Infliximab - Canada

On Mar 07, 2018, Federal court of Canada found patent covering use of Infliximab & Methotrexate valid & infringed by Hospira.

The trial concerned the validity of Canadian Patent No. 2,261,630 [the 630 Patent] which essentially details the adjunctive use of methotrexate [MTX] and the anti-tumour necrosis factor-α [anti-TNF-α] antibody “infliximab” for the treatment of rheumatoid arthritis [RA] and other autoimmune diseases. The Plaintiff in this action is Hospira Healthcare Corporation [Hospira], an interested party under s 60(1) of the Patent Act, RSC 1985, c P-4. Hospira markets, uses, and sells the biosimilar infliximab in Canada under the commercial name Inflectra as a treatment for RA. The Defendant in this action is the Kennedy Trust for Rheumatology Research [Kennedy]. 

INVALIDATION

With respect to common general knowledge court said that the literature and the expert evidence clearly established that MTX was a popular treatment option for severe RA and that it was one of the more popular, if not the most popular, DMARD for treating severe RA.  In terms of anti-TNF-α and other biologics, the efficacy of infliximab was part of the common general knowledge due to the publication of the Elliott studies in 1994 and 1995. The literature of the time however, does not disclose a consensus with respect to the benefit of combination therapy. The weight of the evidence, Strand notwithstanding, was that it was impossible to predict the outcome of a clinical trial of a novel therapy in RA, especially until attempted in humans. The common general knowledge, as described, pointed away from what was claimed in the 630 Patent.

Novelty:

Court held that Hospira took an improper approach in its anticipation arguments. Hospira sought to assemble an “anticipatory mosaic” by arguing that one piece of prior art should be read in conjunction with a second piece of prior art that is cited in the first. This is an incorrect approach that ignores the emphasis on a single reference. Further, it would be absolutely remarkable if all of the allegedly anticipatory documents actually anticipated the invention disclosed in the 630 Patent. The evidence does not support that conclusion & none of the allegedly anticipatory documents anticipate the invention disclosed by the 630 Patent.

Obviousness:

Hospira claimed that the 630 Patent was obvious or at least obvious to try. It contended many things but principally that the inventors had an easy time coming up with the invention because “everyone knew” it would work. Although it may have been reasonable, based on the state of the art, to carry out the combination trials that led to this invention, it was not obvious to do so. A number of potential biologic targets had been identified, and a number of methods of dealing with HACA responses had also been identified – therefore, it was not clear that anti-TNF-α was an appropriate target. It was also not clear what should be done to deal with the shortened duration of response/HACA responses that had been identified in the prior art. There was no indication in the prior art that this combination was to be preferred or that it would work to solve the problems identified. Although the POSITA may have had “good reason” to pursue the combination of anti-TNF-α and MTX, it was not self-evident that this combination would work to solve the problem identified in the prior art (i.e., shortened duration of response). Finally, although there was a great deal of motivation to develop a new treatment for RA, it is clear from the literature that this motivation was being pursued in a number of different ways (i.e., trials of different biologics, the majority of which failed). Therefore, the Court concluded that the invention was not obvious to try.

Double Patenting:

The issue was whether the invention disclosed by the 630 Patent should have been included in Canadian Patent No. 2,146,647 [the 647 Patent], which expired in 2013. The 647 Patent indicated that other anti-inflammatory drugs (such as MTX) could be administered in conjunction with the anti-CD4 antibody or the anti-TNF antibody. Hospira argued the 647 Patent could have and should have included the subject matter of the Claims in the 630 Patent. In addition, “[i]f the Claims are construed to cover the administration of anti-TNF-α antibodies to patients receiving MTX along with other DMARDs and/or antibodies, the claims are not patentably distinct from the claims of the ‘647 Patent”. The 647 Patent concerns use of anti-CD4 antibody in conjunction with an anti-tumour necrosis factor antibody for the manufacture of a therapeutic formulation. Court after analyzing the facts concluded that Hospira has not established that an entirely different combination, MTX and anti-TNF-α, ought to have been included in this patent. Further, the two inventions are “patentably distinct” – not only do the patents disclose different combinations, but the 647 Patent discloses a biologic-biologic combination and the 630 Patent discloses a biologic-DMARD combination. Therefore Hospira’s obviousness-type double patenting attack is not sustainable.

Sufficiency:

Hospira’s position was that the 630 Patent is insufficient because the POSITA would not have been able to practice the invention as of February 12, 1998. Hospira submitted that the claims are insufficient because “[t]he disclosure of the ‘630 Patent does not disclose how to perform adjunctive therapy with anti-TNF-α monoclonal antibodies with methotrexate at a dosage or timing of administration over the scope of the claims so as to achieve the Promised Utility”. Court held that Hospira’s argument with respect to sufficiency is tied to its view of the “promised utility”. Given the recent Supreme Court of Canada decision in AstraZeneca Canada Inc v Apotex Inc, 2017 SCC 36, [2017] 1 SCR 943 [AstraZeneca] and the rejection of the “promise of the patent”, Hospira’s argument with respect to sufficiency is based on a shaky foundation. Hospira has not led any evidence that would tend to establish that the 630 Patent is insufficient. Its own experts acknowledge that there is nothing unique or inventive in the way infliximab and MTX have at all times been commercially available. The doses of infliximab and MTX as well as the dosing regimens are disclosed in the Examples.

INFRINGEMENT

Kennedy submitted at trial that the Asserted Claims, Claims 1-3, 5, 6, 9, 10-12, 15, 17-19, 21, 22, 25, 26, 28, 31, 33, and 39-42, are infringed. Hospira was alleged to have infringed the Asserted Claims by making Inflectra and selling it in Canada for the treatment of RA. Kennedy asserted that the only difference between Hospira’s infliximab and Kennedy’s infliximab is that Hospira’s infliximab has a single additional amino acid at the C-terminal (the non-binding end of the antibody). This is cleaved instantaneously in vivo. Kennedy submitted that the POSITA would have known, in 1998, that this additional amino acid “could not impact the antibody’s ability to bind to TNFα and impede binding to TNFα receptors”. Relying on Di Battista’s evidence with respect to glycosylation, Kennedy submitted that there is “no material difference between the amounts and types of glycosylation structures present in Hospira’s infliximab and those present on the infliximab described in the 630 Patent”. Further, there are detectible glycosylation differences even within samples of Hospira’s infliximab because of microheterogeneity.

Even if the court construes the asserted claims to include the combination of a TNF-α antibody and MTX, Hospira claimed that it has not infringed the asserted claims because there is no evidence that Hospira marketed or sold the combination of MTX and Inflectra. Infringement of a combination requires “a taking of the entire combination, i.e. a taking of all the essential elements of the combination as claimed”. Hospira submitted that as the Swiss-type claims refer to the manufacture of a medicament and Inflectra is not made in Canada and is not sold to Hospira in Canada, the Swiss-type claims are not infringed. Further, the pharmaceutical composition claims cannot be infringed for the same reason.

Court held that on a balance of probabilities, Inflectra is to be used for treatment of MTX incomplete responders. At this time, it is only necessary for the Court to conclude that Inflectra is used in MTX incomplete responders – the extent to which Inflectra is used in MTX incomplete responders is a question best left to the damages phase of this litigation. However, the reimbursement criteria and the IMS data indicate that at least some of the patients receiving Inflectra are MTX incomplete responders. That is sufficient for this infringement analysis. Although Inflectra may be produced for use in treating diseases other than RA, this does not establish that it is not produced for use in treating RA. Therefore on a balance of probabilities, that Inflectra is produced for the treatment of RA in combination with MTX. Thus Hospira has infringed the 630 Patent.