Friday, April 29, 2022

Arbitrary Selection?

Merck Sharp & Dohme Corp v Pharmascience Inc 2022 FC 417 Furlanetto J

            2,529,400 / sitagliptin phosphate salt form / JANUVIA / NOC

The key claim at issue in Merck’s 400 patent, Claim 4, is to the crystalline monohydrate form of the dihydrogenphosphate [DHP] salt of sitagliptin, which is used to treat type 2 diabetes [1], [12]. The closest prior art is PCT application WO 03/004498, which disclosed a genus of compounds, specifically exemplifying sitagliptin, among other compounds, both as a free base and hydrochloride salt [11]. The crystalline monohydrate DHP salt was evidently not specifically disclosed.

Pharmascience argued that the 400 Patent is invalid for obviousness and/or insufficiency [3], [64]. The insufficiency attack was a straightforward “how to make” argument, alleging that the disclosed process details were not sufficient to allow a skilled person to make the crystalline monohydrate [255]. This attack failed on the facts: [277–78].

The more interesting attack was obviousness. Given that sitagliptin was specifically disclosed in WO498, the inventive step lay in selecting sitagliptin as the lead compound from the other compounds, or in selecting the salt form, or in the combination of those decisions. As I see it—and this is not the way Pharmascience expressed it—the basic case for obviousness is that Merck just chose sitagliptin arbitrarily from the compounds disclosed in WO498, then did more or less routine salt screening to come up with a salt form with reasonable stability and manufacturing properties.

Suppose a genus patent discloses a class of compounds as having certain useful properties, such as utility in treating diabetes. There is no invention in picking one compound at random from the genus and showing that it is useful in treating diabetes; the genus patent told of us that all members of the genus are useful for that purpose, and the compound is a member of the genus, so of course it is useful in treating diabetes. This is known in European law as an “arbitrary selection”: see Dr Reddy's [2009] EWCA Civ 1362 [44]–[52]; and see Actavis v ICOS [2019] UKSC 15 discussed here. While the term “arbitrary selection” is not as commonly used in Canadian law, the same principle has been recognized in Canadian law: see Teva v Janssen 2018 FC 754 [198], Locke J, expressly noting that arbitrariness is not inventive; Millennium v Teva 2019 FCA 273, applying the principle; Janssen v Teva 2015 FC 247, also applying the principle. This is why a selection must have some special property over what is already known about the genus: this is not a matter of special rules applicable to selection patents, but simply a reflection of the fact that if the selected compound has no advantage, then it is not inventive to select it. Supose I hand you a bag, saying “This is full of red rocks” and I pull out a handful of rust-coloured pebbles of various shapes and sizes to show you. If you reach into the bag yourself and pull out another rusty pebble, no one will be surprised. Now, I can’t predict in advance exactly which rusty pebble you will take from the 100s in the bag—precisely because the selection is arbitrary. An arbitrary selection is both uninventive and unpredictable at the same time.

I don’t see much in Furlanetto J’s decision to suggest that the selection of sitagliptin was anything other than arbitrary. She states:

[203] The evidence indicates that the [skilled person] would not have any specific motivation arising from WO498 to focus on the particular crystalline form of a salt of sitagliptin over the other compounds disclosed within WO498.

But an arbitrary selection is exactly one where there is no particular motivation to pick the compound over the other compounds of the genus, precisely because one is as good as the other.

Furlanetto J also noted that “In June 2003, the only publication on sitagliptin was WO498. There was no indication as to its activity, efficacy, toxicity or tolerability. Further, the general level of potency reported in WO498 indicated a level of potency that was 45 to 167 times less than [another compound known in the prior art]" [210]. This was generally in a support of a “teaching away” argument. But teaching away is evidence of non-obviousness when the compound that was disparaged is subsequently discovered to have exceptional properties. I don’t see anything to that effect in Furlanetto J’s discussion.

Furlanetto J concluded

[212] There is no evidence that the PSA would be drawn to sitagliptin as a starting point for further development. On the basis of the prior art, it cannot be concluded that there was motivation for anyone other than Merck to move forward with sitagliptin as a lead compound.

Again, this is consistent with saying that Merck selected sitagliptin arbitrarily.

I’m not saying that the selection was arbitrary; only that the decision doesn’t identify this possibility and explain why it’s not. I think part of the reason for this is the focus on the inventive concept. Of course, the Windsurfing / Polozzi framework invites us to identify the inventive concept, but it is now recognized that this can be treacherous, with the FCA having wrestled with the question of whether a focus on the inventive concept is unhelpful, helpful or necessary: see here, here and here. This is a context where it seems to have been unhelpful. Pharmascience argued that “the choice of sitagliptin as the starting point does not form part of the inventive concept” [207]. Once we decide that it is, the question becomes whether that was obvious, and that leads to the asking whether it was predictable, which, in my view, is the wrong question.

The question might have been addressed with an objective problem-and-solution approach, in which case the issue of arbitrary selection would have been addressed in identifying the objective problem. Or it might have been addressed simply by asking is whether there was an inventive step involved in choosing sitagliptin.

There is also the old IG Farbenindustrie (1930) 47 RPC 289 (Ch) in Sanofi 2008 SCC 61 [10]–[11] approach to selection patents. Furlanetto J had a fairly long discussion of whether the claimed invention was a “selection patent” over WO498 invention of [77]–[95]. While she recognized that the validity requirements are the same either way, she expressed the view that this assists the Court “in understanding ‘the nature of the beast’” and makes it “easier to compare the facts of the particular case before the court with other previous fact scenarios” [80]. Ultimately she decided that it was a selection, but this doesn’t seem to have played any important role in the obviousness analysis.

In particular, she didn’t mention the IG Farben factors. There is good reason for this omission. The IG Farben factors have fallen out of favour, for two main reasons. First, as Rennie JA pointed out in Apotex v Shire 2021 FCA 52 [32] “A selection patent is subject to the same requirements and vulnerable to the same attacks as any other patent, including attacks based on anticipation and obviousness.” The IG Farben factors must therefore either be duplicative of standard grounds of attack, or wrong. And, as discussed here, the second and third IG Farben factors are arguably wrong, or at least problematic—though these factors were rarely if ever actually used to strike down a patent.

So there are good reasons to avoid the IG Farben approach. With that said, there is a reason the IG Farben factors were used for so long. It is the first factor that was almost always the crux of the analysis:

1. There must be a substantial advantage to be secured or disadvantage to be avoided by the use of the selected members.

This factor is a convenient way of expressing the inventive step requirement in the context of selection patents. It directly addresses the problem of arbitrary selection. As just discussed, if an entire genus has certain properties, it is obvious that any member of the genus will also have those properties. There is no invention in reaching into the bag of rocks and pulling out a rusty pebble; but if you rummage around and pull out a ruby, to everyone’s astonishment, that deserves a reward. The “advantage to be secured or disadvantage to be avoided” is the extra ingredient ensures the patentee has extracted a ruby from the bag, and not another red rock.

So, while the first factor is strictly redundant, in the sense that it simply encapsulates the inventive step requirement, it nonetheless poses that requirement in the context of selection patents in a way that is perhaps more helpful than the Windsurfing / Pozzoli focus on the inventive concept.

There seems to be more of a case that the development of the crystalline monohydrate form of the DHP salt was inventive, as there was a significant amount of work involved. But it seems that it was routine to develop the DHP salt [226]–[229], which was suitable for tableting. Developing the particular crystalline monohydrate form was challenging, but it is not clear to me that it offered significant advantages over the DHP. What was the problem solved by the crystalline monohydrate? It was difficult to develop, but if it did not solve any problem, in what way was it inventive? I have to admit that I came away with the nagging feeling that the inventors developed the DHP salt, and its properties were just fine, but they kept on going to develop something more difficult, just because they knew that the routine work to develop the DHP salt would not support a patent. There’s nothing in the decision that I can point at to support that notion, but I don’t see anything to rule it out, either. If that’s right, this is different from arbitrary selection, since the crystalline monohydrate was difficult to develop, but it’s still not clear to me that it’s inventive. Arbitrary selection is reaching into the bag and extracting a random rock that has the same properties as the others that were already known; inventive selection is rummaging painstakingly through the bag to find the single ruby; developing the crystalline monohydrate seems to have been like rummaging painstakingly through the bag to find the rusty rock that is most nearly spherical, even though being spherical offers no practical advantage over any other shape. One may at least question whether that is deserving of a patent.

Ultimately, even accepting all of Furlanetto J’s factual findings, I am having difficulty putting my finger on the inventive step in this invention. Assuming I’m not just missing the something, this strikes me as problematic. We need a doctrinal framework to guide the analysis, but in the end, a good framework should do more than simply generate an answer—it should help us understand the nature of the contribution that deserves the reward of a patent. I don’t see anything specifically wrong doctrinally with Furlanetto J’s analysis, and I suspect that ultimately my difficulty lies with the way the problem has been framed, with the focus on identifying the inventive concept.

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