Ibuprofen & Famotidine – USA

 

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.