United Therapeutics Corporation v. Liquidia Technologies, Inc.

Filing 241

MEMORANDUM OPINION providing claim construction for multiple terms in U.S. Patent No. 9,593,066 and U.S. Patent No.9,604,901. Within five days the parties shall submit a proposed order consistent with this Memorandum Opinion. Signed by Judge Richard G. Andrews on 11/18/2021. (nms)

Case 1:20-cv-00755-RGA-JLH Document 241 Filed 11/18/21 Page 1 of 10 PageID #: 16114

IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF DELAWARE

UNITED THERAPEUTICS
CORPORATION,
Plaintiff,
Civil Action No. 20-755-RGA

V.

LIQUIDIA TECHNOLOGIES , INC.,
Defendant.

MEMORANDUM OPINION

Michael J. Flynn, MORRIS, NICHOLS , ARSHT & TUNNELL LLP, Wilmington, DE; William
C. Jackson, BOIES SCHILLER FLEXNER LLP, Washington, D.C.; Douglas H. Carsten
(argued), Jiaxio Zhang, MCDERMOTT WILL EMERY LLP, Irvine, CA; Adam Burrowbridge,
MCDERMOTT WILL EMERY LLP, Washington, D.C. ,
Attorneys for Plaintiff.
Karen Elizabeth Keller, SHAW KELLER LLP, Wilmington, DE; Jonathan R. Davies (argued),
Sanya Sukduang (argued), Douglas W. Cheek, COOLEY LLP, Washington, D.C.; Brittany
Cazakoff, COOLEY LLP, Palo Alto, CA,
Attorneys for Defendant.

Novemberl [, 2021

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Before me is the issue of claim construction of multiple terms in U.S. Patent No.
9,593 ,066 ("the ' 066 patent") and U.S . Patent No. 9,604,901 ("the ' 901 patent"). The parties
submitted a Joint Claim Construction Brief (D.I. 75), and I heard oral argument on June 4, 2021
(D .I. 161 ). The parties argued for constructions of five claim terms, and I construed three terms
at the hearing. (D.I. 119). I requested supplemental briefing on the remaining two terms, which
the parties have provided. (D.I. 125). I now construe the remaining two terms, which appear in
the ' 901 patent.
I.

BACKGROUND

The ' 901 patent relates to "an improved process to convert benzindene triol to treprostinil
via salts oftreprostinil and to purify treprostinil." (' 901 patent, abstract). Plaintiff filed this
action for infringement of the ' 066 patent and the ' 901 patent based on Defendant' s submission
of New Drug Application No. 213005. (D.I. 1). Defendant petitioned for IPR of both patents.
(D.I. 76-1 , Exs. Pl & P2). The PTAB denied institution ofIPR for the ' 066 patent and granted
institution ofIPR for the ' 901 patent. (D.I. 76-1 , Ex. P3). On October 8, 2021 , the PTAB issued
a final written decision, finding claims 1- 5, 8, and 9 of the ' 901 patent to be unpatentable.
Liquidia Techs. , Inc. v. United Therapeutics Corp. , No. IPR2020-00770, 2021 WL 4860733, at
*1 (P.T.A.B. Oct. 8, 2021). The PTAB also found that Defendant had not established that claims
6 and 7, which depend from claim 1, were unpatentable. Id.
The disputed terms appear in independent claim 1 and are also fully set forth in method
claim 8. The following claims are thus the most relevant for purposes of this Markman:
Claim 1 of the '901 patent

1. A pharmaceutical batch consisting of treprostinil or a salt thereof and impurities
resulting from (a) alkylating a benzindene triol, (b) hydrolyzing the product of step (a) to
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form a solution comprising treprostinil, (c) contacting the solution comprising treprostinil
from step (b) with a base to form a salt of treprostinil, (d) isolating the salt of treprostinil,
and (e) optionally reacting the salt of treprostinil with an acid to form treprostinil, and
wherein the pharmaceutical batch contains at least 2.9 g of treprostinil or its salt.
Claim 8 of the '901 patent
8. A method of preparing a pharmaceutical batch as claimed in claim 1, comprising (a)
alkylating a benzindene triol, (b) hydrolyzing the product of step (a) to form a solution
comprising treprostinil, (c) contacting the solution comprising treprostinil from step (b)
with a base to form a salt of treprostinil, (d) isolating the salt of treprostinil, and (e)
optionally reacting the salt of treprostinil with an acid to form treprostinil.

II.-

LEGAL STANDARD
"It is a bedrock principle of patent law that the claims of a patent define the invention to

which the patentee is entitled the right to exclude." Phillips v. AWH Corp., 415 F.3d 1303, 1312
(Fed._Cir- 2005) (en bane) (internal quotation marks omitted)

•

'"

[T]here is no magic formula or

catechism for conducting claim construction. ' Instead, the court is free to attach the appropriate
weight to appropriate sources ' in light of the statutes and policies that inform patent law. " '

SoftView LLC v. Apple Inc. , 2013 WL 4758195 , at *1 (D. Del. Sept. 4, 2013) (quoting Phillips,
415 F.3d at 1324) (alteration in original). When construing patent claims, a court considers the
literal language of the claim, the patent specification, and the prosecution history. Markman v.

Westview Instruments, Inc. , 52 F.3d 967, 977-80 (Fed. Cir. 1995) (en bane), aff'd, 517 U.S. 370
(1996). Of these sources, "the specification is always highly relevant to the claim construction
analysis. Usually, it is dispositive; it is the single best guide to the meaning of a disputed term."

Phillips, 415 F.3d at 1315 (internal quotation marks omitted).
" [T]he words of a claim are generally given their ordinary and customary meaning ....
[Which is] the meaning that the term would have to a person of ordinary skill in the art in
question at the time of the invention, i.e., as of the effective filing date of the patent application."

Id. at 1312-13 (citations and internal quotation marks omitted). "[T]he ordinary meaning of a
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claim term is its meaning to [an] ordinary artisan after reading the entire patent." Id. at 1321
(internal quotation marks omitted). "In some cases, the ordinary meaning of claim language as
understood by a person of skill in the art may be readily apparent even to lay judges, and claim
construction in such cases involves little more than the application of the widely accepted
meaning of commonly understood words." Id. at 1314.
When a court relies solely upon the intrinsic evidence-the patent claims, the
specification, and the prosecution history-the court' s construction is a determination oflaw.

See Teva Pharm. USA, Inc. v. Sandoz, Inc. , 574 U .S. 318, 331 (2015). The court may also make
factual findings based upon consideration of extrinsic evidence, which " consists of all evidence
external to the patent and prosecution history, including expert and inventor testimony,
dictionaries, and learned treatises." Phillips, 415 F.3d at 1317-19 (internal quotation marks
omitted). Extrinsic evidence may assist the court in understanding the underlying technology,
the meaning of terms to one skilled in the art, and how the invention works. Id. Extrinsic
evidence, however, is less reliable and less useful in claim construction than the patent and its
prosecution history. Id.

III.

CONSTRUCTION OF DISPUTED TERMS
1.

"pharmaceutical batch" (claims 1-4, 6, and 8)
a. Plaintiff's proposed construction: " a specific quantity of treprostinil ( or its salt)
that is intended to have uniform character and quality, within specified limits, and
is produced according to a single manufacturing order during the same cycle of
manufacture, wherein the uniform character and quality is such that it still
contains impurities resulting from the method by which it is produced"
b. Defendant 's proposed construction: "pharmaceutical batch made according to the
process recited in steps (a)- (d) and optionally (e), wherein no purification steps
appear between alkylation and salt formation"
c. Court 's construction: plain and ordinary meaning

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Plaintiffs proposed construction imports a definition from an FDA regulation, which
defines "batch" as "a specific quantity of a drug or other material that is intended to have
uniform character and quality, within specified limits, and is produced according to a single
manufacturing order during the same cycle of manufacture." 21 C.F.R. § 210.3(b)(2).
Plaintiffs expert Dr. Robert Ruffolo asserts that a person of ordinary skill in the art
would have understood the term "pharmaceutical batch" to incorporate this regulatory definition
since the '901 patent is "a pharmaceutical patent that is related to the commercial manufacturing
of a pharmaceutical API of an FDA-approved marketed drug." (D.I. 76-1 , Ex. P4, 175). 1 But I
am not convinced that a POSA would interpret the term "pharmaceutical batch" to incorporate an
FDA regulatory definition, especially because there are no references to the FDA or to FDA
regulations in the ' 901 patent. Thus, I deny Plaintiffs attempt to import this FDA regulatory
guidance into the plain and ordinary meaning of this term.
Defendant's proposed construction simply adds a limitation to the plain and ordinary
meaning of "pharmaceutical batch"-i.e., that no purification steps appear between alkylation
and salt formation. In support of this construction, Defendant points to statements made by
Plaintiff during the IPR of the ' 901 patent. For example, in its Patent Owner Preliminary

1

Plaintiff also argues that "pharmaceutical batch" is distinct from "batch." Plaintiff claims that a
POSA would understand that the claimed process includes a "pharmaceutical batch," while the
prior art process includes a "batch." (D.I. 75 at 45-46). Plaintiff reasons that the claimed process
involves commercial manufacturing, while the prior art process describes a smaller-scale drug
development process. (Id. at 46; D.I. 76-1 , Ex. P4, 186). I am unclear as to how this distinction
is reflected in Plaintiffs proposed construction. To the extent that Plaintiff is arguing that
"pharmaceutical" denotes a commercial character, I cannot agree. The ' 901 patent specification
expressly defines "pharmaceutically acceptable" as "being useful in preparing a pharmaceutical
composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable
and includes being useful for veterinary use as well as human pharmaceutical use." (' 901 patent,
5:27-31; see also D.I. 78-1 , Ex. D9 at 113:12-115:20). This definition includes no reference to a
"commercial" character. It does not seem consistent with Plaintiffs argument that a POSA
would understand "pharmaceutical batch" to import an FDA definition.
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Response, Plaintiff argued that the prior art did not permit large-scale synthesis. Plaintiff told
the PTAB, "This perspective is critical in the context of the claimed phannaceutical composition,
in which, e.g. , no purification steps appear between alkylation and salt formation." (D.I. 77-1 ,
Ex. D5 at 56; see also Ex. D7 at 58 ("Rather, the POSA must have been motivated to combine
the prior art in the way claimed in the ' 901 patent (e.g. , not purified before salt formation), and
had a reasonable expectation of success in doing so.")). Defendant argues that these statements
amount to a disclaimer of an intermediate purification step. (D.I. 75 at 47).
The Federal Circuit has held, "[S]tatements made by a patent owner during an IPR
proceeding, whether before or after an institution decision, can be considered for claim
construction and relied upon to support a finding of prosecution disclaimer." Aylus Networks,

Inc. v. Apple Inc., 856 F.3d 1353, 1362 (Fed. Cir. 2017). "Of course, to invoke the doctrine of
prosecution disclaimer, any such statements must ' be both clear and unmistakable. "' Id. at 1361.
Plaintiff withdrew the purported disavowals before the PTAB took any steps in reliance on them.

(See D.I. 125-1, Ex. Jl; Ex. 12 at 36:7-8, 69:14). Thus, I find no clear and unmistakable
disclaimer of claim scope.
Defendant' s construction is also inconsistent with the '901 patent specification, which
discloses examples where there are purification steps between alkylation and salt formation. (See
D.I. 76-1 , Ex. P4, ,r,r 54, 92). Example 2, "Hydrolysis of Benzindene Nitrile," describes
removing impurities with ethyl acetate; washing with water, a solution ofNaHCO3, and a
solution of NaCl; and filtering with Celite® 545. ('901 patent, 11 :58-12:14). Thus, I decline to
adopt Defendant's proposed construction.
I instead apply the plain and ordinary meaning, which is, as always, the default in claim
construction. Phillips, 415 F.3d at 1316.

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2.

"contacting the solution comprising treprostinil from step (b) with a base to
form a salt of treprostinil" (claims 1 and 8)
a. Plaintiff's proposed construction: plain and ordinary meaning
b. Defendant 's proposed construction: "contacting the solution comprising
treprostinil from step (b) with a base to form a salt of treprostinil, wherein the salt
is formed without isolation of treprostinil after alkylation and hydrolysis"
c. Court 's construction: "contacting the solution comprising treprostinil from step
(b) with a base to form a salt of treprostinil, wherein the salt is formed without
isolation of treprostinil after alkylation and hydrolysis"
In its final written decision, the PTAB construed this term and agreed with Defendant

that, based on the intrinsic evidence, "treprostinil is not isolated from the solution formed in step
(b) before forming a salt in step (c)." Liquidia, No. IPR2020-00770, 2021 WL 4860733 , at *12.
"The PTAB ' s construction is not binding on this Court, but, where the construction is similar to
that of a district court's review, it is appropriate for me to take the PTAB' s claim construction
into consideration." Genuine Enabling Tech. , LLC v. Sony Corp., 2020 WL 1140910, at *7 (D.
Del. Mar. 9, 2020) (internal quotation marks and citation omitted). Here, it is appropriate for me
to consider the PTAB ' s construction of this term because the PTAB applied "the same claim
construction standard that would be used to construe the claim in a civil action under 35 U.S.C. §
282(b)"-i.e., the Phillips standard. Liquidia, No. IPR2020-00770, 2021 WL 4860733 , at *7
(quoting 37 C.F.R. § 42.l00(b)).
I find the PTAB ' s reasoning to be persuasive. First, the claim language supports a
construction excluding an intermediate isolation step. Step (c) of claim 1 requires "contacting

the solution comprising treprostinilfrom step (b) with a base to form a salt of treprostinil." ('901
patent, 17:27-29 (emphasis added)). This claim language dictates that the solution oftreprostinil
from step (b)-not treprostinil isolated as a solid from step (b )-is what is used to form a salt in
step (c).
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Second, the ' 901 patent specification supports this construction. Example 2 provides,
"The filtrate (pale-yellow) was reduced to volume of 35-40 L by evaporation in vacuo at 50-55 °

Cfor direct use in next step." (Id., 12:15-17 (emphasis added)). Example 3 describes the next
step, conversion of treprostinil to treprostinil diethanolamine salt. It provides, "A 50-L,
cylindrical reactor ... was charged with a solution of treprostinil in ethyl acetate (35-40 Lfrom

the previous step) ...." (Id. , 13:13-17 (emphasis added)). These examples are consistent with
the claim language and show that the solution of treprostinil formed in step (b) is used
immediately in step (c), with no isolation oftreprostinil between the steps. 2
Plaintiff argues that Defendant' s construction improperly reads out a preferred
embodiment of the claimed invention. (See D.I. 75 at 64; D.I. 161 at 68:10-71:14). Example 2
provides that the treprostinil is formed in an aqueous layer and then "extracted with ethyl acetate
. .. to remove impurities soluble in ethyl acetate." (' 901 patent, 11 :58-60). The treprostinil is
transferred from the aqueous layer to the organic layer (ethyl acetate). (Id. , 11:62- 12:3). The
organic solution is then used in the salt formation step. (Id. , 12:15-17; D.I. 161 at 67:8-15,
69:20-70: 19). Plaintiff contends that, in this example, treprostinil is isolated before the salt
formation step, so Defendant' s construction is improper. (See D.I. 161 at 73:3-74:23).

2

Defendant also argues that Plaintiff disclaimed an intermediate isolation step through
statements made during the IPR of the ' 901 patent. (See, e.g. , D.I. 77-1 , Ex. D7 at 11 ("[C]laim 1
requires the solution in which treprostinil is formed be used directly in the next salt-forming step
without isolating treprostinil in between."); id. at 15 ("Each claim of the ' 901 patent further
requires forming the salt without isolating the intermediate acid."). Plaintiff later withdrew these
statements. (D.I. 125-1 , Ex. J2 at 22:10-14, 26:12-13). The PTAB dismissed Plaintiff's request
to withdraw these statements as moot because it construed the "contacting" term based solely on
the intrinsic evidence. Liquidia, No. IPR2020-00770, 202 1 WL 4860733, at *22. Since the
PTAB did not rely on these withdrawn statements, I find no clear and unmistakable disclaimer of
claim scope. Regardless, the intrinsic evidence supports Defendant' s construction, and thus I
would reach the same result whether I considered the statements or not.
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Defendant responds that this example involves purification, not isolation, and that
Plaintiff and its expert are conflating the terms "purification" and "isolation." (Id. at 71:19-72:6).
I agree. At oral argument, Plaintiff referred to Example 2's steps as "purification steps," not
"isolation steps." (See, e.g. , id. at 66:4-6 ("There are purification and work-up steps that are
identified in example two .... "); id. at 67:15-17 ("[T]here are purification steps in between.");
id. at 71: 12-14 ("[W]e just saw that there ' s purification steps that are occurring there.")). Dr.

Ruffolo also referred to these steps as "purification steps" in his initial declaration. (D.I. 76-1 ,
Ex. P4, ,r 54; Ex. PS , ,r 17).

In his supplemental declaration, Dr. Ruffolo states, " [A] POSA would understand that a
compound can be purified to isolation, even while it is maintained in a solvent, which is often
done for practical considerations (e.g., material transfer) in manufacturing plants." (Id. , Ex. PS , ,r
21; see also id. , ,r 15 (" [I]t is common for compounds to be isolated (i.e. , separated from many
impurities and other contaminants resulting from previous chemical reactions) and retained in a
solution state in commercial manufacturing processes for practical reasons, such as facilitating
material transfer."); id. , ,r 17 ("It is clear that these many purification steps result in isolation of
treprostinil (from many impurities and contaminants) prior to the salt formation step, regardless
of whether the isolated treprostinil is in an aqueous phase, organic phase or solid phase.")). But
Dr. Ruffolo ' s assertions that isolation and purification are essentially the same and that a
compound can be isolated even when it is still in solution are inconsistent with the use of the
terms "isolation" and "purification" in the ' 901 patent.
The '901 patent specification uses both terms, but in different contexts. (See, e.g. , '901
patent, 16:67-17:1 ("The purification ofbenzindene nitrile by column chromatography is
eliminated."); 17:8-10 ("[T]he treprostinil salts can be synthesized from the solution of

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treprostinil without isolation."). There are no places in the ' 901 patent where these terms appear
to be used as synonyms. Thus, I think it is reasonable to conclude that these terms have different
meanings in the ' 901 patent. See Amgen Inc. v. Sandoz Inc. , 923 F.3d 1023, 1031 (Fed. Cir.
2019) (" [D]ifferent claim terms are presumed to have different meanings." (quoting Helmsderfer
v. Bobrick Washroom Equip. , Inc. , 527 F.3d 1379, 1382 (Fed. Cir. 2008))).
The patent specification uses the terms "isolation" and "isolating" in the context of
isolating a compound as a solid. For example, step (d) in claim 1 requires "isolating the salt of
treprostinil." ('901 patent, 17:29). The specification explains that the salt is isolated as a solid.
(Id. , 13:24--27 ("The treprostinil diethanolarnine salt was collected by filtration using Aurora

filter equipped with filter cloth, and the solid was washed with ethyl acetate (2x8 L).")). Thus,
Defendant' s construction does not read out Example 2, because Example 2 discloses purification
steps, not the isolation oftreprostinil as a solid. (See D.I. 161 at 70:20-71 :2 ("The only
difference is that it' s never reduced to dryness. So, you don't ever have in this specific example a
solid form .... ")).
I will therefore adopt Defendant' s proposed construction, as it is consistent with the claim
language and the specification.
IV.

CONCLUSION

Within five days the parties shall submit a proposed order consistent with this
Memorandum Opinion.

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