United States District Court, D. New Jersey
matter comes before the Court on joint claim construction
submitted by plaintiff Actelion Pharmaceuticals, Ltd., and
defendants Sun Pharmaceutical Industries, Inc., and Sun
Pharmaceutical Industries, Ltd., concerning United States
Patent No. 8, 598, 227 ('"227 patent"). The
'227 patent is listed to market and sell the drug
Veletri, ® a treatment which improves exercise
capacity for individuals suffering from pulmonary arterial
hypertension (PAH). The parties dispute the meaning of
"alkalinizing agent," as used in the '227
patent. The Court held a Markman hearing on November
13 and 14, 2018. The sole claim construction issue is whether
Actelion disclaimed glycine from its definition of
"alkalinizing agent" in statements it made to
distinguish prior art during the prosecution of a divisional
a disease characterized by high blood pressure in the lungs,
which causes shortness of breath, fatigue, and chest pain in
those afflicted, and ultimately results in death from
ventricular failure. (Declaration of Preston K. Ratliff II
("Ratliff Decl."), Ex. 2, Humbert et al., Treatment
of Pulmonary Arterial Hypertension, N. Engl. J. Med. 351;14
(Sept. 30, 2014) ("Humbert"), at 1425-26).
Epoprostenol, also known as prostacyclin, is a naturally
occurring prostaglandin which dilates blood vessels and
inhibits platelet aggregation. (Ratliff Decl., Ex. 5, Flolan
Product Information, at 1).
August 28, 1980, two inventors filed an application for a
United States Patent, which ultimately issued as U.S. Patent
No. 4, 335, 139 ("the Watts Patent"). (See
Declaration of Paul N. Harold (Harold Decl.), Ex. I, United
States Patent No. 4, 335, 139). The Watts patent claims:
A pharmaceutical formulation comprising an active compound
selected from prostacyclin, 15-methyl-prostacyclin, 16,
16-dimethylprostacyclin or a pharmaceutically acceptable salt
of any one of those in association with a pharmaceutically
acceptable buffer having a pH of at least 9 and based on a
pharmaceutically acceptable amino acid as a buffering acid as
a buffering acid in the buffer and, optionally, a further
pharmaceutically acceptable carrier.
(Id. at 8:35 to 43). The invention claimed by the
Watts Patent had an "antiaggregatory effect on blood
platelets" and was "useful, for example, in
preventing or mitigating the formation of thrombi or emboli
during extra corporeal circulation of blood."
(Id. at 1:16 to 19).
"[i]ntravenous prostacyclin (epoprostenol) was first
used to treat primary pulmonary hypertension in the early
1980s," it was first approved by the FDA for treatment
of PAH in 1995, and subsequently marketed by GlaxoSmithKline
as Flolan. (Ratliff Decl., Ex. 2, Humbert, et al.,
Treatment of Pulmonary Arterial Hypertension, N. Engl. J.
Med. 2004: 351:1425-36 (Sept. 30, 2004); Ex. 1, U.S.
Patent Number 8, 598, 227 ('"227 Patent")).
Flolan consists of "epoprostenol sodium equivalent to
either 0.5 mg... or 1.5 mg... epoprostenol, 3.76 mg glycine,
2.93 mg sodium chloride, and 50 mg mannitol."
(Id.). Clinical studies have shown that epoprostenol
improves exercise tolerance, hemodynamics, and long-term
survival, and can render lung transplants unnecessary in
patients with severe forms of PAH. (Id. at 6-7;
Ratliff Decl., Ex. 2, Humbert et al., at 1430).
some considered Flolan-brand epoprostenol, with a half-life
of just several minutes, to be highly unstable; it was
administered by continuous infusion via a portable pump
connected to a catheter permanently tunneled into the
patient's subclavian vein. (Ratliff Decl., Ex. 2, Humbert
et al., at 1430). Flolan is a freeze-dried product, which is
reconstituted using a proprietary sterile diluent prior to
its infusion. (Ratliff Decl., Ex. 5, Flolan Product
Information, at 7, 20-21, 28). The sterile diluent for Flolan
"is supplied in 50-mL glass vials containing 94 mg
glycine, 73.5 mg sodium chloride, sodium hydroxide (added to
adjust pH), and Water for Injection, USP." (Id.
at 1). One reservoir of reconstituted Flolan could be stored
in refrigerated conditions for no more than forty hours and
administered at room temperature for only eight hours.
(Id. at 27-28).
Palepu, an inventor, later discovered "that epoprostenol
in the presence of an alkalinizing agent, and high pH ... is
very stable compared to Flolan." (Ratliff Decl.), Ex. 1,
'227 Patent, at 4:15 to 18). The new formulation,
marketed as Veletri®, allows epoprostenol to be stored in
refrigerated conditions for up to eight days and remains
stable at room temperature for forty-eight to seventy-two
hours. (Ratliff Decl., Ex. 4, Veletri Highlights of
Prescribing Information, at 4-5).
2006, Palepu filed a provisional application with the Patent
and Trademark Office (PTO) titled "Novel Epoprostenol
Formulation and Method of Making Thereof." (Declaration
of Paul N. Harold (Harold Decl.), Ex. C, Provisional Patent
Application Nos. 60/783, 429, 60/772, 563, and 60/764, 769).
The '227 patent, a division of the 2006 application,
names Actelion as assignee. (See '227 Patent, at
cover (60)). The patent examiner restricted that prior
application because it contained three "groups of
inventions": (1) "a method of making a
composition"; (2) "a composition"; and (3)
"a method of treating a patient." (Harold Decl.,
Ex. F, May 7, 2010 Office Action Summary, at 2). The examiner
required Actelion "to elect a single invention to which
the claims must be restricted." (Id.).
elected to prosecute the "composition" claims in a
divisional application that would result in United States
Patent Number 8, 318, 802 (the '802 patent). (Harold
Decl., Ex. G, Response to Restriction Requirement). By way of
background, Actelion's initial application sought to
Claim 16 (Previously Presented): A pharmaceutical composition
(a) epoprostenol or a salt thereof; and
(b) an alkalinizing agent, wherein when the
composition is reconstituted, the pH of the reconstituted
solution is greater than 11.
Claim 19 (Original): The composition of claim 16, wherein the
alkalinizing agent is selected from the group
consisting of arginine, lysine, meglumine, N-methyl
glucosomine, an amino acid with a pKa of 9.0 and
above, trisodium phosphates, sodium carbonates, and
(Id. at 4-5 (emphasis added)). The examiner rejected
that initial application noting that prior art "teaches
stabilized formulations of prostacyclin (which is also known
as epoprostenol) with an amino acid and a base . . . and they
further specify glycine and arginine as amino acids to be
used as buffers." (Harold Decl., Ex. H, August 17, 2010
Office Action Summary, at 4). The examiner found the claims
"fail[ed] to particularly point out and distinctly claim
the subject matter which applicant regards as the
invention" because, as to claim 19, "[a]rginine is
claimed as an alkalinizing agent . . . and glycine is an
amino acid with a pKa above 9 and thus they teach
compositions comprising both prostacyclin/epoprostenol and an
alkalinizing agent." (Id. at 4-5). The examiner
also noted that claim 16 "would not require any specific
pH in the composition." (Id. at 4). In other
words, she concluded the claimed invention was insufficiently
distinct from the prior art.
submitted another response with, in pertinent part, the
Claim 16 (Currently amended): A pharmaceutical composition
that is capable of being reconstituted with a
conventional intravenous fluid to a pH greater than 12
(a) epoprostenol or a salt thereof; and
(b) an alkalinizing agent
(c) an inorganic base selected from the group consisting
of sodium hydroxide and ...