On Dec. 12, 2022, Delaware court delivered mixed ruling on infringement and invalidity in a Hatch-Waxman case.

 

Plaintiffs (Ferring / Polypeptide Laboratories) brought infringement action against Defendant (Fresenius) as later filed ANDA with FDA seeking approval to market a generic version of Ferring’s FIRMAGON® product before the expiration of US patents: 9,579,359 (“the ’359 patent”), 10,729,739 (“the ’739 patent”), 10,973,870 (“the ’870 patent”), 9,415,085 (“the ’085 patent”), 10,695,398 (“the ’398 patent”) and 8,828,938 (“the ’938 patent”). The parties stipulated to infringement of claim 10 of the ’938 patent.

 

Infringement:

Side effects patents (‘359, ‘739 & 870 patent)

Fresenius does not dispute direct infringement of the asserted claims of the ’359 and ’739 patents but disputes induced infringement. There are two active steps in the claims of the ’359 and ’739 patents: first, administering
an initial dose of 160-320 mg of degarelix in two subcutaneous injections and, second, administering a maintenance dose of 60-160 mg of degarelix once every 20-36 days thereafter. Fresenius’s proposed label instructs healthcare providers to practice these steps to treat advanced prostate cancer. And administering the steps in the manner called for by the proposed label will result in the reduced likelihood of the side effects claimed by these patents. Moreover, Plaintiffs have shown that Defendant knew that performing the steps in the manner directed by its proposed label would cause the claimed reduction in side effects.

The only dispute about either direct or induced infringement of the asserted claims of the ’870 patent is the presence of the claim element “choosing a dosing regimen of degarelix over gonadotrophin releasing hormone (GnRH) agonist treatment to decrease the likelihood of developing a musculoskeletal disorder or a connective tissue disorder”. Court said that at least some healthcare providers will use the ANDA product in a manner that directly infringes the asserted claims of the ’870 patent. The question of induced infringement of the claims of the ’870 patent turns on whether Fresenius has the specific intent to induce healthcare providers to choose degarelix over a GnRH agonist. Here, Fresenius knew of the ’870 patent and believed degarelix offered “better clinical outcomes” than alternatives. But there is no evidence that Fresenius knew that administration of degarelix would decrease the likelihood of developing a musculoskeletal disorder or a connective tissue disorder compared to GnRH agonist treatment. Moreover, even if Fresenius had known, mere knowledge of potential infringing uses is insufficient to prove inducement. That is particularly true, where, Plaintiffs have not claimed that degarelix is chosen primarily for avoiding musculoskeletal side effects.

CV patents (‘085 & ‘398 patent)

It is acknowledged that it is generally known that there is an increased risk of cardiovascular events with GnRH agonist treatment compared to degarelix and likely that at least some physicians who are aware of that increased risk would be motivated to choose an degarelix to treat certain patients. The dispute as to inducing infringement of the CV patents centers on the claim language “selecting a subject with a history of at least one cardiovascular event and prostate cancer”. Plaintiffs argue that Fresenius will induce infringement of these claims because Fresenius’s
proposed label does not contain a warning about cardiovascular risk whereas GnRH agonists do contain such a warning. Combining this with healthcare providers’ knowledge about the cardiovascular risk attendant to treating prostate cancer with GnRH agonists and antagonists, Plaintiffs assert that the absence of a warning will encourage healthcare providers to use the ANDA product to infringe the asserted claims of the CV patents. Court said that there is simply no evidence that Defendant has the specific intent to induce infringement of the claims of the CV patents. The clinical trials section of Fresenius’s package insert does not discuss or disclose any of the cardiovascular events specified in the claims (i.e., myocardial infarction, ischemic heart disease, ischemic stroke, hemorrhagic stroke, and other arterial thrombotic/embolic events). That healthcare providers might perceive the absence of a warning as an indication of its relatively safe cardiovascular risk profile is of little consequence. Ultimately, based on the evidence presented, the Court cannot infer specific intent to induce infringement of the claims of the CV patents.

 

Invalidity:

Defendant contends that all of the asserted claims are invalid as anticipated or obvious in light of the prior art or not enabled. Defendant argues that the asserted claims of the ’359 and ’739 patents are obvious in light of Doehn and WO ’049. Court held that it was obvious to split the initiation dose into two injections and the claimed reduction in likelihood of side effects is the natural result of administering degarelix.

With respect to ‘870 patent, court said that Doehn would not have provided one of skill in the art with motivation to choose degarelix over a GnRH agonist to avoid musculoskeletal or connective tissue disorders when treating locally advanced prostate cancer. Accordingly, a POSA would not be taught the “choosing” limitation. As all of the asserted claims of the ’870 patent include this limitation, Fresenius has failed to prove that any asserted claim of the ’870 patent is obvious.

With respect to enablement of side effect patents, court held that Fresenius has failed to prove that a POSA would have to engage in undue experimentation to determine whether the full range of initiation doses and of maintenance doses work because the prior art discloses that they did. Defendant’s expert never addressed the quantity of experimentation necessary, the disclosures in the prior art involving doses within the ranges or the predictability or unpredictability of finding doses that work.

With respect to obviousness of CV patents, court held that in light of the actual teachings of the prior art, it is apparent that Defendant’s obviousness argument is based on improper hindsight. At the relevant time, a POSA having read each paper would not have been taught that a relationship between GnRH agonist treatment and
cardiovascular health exists. Instead, a POSA would have believed that such a relationship might or might not exist and more work had to be done. A glimmer of an idea is not a teaching and more is required for obviousness.

With respect to ‘938 patent, court said that a POSA would not have had a reasonable expectation of success in using Fmoc-SPPS for the manufacture of degarelix with 0.3% or less of the hydantoin impurity. Defendant’s arguments suffer from significant and improper hindsight bias. Moreover, at least some of the secondary considerations asserted by Plaintiffs further support the finding of non-obviousness.

 

Conclusion:

(1) Ferring has proved that Fresenius will induce infringement of claims 3 and 13 of the ’359 patent and claims 16 and 26 of the ’739 patent and that Fresenius infringes claim 10 of the ’938 patent;                                                      (2) Ferring has not proved that Fresenius will induce infringement of any of claims 3, 5, 8 and 14 of the ’870 patent, claim 2 of the ’085 patent and claim 2 of the ’398 patent;                                                                                             (3) Fresenius has proved that claims 3 and 13 of the ’359 patent and claims 16 and 26 of the ’739 patent are invalid for obviousness;                                                                                                                                                              (4) Fresenius has not proved that any of claims 3, 5, 8 and 14 of the ’870 patent, claim 2 of the ’085 patent, claim 2 of the ’398 patent and claim 10 of the ’938 patent are invalid.