Icatibant - USA

On Jun 05, 2018, Delaware district court held that the asserted claims of the patent-in-suit are not invalid under the doctrine of obviousness-type double patenting or prosecution laches in FIRAZYR® Hatch-Waxman litigation.

In this patent infringement action, Shire and Sanofi-Aventis ("Plaintiffs") alleged that Fresenius Kabi USA, LLC, ("Defendant") filed an ANDA with USFDA to manufacture and sell a generic version of FIRAZYR® (icatibant acetate) prior to the expiration of U.S. Patent No. 5,648,333. FIRAZYR® Injection is used for the treatment of acute attacks of hereditary angioedema ("HAE") in adults 18 years of age and older. The court held a four-day bench trial in this matter beginning on January 29, 2018. Plaintiffs have asserted Claim 14 of the '333 Patent. Claim 14 of the '333 Patent claims:

A peptide of the formula H-D-Arg-Arg-Pro-Hyp-Gly-Thia-Ser-D-Tic-Oic-Arg-OH or a physiologically tolerable salt of said peptide.

Fresenius asserted that claims are invalid under the doctrine of obviousness-type double patenting ("OTDP") in light of the prior arts including, U.S. Patent No. 5,597,803 & under prosecution Laches.

Obviousness-Type Double Patenting:

The obviousness-type double patenting analysis hinges on whether (1) the removal of the N-terminal modification Fmoc from the peptides of Claim 1 of the '803 Patent results in Claim 14 of the '333 Patent; and (2) whether the N-terminal modifications in the '803 Patent are intended to be permanent and integral components of the final peptide. Claim 14 of the '333 Patent claims a single ten-amino acid peptide known as icatibant and relates to "Peptides Having Bradykinin Antagonist Action." In contrast, the '803 Patent relates to "Bradykinin Peptides with Modifications at the N-Terminus" and covers Fmoc-icatibant. Because Claim 1 of the '803 Patent allows for modifications in the peptide sequence at two positions, the court found that the claims themselves are different under step one of the analysis even though they share some inventors and are assigned to the same company.

Court next considered step 2 inquiry whether the differences in subject matter of the two patents render the claims patentably distinct-i.e., the later claim is not obvious over or anticipated by an earlier claim. In arguing that the claims are not patentably distinct, Defendant made three primary arguments. First, Defendant argued that the only difference between Claim 1 of the '803 Patent and Claim 14 of the '333 Patent is the presence or absence of the extra N-protecting groups-the Z and P groups. Second, Defendant argued that the only difference between Fmoc-icatibant and icatibant is the presence of Fmoc.  Third, Defendant argued it presented clear and convincing evidence demonstrating that a POSA would have been motivated to remove the Fmoc and that they would have had a reasonable expectation that the resulting peptide would be a bradykinin antagonist. 

The court found that persons having ordinary skill in the art would not have removed Fmoc based on the patent itself and the prior art. As of 1989, it was known that the addition of N-terminal modifications could confer significant benefits to the resulting peptide, including reduction of side effects and resistance to enzymatic degradation. Finally, the court found that, contrary to Defendant's assertion, every example of a peptide of formula I contains Z and every peptide evaluated for biological activity has a Z group. The court, therefore, held that a POSA in 1989 using Claim 1 of the '803 Patent as a starting point, would not have been motivated to remove the N-terminal modifications from the peptides of Claim 1 of the '803 patent to result in Claim 14 of the '333 Patent.

Defendant next argued that a POSA would understand that Claim 14 of the '333 Patent does not recite any biological activity and that and Claim 1 of the '803 Patent recites biological activity but does not require it. Specifically, Defendant asserted that the POSA would have reasonably expected the icatibant peptide remaining after Fmoc removal would be a bradykinin antagonist based on its structure and the icatibant peptide would be consistent with the prior art Stewart SAR Data. In contrast, Plaintiffs asserted that Claim 14 of the '333 Patent concerns bradykinin antagonist activity because, among other reasons, every example in the '333 Patent is a bradykinin antagonist. Court held that the specification of the '803 patent contemplates two different functional roles for Fmoc: (1) a protecting group used during synthesis that is removed from a peptide under construction, meaning while that peptide is attached to the resin or still has side chain protective groups, or both; or (2) an integral component of the final peptide product. Therefore, the peptides in the '803 Patent are not under construction and are, therefore, not intermediates. That distinction would have instructed the POSA that the modification was permanent, and would not have motivated the POSA to remove Fmoc.

The court, also considered secondary consideration thought prima facie case of obviousness was not established. Court found that the secondary considerations weigh against a finding of obviousness-type double patenting.

Prosecution Laches:

"The doctrine [of prosecution laches] 'may render a patent unenforceable when it has issued only after an unreasonable and unexplained delay in prosecution' that constitutes an egregious misuse of the statutory patent system under the totality of the circumstances." It also requires a showing of prejudice, which in turn requires "evidence of intervening rights, i.e., that either the accused infringer or others invested in, worked on, or used the claimed technology during the period of delay." The '333 Patent issued from U.S. Patent Application 08/487,442 ("the '442 Application"), which was filed on June 7, 1995. The '442 Application claims priority to five German patent applications and ten U.S. patent applications.

Defendant primarily argued that Plaintiffs' four year delay in prosecuting the patent between 1991 and 1995 was unreasonable and unexplained because, during that time, applicants failed to provide a substantive response to the PTO. Specifically, Defendant asserted that Plaintiffs failed to provide the Patent Office with the in vivo data requested to support utility of the '162 application and, instead, argued the in vitro data was sufficient, which delayed prosecution. Defendant argued Plaintiffs had the in vivo data related to icatibant, as early as March 1989 prior to the original '162 application filing date.

Court held that "there are legitimate grounds for refiling a patent application which should not normally be grounds for a holding of laches, and the doctrine should be used sparingly lest statutory provisions be unjustifiably vitiated." The filing of multiple continuing applications is not per se unreasonable. Novozymes AIS v. Genencor Int'!, Inc., 446 F. Supp. 2d 297, 333-34 (D. Del. 2006). In the instant case, the court found Plaintiffs actively prosecuted without an unreasonable or unexplained delay. The '333 Patent resulted from German priority and U.S. applications of three distinct inventions. In addition to the evidence adduced at trial, prosecution laches has not been applied to an alleged four-year-delay. The court, therefore, found that Defendant did not establish by clear and convincing evidence that there was an unreasonable and unexplained delay in the prosecution of the '333 Patent. Thus, Claim 14 of the '333 Patent is not invalid under the doctrine of prosecution laches.