On Feb. 14, 2017, a New Jersey Federal judge
found that Dr. Reddy’s proposed generic infringed the following three patents (US
Patent 7,947,724, US Patent 8,729,094, and US Patent 9,066,980) covering the
anti-nausea drug Aloxi. This case arose
from Dr. Reddy’s submission of a so-called “Paper NDA” under § 505(b)(2). There
is separate and ongoing litigation regarding various Abbreviated New Drug
Applications filed under 21 U.S.C. § 505(j) to manufacture generic versions of
Helsinn’s branded palonosetron product.
An
example of an asserted claim is claim 1 of US Patent 9,066,980 , to which Dr.
Reddy’s only raised an invalidity defense:
1. A pharmaceutical
single-use, unit-dose formulation for intravenous administration to a human to
reduce the likelihood of cancer chemotherapy-induced nausea and vomiting,
comprising a 5 mL sterile aqueous solution, said solution comprising: a)
palonosetron hydrochloride in an amount of 0.25 mg based on the weight of its
free base, b) optionally a chelating agent, and c) a tonicifying agent in an
amount sufficient to make said solution isotonic, wherein said formulation is
stable at 24 months when stored at room temperature.
The claims and defenses in the
case were as follows:
’724 9 Non-Infringement
’094 22 Invalidity
’094 23 Invalidity
’094 24 Invalidity
’094 25 Invalidity
’094 27 Non-Infringement
’980 1 Invalidity
’980 2 Invalidity
’980 3 Invalidity
’980 4 Invalidity
’980 5 Invalidity
’980 6 Non-Infringement
’980 16 Invalidity
Below are excerpts from the Order on infringement and
invalidity.
Infringement
A
ligand is a molecule that can bind to a metal ion. (Dkt. 175 at 55.) Ligands
can form different types of bonds with metal ions, such as unidentate,
multidentate, and bridging bonds. (Id. at 52–53.) A multidentate ligand is a
molecule that has at least two atoms which can simultaneously make a bond with
a metal ion. (Id. at 55.) Bidentate bonds are a type of multidentate bond
consisting of two bonds between a ligand and a single metal ion, forming a
“chelate” ring structure. (Id. at 53.) A particular molecule may form a chelate
bond in certain circumstances, but not others. (Dkt. 178 at 126.)
DRL’s
Accused Product contains sodium acetate trihydrate. When placed in aqueous
solution, sodium acetate trihydrate dissociates into sodium, acetate, and
water. (Dkt. 175 at 51.) Acetate is capable of forming a pair of simultaneous
bonds with metal ions. (Id. at 61– 63.) Specifically, under certain
circumstances, the two oxygen atoms in acetate are capable of simultaneously
binding to a metal ion to form a four-membered chelate ring. (Id.)
Numerous
scholarly references from peer-reviewed journals support the conclusion that
acetate can under some circumstances act as a multidentate ligand capable of
forming chelate ring structures. See, e.g.: Ishioka (PTX-260); Sakohara
(PTX-273); Bryant (PTX- 274); Schürmann (PTX-231); Weber (PTX-216); Favas
(PTX-221); Martell (PTX-280); Jia (PTX-230); Deepa (PTX-228); Warthen
(PTX-226); Li (PTX-264); Quilès (PTX-236); Jiang (PTX-272); Feldman (PTX-223);
and Kakihana (PTX-237). These articles demonstrate that acetate can form
chelate rings with metal ions under various experimental conditions, including
in a variety of solvents and temperatures. Acetate-metal chelate rings have
been demonstrated through a variety of experimental detection methods,
including x-ray crystallography, extended x-ray absorption fine structure
spectroscopy, infrared spectroscopy, and Raman spectroscopy. Further, these
chelate rings were detected in various applications of acetate and with a
variety of metal ions, including: (1) zinc chelation used in insulin
formulations; (2) lead chelation used in treatment of lead poisoning; (3) iron
chelation used in fertilizers); (4) gadolinium chelation used in medical
imaging dyes; (5) lanthanum chelation used in medical imaging dyes; (6)
ruthenium chelation used in industrial processes; (7) tungsten chelation used
in preparing electrochromic films; and (8) copper chelation used in fertilizers
and for contaminated pharmaceuticals. That acetate is a multidentate ligand
capable of forming a ring structure with a metal ion under certain
circumstances is further supported by expert testimony from both Helsinn and
DRL.
DRL
submitted some evidence that acetate under some circumstances forms unidentate
bonds. At best, we find that this evidence supports only the conclusion that
acetate forms unidentate bonds in certain circumstances while forming
multidentate bonds in other circumstances.
We
construed the term “chelating agent” to mean a “multidentate ligand that can
form a ring structure by reacting with a metal ion.” Under the second step of
the infringement analysis, Helsinn needed to prove by a preponderance of the
evidence that DRL’s accused palonosetron product contains a chelating agent
under our claim construction. Based on a review of all of the evidence
presented at trial, and as reflected in the findings of fact above, we conclude
that Helsinn proved by a preponderance of the evidence that the acetate present
in DRL’s product is a multidentate ligand that can form a ring structure by
reacting with a metal ion. Accordingly, the Accused Product contains a
“chelating agent,” which the parties have stipulated is the determinative issue
to establish infringement here. We therefore find that DRL’s Accused Product
infringes claim 9 of the ’724 patent, claim 27 of the ’094 patent, and claim 6
of the ’980 patent.
Enablement
Weighing
the relevant Wands factors, we conclude that the totality of this evidence does
not support a finding that undue experimentation would be necessary to practice
the asserted claims. See Wands, 858 F.2d at 737. With respect to factor 4, the
nature of the invention requires shelf-life stability at 18 months (claim 16 of
the ’980 patent) and 24 months (claims 22, 23, 24, and 25 of the ’094 patent and
claims 1, 2, 3, 4, and 5 of the ’980 patent). The asserted claims are broad in
scope as they cover a range of formulations (factor 8). But the ’351
application and Example 4 provide sufficient direction and guidance to teach a
POSA to practice the full scope of the formulations (factors 2 and 3). The ’351
application discloses stable 0.05 mg/mL palonosetron formulations. The ’351
application teaches that formulations with this optimal palonosetron
concentration have the claimed 18-month and 24-month shelf stability. The ’351
application also teaches that specific categories of excipients may be used to
improve upon that stability. Thus, based on the ’351 application, we find that
a POSA would have been able to practice the full scope of the claimed inventions
without extensive experimentation (factor 1). A POSA may need to perform
routine stability studies to confirm that the formulations possessed the
requisite 18-month or 24-month shelf-life stability but such testing does not
rise to the level of undue experimentation.
Written Description
We
have considered the arguments and evidence presented by DRL and the
countervailing arguments and evidence by Helsinn, and find that Helsinn’s
evidence is more persuasive on the matter of written description. The ’351
application discloses to a POSA a range of 0.05 mg/mL palonosetron formulations
that are stable at room temperature for 18 and 24 months. These formulations
include stable embodiments containing 0.05 mg/mL palonosetron and a tonicifying
agent, and 0.05 mg/mL palonosetron and mannitol with the formulation adjusted
to the optimal pH range. We conclude that DRL has failed to meet its burden of
demonstrating, by clear and convincing evidence, that the asserted claims lack
adequate written description of the claimed stability limitation
