing en banc on September 26, 2023, and a copy of its order is
`
`attached as Exhibit D. Unless extended, the deadline to file a petition
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`for a writ of certiorari is December 26, 2023. This application is timely.
`
`1
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`

`

`
`
`See Sup. Ct. R. 30.2. This Court’s jurisdiction would be invoked under 28
`
`U.S.C. § 1254(1).
`
`1.
`
`The court of appeals’ affirmance of Respondent’s judgment for
`
`induced patent infringement against Applicant, notwithstanding that
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`Applicant had obtained a determination that the claims in the patent are
`
`unpatentable in inter partes review (IPR) before the Patent Trial and
`
`Appeal Board (PTAB), is contrary to this Court’s recognition in Commil
`
`USA, LLC v. Cisco Systems, Inc., 575 U.S. 632 (2015), that it is a defense
`
`to induced patent infringement if a patent is “invalid, and shown to be so
`
`under proper procedures,” such as by “seek[ing] inter partes review at the
`
`Patent Trial and Appeal Board.” Id. at 644–45. The court of appeals’
`
`ruling is also contrary to this Court’s precedent that federal courts must
`
`generally give preclusive effect to the decisions of federal administrative
`
`agencies if the ordinary elements of issue preclusion are met. See B & B
`
`Hardware, Inc. v. Hargis Indus., Inc., 575 U.S. 138, 141–42, 152 (2015).
`
`As this Court has stressed, “issue preclusion is not limited to those
`
`situations in which the same issue is before two courts.” Id. at 148.
`
`2.
`
`Both Applicant and Respondent are biotechnology or
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`biopharmaceutical companies. Respondent sued Applicant in district
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`- 2 -
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`

`

`
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`court for
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`infringement and
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`induced
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`infringement of certain of
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`Respondent’s patents, including a patent for a method of treating
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`pulmonary hypertension. In parallel, Applicant filed a petition with the
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`PTAB for inter partes review of that patent on the ground that its claims
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`are unpatentable as obvious over prior art. Ex. C at 4. On July 19, 2022,
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`the PTAB agreed with Applicant and issued a Final Written Decision
`
`determining that the claims in Respondent’s patent were obvious and
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`thus unpatentable, which the agency later reiterated on rehearing. Id.
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`3.
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`Applicant then argued in the instant litigation that the
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`PTAB’s determination meant that Applicant could not be liable for
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`induced infringement of Respondent’s patent. On August 31, 2022, the
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`district court in this case issued its post-trial opinion. See Ex. A. The
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`district court declined to give the PTAB decision preclusive effect as a
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`defense to the claim of induced infringement, stating that the PTAB’s
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`decision “does not have collateral estoppel effect until that decision is
`
`affirmed or the parties waive their appeal rights.” Id. at 36.
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`4. On July 24, 2023, while Respondent’s appeal of the PTAB
`
`decision was pending, the Federal Circuit affirmed the district court’s
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`judgment. See Ex. C. With respect to Applicant’s argument that the
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`- 3 -
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`

`

`
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`PTAB’s determination that the claims in the patent were unpatentable
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`meant that Applicant could not be held liable for induced infringement
`
`in this litigation, the Federal Circuit held that the PTAB decision “has
`
`no impact here” because it was “pending on appeal in this court,”
`
`reasoning that a such a decision “does not have collateral estoppel effect
`
`until that decision is affirmed or the parties waive their appeal rights.”
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`Id. at 19. The court of appeals denied Applicant’s petition for rehearing
`
`en banc on September 26, 2023. Ex. D.
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`5. “For good cause, a Justice may extend the time to file a petition
`
`for a writ of certiorari for a period not exceeding 60 days.” Sup. Ct. R.
`
`13.5. This case presents important issues concerning both the preclusive
`
`effects of PTAB decisions in parallel patent infringement litigation and
`
`issue preclusion in the context of agency decisions more broadly. A 30-
`
`day extension of time is necessary to allow counsel to prepare the petition
`
`addressing these issues. Counsel for Applicant also have significant
`
`professional obligations during the period in which the petition would
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`otherwise need to be prepared, including a motion for summary judgment
`
`and Daubert motions due on December 20 in Ryanair DAC v. Booking
`
`Holdings Inc., No. 20-1191-WCB (D. Del.), a merits brief due on
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`- 4 -
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`

`

`
`
`December 27 in Hankins v. Wheeler, No. 23-30711 (5th Cir.), and a trial
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`beginning on January 16 in VectorFlow v. HID Global, No. 1:21-cv-1769
`
`(D. Del.). Counsel also have personal commitments for the upcoming
`
`holidays that will conflict with preparation of the petition under the
`
`current deadline. Applicant is not aware of any party that would be
`
`prejudiced by a 30-day extension.
`
`Accordingly, good cause exists for this application, and Applicant
`
`respectfully requests a 30-day extension of time within which to file a
`
`petition for a writ of certiorari, to and including January 24, 2024.
`
`Dated: December 15, 2023
`
`Respectfully submitted,
`
`/s/ Kathleen R. Hartnett
`KATHLEEN R. HARTNETT
`Counsel of Record
`COOLEY LLP
`3 Embarcadero Center, 20th Floor
`San Francisco, CA 94111
`(415) 693-2000
`khartnett@cooley.com
`
`ADAM S. GERSHENSON
`ALEX ROBLEDO
`COOLEY LLP
`500 Boylston Street
`Boston, MA 02116
`(617) 937-2300
`agershenson@cooley.com
`
`SANYA SUKDUANG
`
`- 5 -
`
`

`

`
`
`
`
`
`
`COOLEY LLP
`1299 Pennsylvania Ave., Ste. 700
`Washington, DC 20004
`(202) 842-7800
`ssukduang@cooley.com
`
`PATRICK J. HAYDEN
`COOLEY LLP
`55 Hudson Yards
`New York, NY 10001
`(212) 479-6000
`phayden@cooley.com
`
`Counsel for Applicant Liquidia
`Technologies, Inc.
`
`- 6 -
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`

`

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`
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`
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`
`
`
`EXHIBIT A
`EXHIBIT A
`
`
`
`

`

`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 1 of 55 PageID #: 36513
`
`IN THE UNITED STATES DISTRJCT COURT
`FOR THE DISTRJCT OF DELAWARE
`
`UNITED THERAPEUTICS
`CORPORATION,
`
`Plaintiff,
`
`V.
`
`LIQUIDIA TECHNOLOGIES, INC.,
`
`Defendant.
`
`Civil Action No. 20-755-RGA
`
`TRJAL OPINION
`
`Jack B. Blumenfeld, Michael J. Flynn, Sarah E. Simonetti, MORRJS, NICHOLS, ARSHT &
`TUNNELL LLP, Wilmington, DE; Huiya Wu, GOODWIN PROCTER LLP, New York, NY;
`William C. Jackson, Eric Levi, GOODWIN PROCTER LLP, Washington, DC; Douglas H.
`Carsten, Mandy H. Kim, Arthur Dykhuis, Jiaxiao Zhang, Katherine Pappas, MCDERMOTT
`WILL & EMERY LLP, Irvine, CA; Ian B. Brooks, Adam W. Burrowbridge, Joshua Revilla,
`Timothy M. Dunker, MCDERMOTT WILL & EMERY LLP, Washington, DC; Harrison Gunn,
`GOODWIN PROCTER LLP, Boston, MA,
`
`Attorneys for Plaintiff.
`
`Karen E. Keller, Nathan R. Hoeschen, SHAW KELLER LLP, Wilmington, DE; Sanya
`Sukduang, Jonathan Davies, Douglas W. Cheek, Adam Pivovar, Brittany Cazakoff, COOLEY
`LLP, Washington, DC; Erik Milch, COOLEY LLP, Reston, VA; Ivor Elrifi, COOLEY LLP,
`New York, NY; Deepa Kannappan, Lauren Krickl, Kyung Taeck Minn, COOLEY LLP, Palo
`Alto, CA,
`
`Attorneys for Defendant.
`
`August 3 { , 2022
`
`

`

`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 2 of 55 PageID #: 36514
`
`United Therapeutics Corporation ("UTC") brought this action against Liquidia
`
`Technologies, Inc. for infringement of U.S. Patent Nos. 9,593,066 ("the '066 patent"), 9,604,901
`
`("the ' 901 patent"), and 10,716,793 ("the '793 patent") under 35 U.S.C. § 27l(e)(2)(A).
`
`(D.I. 1,
`
`16). I held a four-day bench trial.
`
`(D.I. 402-405). 1 The disputes at trial were related to the
`
`infringement and validity of claims 1, 2, 3, 6, 8, and 9 of the '066 patent and claims 1, 4, 6, 7,
`
`and 8 of the '793 patent. The ' 901 patent is no longer at issue.
`
`I have considered the parties' post-trial submissions. (D.I. 406,407, 408,409, 411 , 412,
`
`413 , 414, 415, 416,423 , 424). Having considered the documentary evidence and testimony, I
`
`make the following findings of fact and conclusions of law pursuant to Federal Rule of Civil
`
`Procedure 52(a).
`
`I.
`
`BACKGROUND
`
`UTC is the holder of New Drug Application ("NDA") No. 022387 for Tyvaso®, an
`
`inhaled solution formulation of treprostinil approved for the treatment of pulmonary arterial
`
`hypertension and pulmonary hypertension associated with interstitial lung disease.
`
`(D.I. 322-1,
`
`Ex. 1, ,r,r 5, 12). The '066 and '793 patents are listed in the FDA's Orange Book for Tyvaso®.
`
`(Id., ,r 14). The ' 066 patent discloses an improved process for preparing treprostinil.
`
`(See ITX
`
`2). The ' 793 patent discloses a method of administering treprostinil by inhalation.
`
`(See JTX
`
`3).
`
`Liquidia submitted NDA No. 213005 under§ 505(b)(2) of the Federal Food, Drug, and
`
`Cosmetic Act seeking FDA approval for the manufacture, use, and sale of its proposed product
`
`LIQ861 (Yutrepia™).
`
`(D.I. 322-1 , Ex. 1, ,r 2). LIQ861 is a dry powder formulation of
`
`1 I cite to the trial transcript as "Tr." The trial transcript is consecutively numbered.
`1
`
`

`

`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 3 of 55 PageID #: 36515
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`treprostinil sodium.
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`(Id., 116). The FDA tentatively approved LIQ861 for the treatment of
`
`pulmonary arterial hypertension.
`
`(Id., 11 17-18).
`
`Liquidia's NDA contains Paragraph IV certifications alleging that both the '066 and '793
`
`patents are invalid and/or will not be infringed by the manufacture, use, or sale of its proposed
`
`product. (Id., 1 8). UTC received notice of Liquidia' s Paragraph IV certifications and initiated
`
`the present lawsuit.
`
`(Id., 1 9).
`
`II.
`
`INFRINGEMENT OF THE '066 PATENT
`
`A.
`
`Legal Standard
`
`A patent is directly infringed when a person "without authority makes, uses, offers to sell,
`
`or sells any patented invention, within the United States or imports into the United States any
`
`patented invention during the term of the patent." 35 U.S.C. § 271(a). Determining
`
`infringement is a two-step analysis. Markman v. Westview Instruments, Inc. , 52 F.3d 967, 976
`
`(Fed. Cir. 1995) (en bane), ajf'd, 517 U.S. 370 (1996). First, the court must construe the
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`asserted claims to ascertain their meaning and scope.
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`Id. The trier of fact must then compare
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`the properly construed claims with the accused infringing product.
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`Id. This second step is a
`
`question of fact. Bai v. L & L Wings, Inc. , 160 F.3d 1350, 1353 (Fed. Cir. 1998). The patent
`
`owner bears the burden of proving infringement by a preponderance of the evidence.
`
`SmithKline Diagnostics, Inc. v. Helena Lab '.Ys Corp., 859 F.2d 878, 889 (Fed. Cir. 1988).
`
`In a Hatch-Waxman case, the plaintiff's infringement claim is based on the accused
`
`infringer' s future conduct, rather than past acts of infringement. Under § 271 ( e )(2), the
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`"infringement inquiry ... is focused on the product that is likely to be sold following FDA
`
`approval." Abbott Lab '.Ys v. TorPharm, Inc., 300 F.3d 1367, 1373 (Fed. Cir. 2002). "Because
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`drug manufacturers are bound by strict statutory provisions to sell only those products that
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`2
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`

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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 4 of 55 PageID #: 36516
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`comport with the []ND A' s description of the drug, an []NDA specification defining a proposed[]
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`drug in a manner that directly addresses the issue of infringement will control the infringement
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`inquiry." Id. For product-by-process claims, the infringement inquiry is focused "on the
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`process of making the product as much as it is on the product itself." Amgen Inc. v. F. Hoffman(cid:173)
`
`La Roche Ltd, 580 F.3d 1340, 1370 (Fed. Cir. 2009). Thus, "a product-by-process claim is not
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`infringed by a product made by a process other than the one recited in the claim." Id.
`
`B.
`
`Asserted Claims of the '066 patent
`
`1. A pharmaceutical composition comprising treprostinil or a pharmaceutically
`acceptable salt thereof, said composition prepared by a process comprising providing a
`starting batch of treprostinil having one or more impurities resulting from prior alkylation
`and hydrolysis steps, forming a salt of treprostinil by combining the starting batch and a
`base, isolating the treprostinil salt, and preparing a pharmaceutical composition comprising
`treprostinil or a pharmaceutically acceptable salt thereof from the isolated treprostinil salt,
`whereby a level of one or more impurities found in the starting batch oftreprostinil is lower
`in the pharmaceutical composition, and wherein said alkylation is alkylation ofbenzindene
`triol.
`
`2. The pharmaceutical composition of claim 1, wherein the salt is isolated in crystalline
`form.
`
`3. The pharmaceutical composition of claim 1, wherein the base is selected from the
`group consisting of sodium, ammonia, potassium, calcium, ethanolamine, diethanolamine,
`N-methylglucamine, and choline.
`
`6. The pharmaceutical composition of claim 1, wherein the isolated salt is stored at
`ambient temperature.
`
`3
`
`

`

`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 5 of 55 PageID #: 36517
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`8. A process of preparing a pharmaceutical product compnsmg treprostinil or a
`pharmaceutically acceptable salt thereof, comprising alkylating a triol intermediate of the
`formula:
`
`H
`
`H
`
`.... u,QH
`
`OH
`
`hydrolyzing the resulting compound to form treprostinil, forming a salt of treprostinil stable
`at ambient temperature, storing the treprostinil salt at ambient temperature, and preparing
`a pharmaceutical product from
`the
`treprostinil salt after storage, wherein
`the
`pharmaceutical product comprises treprostinil or a pharmaceutically acceptable salt
`thereof.
`
`9. A pharmaceutical product prepared by the process of claim 8.
`
`C.
`
`Findings of Fact
`
`1. A POSA would be either a chemical engineer or process research chemist with 3-5 years
`of experience in API and drug manufacturing or a master' s degree in chemistry or
`chemical engineering who collaborated with individuals having 3-5 years of experience
`in API drug manufacturing.
`
`2. Y onsung, based in South Korea, manufactures the treprostinil sodium API used to make
`(Tr. at 74:21-75 :5 (Nuckolls); PTX 20 at 7). Yonsung has
`Liquidia's LIQ861 product.
`a Drug Master File ("DMF") for the treprostinil sodium used in LIQ861.
`(PTX 112
`(Open DMF); PTX 201 (Restricted DMF)).
`
`3. Yonsung synthesizes the treprostinil sodium by alkylating a batch ofbenzindene triol
`("BTO") to provide a batch of"TN0l " (PTX 201 at 7, 22, 35 (DMF Step 10)), then
`performing a hydrolysis step to provide a batch of treprostinil ("TN02") (id. at 8, 23, 36
`(DMF Step 11)), and performing a salt formation step by combining the treprostinil with
`a base (sodium) to yield treprostinil sodium ("TN") (id. at 8, 24, 37 (DMF Step 12); Tr. at
`75:19-76:20 (Nuckolls); Tr. at 407:2-408 :2 1 (Winkler)).
`
`4
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`

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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 6 of 55 PageID #: 36518
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`4. LGM is a U.S. based administrative intermediary between Yonsung and Liquidia. (Tr.
`at 346:7-10 (Kindig); Tr. at 439:2-5 (Winkler)). Yonsung's shipments oftreprostinil
`sodium sometimes go through LGM to Liquidia; however, LGM does not manufacture
`treprostinil sodium, nor is it involved in the development or administration of Liquidia' s
`LIQ861 product. (Tr. at 331 :14-21 (Kindig); Tr. at 366:5-16 (Lenox)).
`
`5. A POSA would understand that the impurities limitations in claim 1 of the ' 066 patent
`refer to any impurities generated during the process steps of alkylating and hydrolyzing a
`batch of BTO (including from side reactions, impurities in reagents, solvents, or starting
`materials).
`
`6. Yonsung's analytical testing oftreprostinil sodium is a reliable and accurate measure of
`impurities in the pharmaceutical composition resulting from the alkylation and hydrolysis
`steps; Liquidia' s processing of the TN into the pharmaceutical composition (LIQ861 bulk
`powder) does not affect those impurities.
`
`7. Liquidia' s proposed LIQ861 product will be prepared by a process which lowers the level
`of one or more impurities resulting from prior alkylation and hydrolysis steps as claimed
`in the '066 patent. The percentage of total "related substance" impurities and the
`amount of total "related substance" impurities increase during the alkylation and
`hydrolysis steps from BTO to the starting batch of treprostinil (TN02), and then decrease
`in the TN batch after the salt formation and isolation steps.
`
`8. Liquidia' s NDA and Yonsung's DMF require treprostinil sodium to be stored at 2°C to
`goc.
`
`9. Liquidia will not use treprostinil sodium batches which have been stored at ambient
`temperature for GMP manufacturing.
`
`10. Liquidia begins preparing a pharmaceutical product during Step 1 of its PRINT process.
`
`D.
`
`Conclusions of Law
`
`1.
`
`Claims 1, 2, and 3
`
`Liquidia only disputes infringement of the impurities limitations in claims 1, 2, and 3.
`
`Claim 1 recites "providing a starting batch of treprostinil having one or more impurities resulting
`
`from prior alkylation and hydrolysis steps . . . wherein said alkylation is alkylation of benzindene
`
`triol." As a preliminary issue, the parties dispute the proper construction of "impurities
`
`resulting from prior alkylation and hydrolysis steps." Liquidia argues that the claimed
`
`impurities must result from alkylation and hydrolysis of "BTO," not the alkylation and
`5
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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 7 of 55 PageID #: 36519
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`hydrolysis of any compound that may be present in the reaction vessel.
`
`(D .I. 411 at 3 ). UTC
`
`argues that the claimed impurities encompass any impurities generated during the process steps
`
`of alkylating and hydrolyzing a batch of BTO (including from side reactions, impurities in
`
`reagents, solvents, or starting materials). (D.I. 408 at 7-8).
`
`UTC ' s construction is correct. The claim language requires that the impurities result
`
`from the "prior alkylation and hydrolysis steps." A POSA would understand that the alkylation
`
`step involves alkylating all materials in a batch ofBTO, not just the single alkylation reaction of
`
`BTO.
`
`(See Tr. at 110:23- 111 :10 (Nuckolls); Tr. at 810:16-19, 818:18-22 (Scheidt); see also
`
`Tr. at 423:15-20 (Winkler) ("[A] real batch of- a bottle ofbenzindene triol could contain
`
`impurities.")). Thus, I find that a POSA would understand that any impurities generated during
`
`the alkylation and hydrolysis steps (including from side reactions) are within the scope of the
`
`claim.
`
`Claim 1 further recites: "whereby a level of one or more impurities found in the starting
`
`batch of treprostinil is lower in the pharmaceutical composition." UTC has identified the
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`LIQ861 bulk powder as the "pharmaceutical composition" and Yonsung ' s TN02 as the "starting
`
`batch oftreprostinil." Liquidia argues that UTC cannot prove infringement of this limitation
`
`because UTC ' s experts only compared the impurities between TN02 and TN, not the LIQ861
`
`powder. (D.I. 411 at 2). UTC responds that Yonsung' s impurities testing for TN is a proper
`
`measure of impurities in the pharmaceutical composition resulting from the alkylation and
`
`hydrolysis steps because Liquidia' s processing of TN into LIQ861 bulk powder has no effect on
`
`the impurities from these steps.
`
`(D.I. 416 at 4). Once Liquidia receives the TN from Yonsung,
`
`6
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`

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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 8 of 55 PageID #: 36520
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`Liquidia uses its proprietary PRINT process2 to prepare the LIQ861 bulk powder using the TN
`
`as the APL
`
`(DTX 204; PTX 20).
`
`In simple terms, Liquidia puts the TN in solution, adds
`
`excipients, and dries this formulation into the powder.
`
`(DTX 204 at 2-6; Tr. at 741:7-16
`
`(Gonda)).
`
`UTC's expert Dr. Nuckolls testified that he "wouldn't expect" Liquidia's processing of
`
`TN to impact the impurities from the alkylation and hydrolysis steps. (Tr. at 157:7-17
`
`(Nuckolls); see also PTX 66 at 96 ("Treprostinil sodium drug substance process impurities are
`
`controlled by the manufacturer, Yonsung Fine Chemicals Co., Ltd. (Yonsung).")). Dr. Nuckolls
`
`also testified that it would be difficult for a POSA to test the impurities resulting from the
`
`alkylation and hydrolysis steps in the LIQ861 bulk powder because the composition has been
`
`mixed with other excipients. (Tr. at 133:25-134:3 (Nuckolls)). Liquidia has not provided any
`
`expert testimony to rebut these opinions; thus, I will credit Dr. Nuckolls' testimony on this point.
`
`I therefore find that the TN impurities are representative of the impurities in the "pharmaceutical
`
`composition" (LIQ861 bulk powder) resulting from the prior alkylation and hydrolysis steps.
`
`Cf Vectura Ltd. v. GlaxoSmithKline LLC, 397 F. Supp. 3d 579, 587-88 (D. Del. 2019) (finding
`
`that comparison testing supported the jury' s infringement verdict where there was evidence that
`
`the tested products were representative of the accused products), aff'd, 981 F.3d 1030 (Fed. Cir.
`
`2020).
`
`To prove infringement of the impurities limitations, UTC compared the (1) amount of
`
`total impurities; (2) number of total impurities; and (3) amount of epi-treprostinil in BTO, TN02,
`
`and TN.
`
`2 PRINT stands for Particle Replication in Nonwetting Templates. (DTX 204 at 2).
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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 9 of 55 PageID #: 36521
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`First, Dr. Nuckolls analyzed the total "related substance" impurities data provided by
`
`Yonsung in its DMF.
`
`(See PTX 201 at 270-72). 3 For two of the three DMF validation batches
`
`(TN 1171010, TN 117K0 10), the percentage of total "related substance" impurities increased
`
`between BTO and TN02, and then decreased in TN.4
`
`(Tr. at 77:23-80:18 (Nuckolls); PTX 201
`
`at 270-72; PTX 326 at 4 (identifying the corresponding BTO, TN0l , and TN02 batch numbers
`
`for each TN batch number)). Dr. Nuckolls opined that these changes in the percentage of total
`
`"related substance" impurities between BTO, TN02, and TN show infringement of the impurities
`
`limitations. (Tr. at 77:23-80: 18 (Nuckolls)).
`
`Second, Dr. Nuckolls analyzed the number of total impurities detected in Yonsung' s
`
`validation batches. To do so, Dr. Nuckolls looked at Yonsung' s underlying high-performance
`
`liquid chromatography (HPLC) data.
`
`(Tr. at 81:8-84:19 (Nuckolls)). HPLC separates
`
`components in a mixture by running the mixture down a column. (Tr. at 81 :8-23 (Nuckolls)).
`
`The mixture's components are separated based on how they interact with the column, so each
`
`component will elute at different retention times, depicted by peaks on a chromatogram. (Id. ;
`
`Tr. at 176:3-18 (Toste)).
`
`To determine the number of impurities, Dr. Nuckolls counted the number ofHPLC peaks
`
`in the chromatograms for BTO, TN02, and TN, excluding the peaks for "the material of interest"
`
`3 Because Liquidia relies on the same impurities data in its NDA, I find these data to be reliable.
`(See PTX 66 at 96; PTX 105 at 7-11 ).
`4 For validation batch TNl 171010, the percentage of "related substance" impurities was 0.07%
`in BTO, 0.20% in TN02, and 0.03% in TN.
`(PTX 201 at 270-72). For validation batch
`TNl 17K010, the percentage of "related substance" impurities was 0.08% in BTO, 0.20% in
`TN02, and 0.01 % in TN.
`(Id.). These results are consistent with Yonsung's acceptance
`criteria, which allow for a greater percentage of "related substance" impurities in TN02 than in
`TN. (Id. (2.0% for TN02; 0.5% for TN)). For validation batch TNl l 7K020, the percentage of
`"related substance" impurities was 0.38% in BTO, 0.21 % in TN02, and 0.01 % in TN.
`(Id.).
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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 10 of 55 PageID #: 36522
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`(e.g., BTO, TN02, and TN) and for the "known impurities" that were "labeled as missing or not
`
`detected." (Tr. at 81:24-83:4 (Nuckolls)). For example, the chromatogram for TN02 for
`
`validation batch TNl 171010 reported six peaks.
`
`(PTX 1540 at 79-80). One of these peaks
`
`identified TN02, which is the material of interest, not an impurity.
`
`(Id.). Thus, this peak was
`
`excluded from the impurities count. The chromatogram also identifies "15-epi-Treprostinil"
`
`and "Treprostinil ethyl ester" as "Peak Names," but reports these impurities as "Missing." (Id.).
`
`Because these known impurities were not detected in this sample, they are also excluded from
`
`the impurities count. Accordingly, Dr. Nuckolls identified three "related substance" impurities
`
`in this batch of TN02.
`
`(Tr. at 82:3-83:4 (Nuckolls)). Dr. Nuckolls testified that for two
`
`validation batches (TNl 171010, TN117K010), the number of"related substance" impurities
`
`increased between BTO and TN02, and then decreased in TN. 5 (Tr. at 81:24-84:19 (Nuckolls)).
`
`Dr. Nuckolls testified that this decrease shows that one or more impurities resulting from the
`
`alkylation and hydrolysis steps are lowered from TN02 to TN.
`
`(Id.).
`
`Liquidia argues that Dr. Nuckolls has failed to show a reduction in impurities "resulting
`
`from prior alkylation and hydrolysis steps .. . wherein said alkylation is alkylation of benzindene
`
`triol." (D.I. 411 at 4 ). Liquidia argues that the reported "total impurities" relied on by Dr.
`
`Nuckolls in his amount of total impurities analysis include "residual solvents and any impurity
`
`5 For validation batch TNl 171010, one "related substance" impurity was identified in BTO,
`three "related substance" impurities were identified in TN02, and one "related substance"
`(Tr. at 82:3-83:4 (Nuckolls); PTX 1536 at 51 (BTO); PTX 1539
`impurity was identified in TN.
`at 77 (TN); PTX 1540 at 79-80 (TN02)). For validation batch TN117K010, two "related
`substance" impurities were identified in BTO, three "related substance" impurities were
`identified in TN02, and one "related substance" impurity was identified in TN.
`(PTX 1410 at
`59-62 (BTO); PTX 1157 at 33-34 (TN02); PTX 1543 at 83-84 (TN)). The underlying HPLC
`chromatogram for validation batch TN117K020 was not available to Dr. Nuckolls. (Tr. at
`84:14-19 (Nuckolls)).
`
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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 11 of 55 PageID #: 36523
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`contained in the reagents or starting materials, not just impurities resulting from the claimed
`
`process steps." (Id.). Liquidia similarly faults Dr. Nuckolls' number of impurities analysis.
`
`Liquidia argues that since Dr. Nuckolls failed to correlate the unidentified HPLC peaks to any
`
`specific impurity, he cannot show that these impurities resulted from the alkylation and
`
`hydrolysis steps. (Id.).
`
`These arguments, however, rely on Liquidia's improper interpretation of the impurities
`
`limitations. As concluded above, a POSA would understand that the claimed impurities include
`
`any impurities generated during the alkylation and hydrolysis steps, including impurities
`
`originating from starting materials or reagents. Thus, Liquidia' s arguments rest on an infirm
`
`foundation.
`
`As described in its DMF, Yonsung uses a twelve-step process to manufacture TN.
`
`(PTIC
`
`201 at 3). Step 10 of this process is the alkylation step--BTO is reacted with the alkylating
`
`agent to produce TN0l. (Tr. at 75 :20-76:2, 76:11-13 (Nuckolls); PTX 201 at 7). Next, in Step
`
`11-the hydrolysis step--TN0l is hydrolyzed to produce TN02.
`
`(Tr. at 76:1-3 , 13-15
`
`(Nuckolls); PTIC 201 at 8).
`
`In Step 12, TN02 is treated with a base to form TN.
`
`(Tr. at 76:3-5,
`
`15-18 (Nuckolls); PTX 201 at 8). Thus, Dr. Nuckolls opined that any increased impurities in
`
`TN02 as compared to BTO resulted from the alkylation and hydrolysis steps, because those were
`
`the steps that were run to synthesize TN02 from BTO.
`
`(Tr. at 80:4-18, 82:3-15 (Nuckolls)).
`
`He further opined that the impurities that were generated during the alkylation and hydrolysis
`
`steps (Steps 10 and 11) were reduced during the final salt formation step (Step 12), as shown by
`
`the reduced levels of impurities in TN as compared to TN02.
`
`(Id.) . I credit Dr. Nuckolls'
`
`testimony over Dr. Winkler' s contrary testimony, which relied on Liquidia's erroneous
`
`construction. (See Tr. at 427: 19-429: 17 (Winkler)).
`
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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 12 of 55 PageID #: 36524
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`Based on the total impurities analyses conducted by Dr. Nuckolls, I find that UTC has
`
`proven that Liquidia will meet the impurities limitations of claim 1. 6 I therefore find that UTC
`
`has proven by a preponderance of the evidence that Liquidia' s proposed LIQ861 product will
`
`infringe claims 1, 2, and 3 of the ' 066 patent. 7
`
`2.
`
`Claim 6
`
`Claim 6, which depends from claim 1, further requires that "the isolated salt is stored at
`
`ambient temperature" before it is used to prepare a pharmaceutical composition. I construed
`
`"ambient temperature" as "room temperature (equal to or less than the range of 15°C to 30°C)."
`
`(D.I. 119). I construed "stored"/"storing"/"storage" to have its plain and ordinary meaning.
`
`(Id.).
`
`Liquidia has represented to the FDA that it will store treprostinil sodium between 2°C
`
`and 8°C. Yonsung' s DMF, which is incorporated in Liquidia' s NDA (see PTX 105 at 3),
`
`specifies the following storage conditions for TN: "STORAGE: Should be kept in a tight
`
`container, protected from moisture and light and stored at 2°C to 8°C." (PTX 112 at 517). The
`
`certificates of analysis for TN and Yonsung' s 2017 List of Finished and Intermediate Products
`
`also include these storage requirements.
`
`(Id. at 448, 450 ("Storage condition: Should be kept in
`
`a tight container, protected from moisture and light and stored at 2 °C to 8 °C (Long-term
`
`storage)."); DTX 43 at 6 (specifying TN' s "Storage Conditions" as "Refrigerated")). LGM, an
`
`intermediary between Yonsung and Liquidia, stores TN in accordance with Yonsung' s set
`
`6 Because I find UTC's first two analyses sufficient to show infringement, I need not consider
`UTC's third analysis, which compares the amount of epi-treprostinil in TN02 and TN.
`7 "To be sure, if at the end of the day, an act that would have been an infringement . . . pertains
`to a patent that is shown to be invalid, there is no patent to be infringed." Cammi! USA, LLC v.
`Cisco Sys., Inc. , 575 U.S. 632,644 (2015). Since I ultimately conclude that claims 1, 2, and 3 of
`the '066 patent are invalid as anticipated, there is ultimately no infringement.
`11
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`Case 1:20-cv-00755-RGA-JLH Document 433 Filed 08/31/22 Page 13 of 55 PageID #: 36525
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`storage conditions. (Tr. at 365:23- 366:4, 367:9-15, 368:2- 7 (Lenox); see also DTX 105).
`
`Liquidia' s raw material specification for