On Nov. 30, 2020, Delaware court found composition patent covering
combination invalid as obvious & not infringing.
Background of the
case:
Plaintiffs (Horizon) owns NDA for DUEXIS® (ibuprofen and
famotidine) tablets, 800 mg / 26.6 mg. It is indicated for the relief of signs
and symptoms of rheumatoid arthritis and osteoarthritis and to decrease the
risk of developing upper gastrointestinal ulcers in patients who are taking
ibuprofen for those indications. Defendant (Alkem) submitted ANDA on March 31,
2018 seeking USFDA approval to market generic version. Horizon sued Alkem in district
of Delaware for infringement of OB listed patents, such as U.S. Patent Nos.
8,309,127, 8,318,202, 8,449,910, 8,501,228 & 8,067,033. By trial the
parties narrowed the case to US’033 patent only.
The asserted patent is directed to stable pharmaceutical
compositions of famotidine and ibuprofen separated by way of barrier layer in a
single dosage form. Independent claim 1
is:
1. A pharmaceutical
composition comprising a first portion
that comprises 800 mg ibuprofen and a second
portion that comprises 26.6 mg famotidine, wherein the surface area of
direct physical contact between ibuprofen and famotidine does not exceed 130
mm2 , wherein no more than about 1% sulfamide is present when the
composition is stored at 40° C. and 75% relative humidity for a period of one
month, wherein the composition is formulated so that release of both the
ibuprofen and the famotidine occurs rapidly at about the same time, wherein
none of the composition, the famotidine, and the ibuprofen is enterically
coated or formulated for sustained or delayed release, and wherein the
composition is for use according to a TID (three times per day) administration
schedule for reducing 4 the risk of developing ibuprofen-induced ulcers in a
human patient requiring ibuprofen for an ibuprofen-responsive condition.
It was known that Ibuprofen (NSAID) causes ulceration when
used in the treatment. Therefore search was carried out to prevent this side
effects. Famotidine is a gastroprotectant which helps to reduce this side
effect. But both these two active ingredients are not compatible when used
together. Therefore, plaintiff come with the dosage form where these two actives
are separated, such as tablet in tablet dosage form. By doing this the
interaction between these two actives was avoided, thus reducing the impurity
formation & providing stable product with no or less side effects.
Obviousness:
Defendant argued that asserted claims are invalid as obvious
over certain prior arts. These prior arts disclosed claimed limitations such as
combination of actives, their dose, their interaction & formation of
impurity etc. One of them was US
2007/0043096, where dispute arose to determine whether it is a prior art under
102(a). [US’096 discloses unit dosage
form comprising ibuprofen & famotidine, in amounts suitable for three times
per day administration.] The
priority date of the US’033 patent is Nov. 2007. US’096 application was
published in Feb. 2007. Defendant argued that US’096 is “by another” as it
mentioned different inventors than the US’033. Plaintiff argued that it is not “by
another” because the inventive idea was conceived by same inventors mentioned
on both US’033 patent & US’096 application. Court, however disagreed &
said that claimed limitation regarding stability was not conceived by these
same inventors. It was a work from other inventor & therefore it is a prior
art under 102(a). Other prior arts disclosed other claimed limitations such as
impurity level, rapid dissolution, reduction of risk of ulcer etc. Plaintiff argued that there was not motivation
& reasonable expectation of success in combining these prior arts. But, district
court disagreed & said that POSA would have reasonable expectation of success
in doing so because most of things were
known in the art with rational behind that.
Indefiniteness:
Defendant argued that the “no more than about 1% sulfamide”
limitation is indefinite because scope of the invention in not clear to POSA.
Defendant argued that the ’033 patent does not define “sulfamide,” provides no
chemical name, structure or specific method of testing for “sulfamide,” does
not refer to the USP or Famotidine Impurity C, and does not provide any method
for identifying or quantifying “sulfamide” in a composition. Court, however,
disagreed & said that a POSA would understand “sulfamide” in the “no more
than about 1% sulfamide” limitation in all the asserted claims to be USP
Famotidine Impurity C. US’033 patent
explains that “sulfamide” is “a principal degradant of famotidine formed by the
interaction of famotidine and ibuprofen.” Therefore, “a POSA would have
understood that ‘sulfamide’ in the ’033 patent does not refer to the small
molecule sulfamide, but instead means Famotidine Impurity C in the USP because
it is the only known principal degradant that contains a sulfamide functional
group and that is formed as a result of the acid-catalyzed hydrolysis of
famotidine.”
Infringement:
Plaintiff argued that Alkem’s ANDA Product infringes the
asserted claims under DOE. Court’s construed - “a first portion” as reciting
“an ibuprofen compartment that is not a core” and “a second portion” as
reciting “a famotidine compartment that is not a shell”. Plaintiff applied DOE theory
to more than one claim element — “a first portion” and “a second portion” — at
the same time. Court said that Plaintiff was specifically instructed at trial
to provide legal support for this, which seemingly contradicts applying DOE on
an element-by-element basis, not to the invention as a whole. Court found DOE theory
inapplicable here but still proceeded with the analysis.
Alkem’s ANDA Product is a tablet-in-tablet dosage form with
a barrier-coated ibuprofen (800 mg) core portion and a famotidine (26.6 mg)
shell portion; on the other hand, the claimed composition required a famotidine
(26.6 mg) core and an ibuprofen (800 mg) shell, with an optional barrier layer.
Defendant argued the difference in design is not trivial stating that Alkem’s
ANDA Product is substantially different in at least two important ways –
stability and dissolution. In terms of stability, Alkem contended that the
asserted claims rely on the geometry of the small famotidine core to reduce
and/or minimize “the surface area of the core, or of direct physical contact
between the incompatible active pharmaceutical ingredients.” Moreover, a
barrier layer is optional in claimed invention due to the design of the
invention. This is not the case with defendant’s product. Court said that the inventive aspect of the
’033 patent is a stable pharmaceutical composition of famotidine and ibuprofen
in a single unit dosage form comprising a famotidine core, having a reduced or
minimal surface area, surrounded by a layer of ibuprofen. The specification
repeatedly highlights the increased stability provided by the disclosed
geometry. Unlike the pharmaceutical composition of the asserted claims,
Defendant’s ANDA Product must use a barrier layer and cannot rely on the
geometry of a small famotidine core. Therefore, in regard to stability,
Defendant’s ANDA Product is substantially different as geometry contributes
nothing to stability.
In terms of dissolution, Defendant argued that its ANDA
Product is substantially different from the claims. Defendant argued that when
DUEXIS® (commercial embodiment of the ’033 patent) is exposed to the
dissolution medium, the ibuprofen begins to dissolve from the shell immediately
and the famotidine does not begin to significantly dissolve until the
dissolution medium further penetrates into the core (i.e., about five minutes
later). When Alkem’s ANDA Product is exposed to the dissolution medium, the
famotidine begins to dissolve from the shell immediately and the ibuprofen does
not begin to significantly dissolve until the dissolution medium further
penetrates into the core (i.e., about fifteen minutes later). Court said that,
Defendant’s arguments are not as strong. While there is a discernable difference
in the release of the ibuprofen and famotidine in Defendant’s ANDA Product
occurring about fifteen minutes later than in DUEXIS®, the later release still
meets the claim limitation of “release of both the ibuprofen and the famotidine
occurring rapidly at about the same time” when “at about the same time” is
defined as the ‘033 patent specification defines it: “release of one API begins
before release of the second API is completed.”
Under “Function-Way-Result” test, Court agreed with
Defendant & said that the ’033 patent specification teaches the use of
geometry, with the option of a barrier layer. Moreover, using the design of the
present invention, the barrier layer can be omitted without sacrificing
stability. Under this view of the “function-way-result” test, while the
function and the result may be substantially the same, the way is not. The way
does not use geometry at all. As Alkem’s ANDA Product requires a barrier layer
as a consequence of its geometrical design, it does not infringe under the
“function-way-result” test.