Patents - Sandoz Ltd v Bristol-Myers Squibb

 

Jane Lambert

Patents Court (Mr Justice Meade) Sandoz Ltd and another v Bristol-Myers Squibb Holdings Ireland (Unlimited) Company  [2022] EWHC 822 (Pat) (7 April 2022)

These were two separate actions for the revocation of a European patent (UK)  1 427 415 B1 (“the patent”).  The patent was held by Bristol-Myers Squibb Holdings Ireland (Unlimited) Company ("BMS") and the proceedings were brought by Sandoz Limited (“Sandoz”) and  Teva Pharmaceutical Industries Limited (“Teva”). BMS counterclaimed against both claimants for infringement which was admitted subject to the validity of the patent. The actions came on for trial before Mr Justice Mrade between 31 Jan and 10 Feb 2022.  By para [257] of his judgment of 7 April 2022 he held that the patent was invalid for lack of plausibility and technical contribution (see Sandoz Ltd v Bristol-Myers Squib Holdings Ireland (Unlimited) Company [2022] EWHC 822 (Pat) (7 April 2022)).

The Patent

The patent was granted for "Lactam-containing compounds and derivatives thereof as factor Xa inhibitors." "Lactam" combines the words "lactone" and "amide". It is a cyclic amide, formally derived from an amino alkanoic acid.  The abstract describes the invention as "lactam-containing compounds and derivatives thereof of Formula I: P4-P-M-M4 or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle." It adds that compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa. The judge discussed the teaching of the patent between para [112] of his judgment and para [147].

Claim 1 was for

“1. A compound, which is represented by formula (1):

or a pharmaceutically acceptable salt thereof.” The judge noted that that was apixaban.   Claim 2 was for "a compound according to claim 1, which is represented by the formula (1).” Claim 7 was for a "compound of claim 1 and 2 for use in treating a thromboembolic disorder.”

Alleged Invalidity

Both claimants alleged that the patent was bad for lack of plausibility.  As the learned judge observed in para [10.2] of his judgment:

"Lack of plausibility is not a ground for revocation in itself and it was run both as Agrevo obviousness and insufficiency. Neither side said it made a difference which head applies, and I agree in the light of the case law to which I refer below, in particular Warner-Lambert and Fibrogen." 

Consequently, he repeatedly used the term "lack of plausibility." in his judgment.

The claimants also alleged that the patent in suit was obvious over WO 00/39131 “Nitrogen Containing Heterobicycles as Factor Xa Inhibitors”.  However, as his lordship explained at para [10.3]:

"This was not a 'classical' obviousness attack: the Claimants do not say it was positively obvious to get to apixaban specifically from `131. Rather, they said that `131 contains very similar teaching to `652 about broad classes of compounds that include apixaban, and that there is no technical contribution in `652 over what `131 discloses."

An additional argument that Teva raised was that claims 1-6 exceeded the technical contribution of the patent and that in particular, the claims to products per se were invalid even if their usefulness was plausible. 

Plausibility

S.72 (1) of the Patents Act 1972 provides several grounds on which a patent may be revoked.  One is that "the invention is not a patentable invention" (s.72 (1) (a)). Another is that "the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art" (s.72 (1) (c)).  S.1 (1) of the Act sets out several conditions for the grant of a patent one of which is that "it involves an inventive step."

The meaning of the term "inventive step" was considered by the Technical Board of Appeal in T 939/92 Agrevo/Triazoles.  Mr Justice Meade quoted long passages of the decision between paras [2.4] and [2.6].  He summarized the Board's conclusion in para [29] of his judgment:

"Thus the key reasoning was that about compounds for which utility was not credible (we would now say plausible), the only technical contribution is providing other compounds, and that cannot be inventive. In an ordinary sense one might say there was no reason to make any particular such other compound, but against the background of the non-solution of any problem there is a minimal reason which is good enough. I think the decision can be summed up by the sentence in 2.5.3 that 'the selection of such compounds must not be arbitrary but must be justified by a hitherto unknown technical effect which is caused by those structural features which distinguish the claimed compounds …'”.

The learned judge then considered the Supreme Court;s decision in  Warner-Lambert Company LLC v Generics (UK) Ltd (t/a Mylan) and another (rev 1) [2018] RPC 21, [2019] Bus LR 360, [2018] UKSC 56, [2019] 3 All ER 95, (2019) 165 BMLR 14 which I discussed in The Supreme Court's Decision on Pregabalin on 6 Dec 2018.  In that appeal, Lord Sumption endorsed the following passage from the Technical Board of Appeal's decision in EXXON/Fuel Oils (T 409/91) [1994] OJ EPO 653:

‘the general legal principle that the extent of the patent monopoly, as defined by the claims should correspond to the technical contribution to the article in order for it to be supported, or justified. … This means that the definitions in the claims should essentially correspond to the scope of the invention as disclosed in the description. … Although the requirements of articles 83 and 84 are directed to different parts of the patent application, since article 83 relates to the disclosure of the invention, whilst article 84 deals with the definition of the invention by the claims, the underlying purpose of the requirement of support by the description, insofar as its substantive aspect is concerned, and of the requirement of sufficient disclosure is the same, namely to ensure that the patent monopoly should be justified by the actual technical contribution to the art.’

Mr Justice Meade observed at para [32] of his judgment that:

"The principal conditions of validity, novelty, inventive step, industrial application and sufficiency are all, in one way or another, directed to satisfying the principle thus expressed."

Lord Sumption had amplified those points at para [37] of his judgment in Warner-Lambert:

"Plausibility is not a term of art, and its content is inevitably influenced by the legal context. In the present context, the following points should be made. First, the proposition that a product is efficacious for the treatment of a given condition must be plausible. Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. As Lord Hoffmann observed in Conor Medsystems Inc v Angiotech Pharmaceuticals Inc [2008] RPC 28, para 28, 'It is hard to see how the notion that something is worth trying or might have some effect can be described as an invention in respect of which anyone would be entitled to a monopoly'. But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56, when addressing the sufficiency of disclosure made in support of claims extending beyond the teaching of the patent. In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83 and 84 and their analogues in section 14 of the Patents Act. In both contexts, the test has the same purpose. Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true. Fifth, that reasonable prospect must be based on what the TBA in Salk (para 9) called “a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se.” Sixth, in Salk, this point was made in the context of experimental data. But the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example, and it is no more than an example, the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect; or to some unifying principle that relates the product or the proposed use to something else which would suggest as much to the skilled person. Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent."

Mr Justice Meade concluded at para [45] of his own judgment that "his analysis of plausibility should be firmly guided by the points in [37] of Warner-Lambert and by the principle laid out by that case that a contribution by the patentee that is in the specification is needed."

The next case that his lordship considered was the Court of Appeal's decision in FibroGen Inc v Akebia Therapeutics Inc  [2021] EWCA Civ 1279.  After setting out the claim in question at para [46] and mentioning Lord Justice Arnold's judgment in Akebia Therapeutics Inc v Fibrogen, Inc.  [2020] EWHC 866 (Pat) at para [48], Mr Justice Meade quoted paras [49] to [59] of Lord Justice Birss's judgment in the appeal.  He paid particular attention to para [53] of that judgment:

"To apply the reasonable prediction principle one has to take three steps. First one must identify what it is which falls within the scope of the claimed class. Second one must determine what it means to say that the invention works. In other words what is it for? Once you know those two things, the third step can be taken: to answer the question whether it is possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim."

He said at [57]:

"Fibrogen represents important recent guidance from the Court of Appeal on sufficiency/plausibility and I intend to bear in mind the three steps identified above." 

However, he cautioned:

"But it is important to recognise too that the context was very different from the present case. The patentee had made an invention which was the identification of the role of a biological mechanism (the enzymatic inhibition) which enabled a treatment effect. This was an important principle. The present case is quite different: BMS asserts that its invention is in identifying a single compound which, based on a known mechanism and known structural understanding would treat a recognised kind of condition of concern. So there really is no useful analogy to the step one and two functional features of [56] in Fibrogen."

In Pharmacia Corporation and others v Merck & Co Inc and another  [2002] ENPR 10, [2001] EWCA Civ 1610, [2002] RPC 41, the Court of Appeal held that simply identifying new compounds without specifying any use would not justify the grant of a patent. However, Mr Justice Meade said at [66] that a patentee is not limited to the most demanding teaching of utility in a specification. He said that the patentee is entitled to try to rely on a less ambitious degree of utility, or a utility of a different but related kind. He concluded at [68] that what that means for an invention to “work” is to be determined from the specification where the claim is not explicit but that the patentee is not restricted to the most ambitious assertion made. That must be fact-dependent and must still be based on the specification.

The last case that his lordship discussed was the Technical Board of Appeal's decision in T 0184/16 Galencium Health which held that there was no requirement to file data in an application in order to establish plausibility.

Evidence and Arguments on Plausibility

The learned judge broke down the argument on plausibility as follows at para [153]:

• Plausibility of factor Xa binding.
• Plausibility of therapy, and
• Selectivity.

Plausibility of Factor Xa Binding

BMS's case was that it was plausible that apixaban was an effective factor Xa inhibitor which was useful as a therapeutic for thromboembolic conditions and also for certain non-therapeutic purposes.  Sandoz and Teva disputed that contention.  They argued that plausibility must depend on what was disclosed about apixaban itself.  Even if it was plausible that apixaban had been tested and found to have a Ki of the order of 10 µM, that would be inadequate for therapeutic and indeed non-therapeutic use.  

The judge considered the parties' arguments and evidence between para [154]and para [215].  He concluded at [216] that the patent did not make it plausible that apixaban would have factor Xa binding of the level of 10 µM as referred to on page 170, or any useful degree of binding.  The problem was that there was simply no reference to apixaban to allow an inference that it was one of the compounds for which useful results had been achieved.  Since there was no plausibility of any meaningful factor Xa binding the patent was invalid because all the applications for apixaban depended on factor Xa binding.

That was enough to dispose of the case but his lordship considered the plausibility of therapy and selectivity issues.  

Plausibility of Therapy

Even if `the patent had made it plausible that apixaban had 10 µM degree of binding that would not make it plausible that it would be useful in therapy because nanomolar potencies were needed for that.

Selectivity

The judge held at [219] that the patent contained nothing to indicate that apixaban was selective for factor Xa as compared with other serine proteases.

Non-Therapeutic Uses

The non-therapeutic uses relied upon were: 

• standard or reference compounds.
• diagnostic assays 
diagnostic agents and adjuncts, in particular as anti-coagulants where blood was to be kept in the fluid state for analysis or biological testing, and 
• lead compounds.

There was no or insufficient evidence to support any of those uses.

Obviousness over WO 00/39131

The judge summarized the PCT application between paras [234] and [235.4].  He noted that the application had been filed by Du Pont Pharmaceuticals which was now a subsidiary of BMS, that two of the inventors of that invention had also invented the invention in suit, that the application asserted that apixaban would be useful as anticoagulants for treating thromboembolic disorders and that the teaching as to non-therapeutic uses was the same as in the patent in suit.  His lordship said at [236] that the attack was based on a lack of technical contribution.  He continued at [238]: 

"I have found that `652 lacks plausibility within its own terms, without the need to consider any prior art. It is therefore bound to lack any technical contribution over `131 and in that very limited sense this attack succeeds."

He could not see that there was any realistic way in which plausibility of the patent in suit could succeed based purely on teaching that is in `131.   He observed that while the attack succeeded in the limited sense identified above, it did not add anything and it did not require any additional factual findings.

Teva's Additional Argument

Mr Justice Meade did not consider Teva's additional argument that given that the structure of apixaban was obvious,  there was no invention necessary to make it and therefore the only possible technical contribution would lie in its use for a particular purpose. Any claim not limited to a particular use made plausible by the specification would be invalid for exceeding the technical contribution.  The judge described that argument as "radical."  It was not supported by any UK authority.  Sandoz did not endorse it.   Having found that the patent was invalid for other reasons, his lordship did not consider it necessary or expedient to decide the point.

Amendment

BMS;s proposed amendments were to be found at para [150]:

“7A. A compound of claim 1 or 2 that is a factor Xa inhibitor for use in treating a thromboembolic disorder.
7B. A compound of claim 1 or 2 that is an effective factor Xa inhibitor for use in treating a thromboembolic disorder.”

The claimants opposed the amendments on the basis that there was added matter because the application did not disclose apixaban specifically as a factor Xa inhibitor, and on the basis that there was a lack of clarity.   The judge rejected the added matter contention and lack of clarity was barely argued.  He concluded that the amendments would have been allowable but they would do nothing to cure the invalidity of the patent.  He, therefore, refused the amendment.

Further Information

This is an important case on plausibility which should be studied closely.   It analyses the EPO and English case law although it does not advance the law. Anyone wishing to discuss this case can call me on +44 (0)20 7404n 5252 or send me a message through my contact form.