A patent in the cross hairs

Frankly, I am not so fond of the finasteride litigation, previously discussed here, here and there. But this may simply have something to do with the fact that I am sensitive to the issue of hair loss.

That said, I am grateful to Denis Schertenleib for drawing my attention to the cassation ruling issued a few days ago on this topic.

As a reminder, European patent No. EP 0724444 to Merck Sharp & Dohme Corp. relates to the second medical use of finasteride for the treatment of androgenic alopecia, with a particular dosage regimen.

The French part of EP’744 was declared invalid twice by the Paris Cour d’appel: the first time for lack of novelty (what I would call the Actavis part of the lawsuit), and the second time for insufficiency of disclosure (the Teva part of the lawsuit).

Merck did not bow and tried its luck in front of the Cour de cassation – to no avail.

The cassation ruling (Teva part) is interesting in that it confirms the sufficiency standard to be applied in the field of therapeutic inventions.

Merck argued that the appeal decision (which, again, can be found on this page) was legally incorrect on 9 different grounds – or “branches“, as they are nicely called in the supreme court parlance. As I tend to find cassation decisions unreadable, I will try to reformulate these grounds in my own words.

On a general standpoint:

1. The question that the appeal judges should have addressed is only whether the drug with the right dosage could be manufactured by the skilled person.

2. The appeal judges mixed up sufficiency with novelty and inventive step, as they examined whether there was a “specific technical teaching” in the patent, and wrongly looked for a comparison of the invention with the state of the art in the patent. They should have focused on whether the information in the patent made it plausible that the claimed dosage was therapeutically effective.

Example 4 of EP’444 describes a protocol for measuring haircount in subjects. As I commented in my earlier post, its conclusion is rather vague and unspecific in terms of technical effect achieved, which led it to be disregarded by the Cour d’appel. The following grounds were raised in relation with this example 4:

3. The appeal judges failed to realize that the example 4 shows the technical effect linked to the claimed low dosage of finasteride.

4. The appeal judges said that clinical tests are not required for showing a therapeutic use, but then contradicted themselves when they disregarded the example as not corresponding to an actual clinical test.

5. The appeal judges failed to realize that the example provides a methodology making it possible for the skilled person to verify the claimed therapeutic use.

As for example 5 of the patent, it is supposed to show a reduction in the amount of dihydro testosterone (DHT) in the scalp of patients taking finasteride. But it is also quite imprecise and kind of looks like a paper example (just like example 4). The following grounds were raised in relation with this example 5:

6. The same contradiction already mentioned in item 4. happened again when the appeal judges discussed example 5.

7. The appeal judges failed to realize that example 5 shows that the claimed dosage has an effect on the metabolic mechanism involved in alopecia – so that example 5 indirectly also supports the technical effect linked to the claimed low dosage of finasteride.

8. The appeal judges held that the example was doubtful in view of the leaflet of the Propecia drug, without checking if this leaflet was available to the skilled person at the priority date.

9. The example mentions a reduction in the amount of DHT in the scalp of patients after 6 weeks, which is why the Cour d’appel found it doubtful, as the effect on hair growth is supposed to occur after 12 weeks at least. But the court should have realized that this is normal as hair growth can only occur after the reduction in the amount of DHT.

Is Santa going to mail some interesting decisions to me this Christmas?

As usual, the Cour de cassation did not address in a detailed manner each criticism and basically simply stated that the Cour d’appel was right and that the grounds of cassation are ill-founded.

In particular, there is (alas) no general discussion on the level of plausibility required from a patent, and on the conditions under which post-published evidence may be relied upon.

Items No.8 and 9 in the above list were treated slightly differently, though. Those were found to relate to a redundant ground (“un moyen surabondant“) in the appeal decision, which means that the Cour de cassation refrained from stating whether they are correct or not, as anyway there are enough correct grounds in the appeal decision for it to be confirmed.

The key part of the ruling is translated in its entirety below (I have taken the liberty of dividing up the never-ending single sentence of the ruling into hopefully more intelligible bits):

[…] Firstly, when a claim relates to a [second] therapeutic application of a substance or composition, obtaining this therapeutic effect is a functional technical feature of the claim. Therefore, in order to meet the requirement of sufficiency of disclosure, it is not necessary to clinically demonstrate this technical effect; but the patent application must directly and unambiguously reflect the claimed therapeutic application, so that the skilled person can understand, based on commonly accepted models, that the results reflect this therapeutic application. 

The decision mentions first that, regarding claim 1 […], the description does not indicate what the technical advantage or effect resulting from this type of oral administration is. It does not contain any element showing the potential efficacy of any finasteride dosage, and does not comprise any information on the new effect of the claimed dosage and the particular properties of this new therapeutic application. The dosage between 0.05 and 1.0 mg is unrelated to the administration rate and patient body weight. Then, according to the decision, the description of the patent only mentions the “surprising and unexpected” discovery of this new therapeutic application, without describing its particular pharmacological properties relative to the state of the art, which only derive from an arbitrary selection. In view of these findings, the Cour d’appel was in a position to deduce that the patent application did not directly and unambiguously reflect the claimed therapeutic applications; and that the skilled person unaware of any specific technical teaching was not able to reproduce the invention and had to implement a research program him/herself; so that [claims 1 to 3 were] insufficiently disclosed.  

Secondly, regarding the the examples cited in the description of the patent, the appeal decision […] disregarded examples 1 and 2, which relate to the preparation of finasteride, the manufacturing process of which was known for years; and example 3, which does not relate to androgenic alopecia.

[The decision] notes on the one hand that example 4 discloses a photographic protocol for detecting hair growth by counting on a period of twelve months and holds that, since [the example] does not give any information on the conditions of a potential test and does neither describe the experiments nor the technical effect resulting from the lowering of the claimed dosage relative to prior art dosages, this example appears to be a measurement method and cannot be considered as a report on a trial. 

[The decision] notes on the other hand that example 5 does not provide any detail on the experimentation or protocol applied when finasteride is administered for six weeks. The results have shown a significant reduction in the amount of DHT but have not established hair growth or the stop of hair loss. [The decision] holds that, in the absence of any comparison criterion, whereas the reduction in DHT levels in scalp due to the administration of finasteride was already known, this example does not make it possible to compare the effects of the claimed dosage relative to a higher dosage, of the order of 5 mg, disclosed in the state of the art. 

Based on these findings, the Cour d’appel did not misrepresent the patent and did not require a clinical demonstration of the therapeutic effect of the new dosage. [Thus, the Cour d’appel rightly] considered that these examples did not directly and unambiguously reflect the claimed therapeutic application and could not remedy its insufficiency of disclosure as already noted above.

This approval of the approach taken by the appeal judges is of course important for all practitioners in the pharma field.

The trend is now once and for all confirmed, per which patents considered as “paper patentsi.e. seen as overly speculative at the date of filing, will not fare well in France.

Before concluding this post and wishing all readers happy holidays, a final word on two procedural aspects.

First, Merck also criticized the appeal decision for holding Teva’s nullity claim admissible, although, when the first instance judgment was issued in the Teva part of the lawsuit, the patent had already been revoked by the Tribunal de grande instance in the Actavis part of the lawsuit.

The Cour de cassation held that:

[…] The Cour d’appel rightly stated that the decision revoking a patent has an absolute effect [with respect to third parties] only once it is res judicata, that the [Actavis first instance] judgment was under appeal, and deduced that the Teva companies were admissible in seeking the revocation of the same patent. 

This is a welcome clarification.

The last point is that Merck of course also filed a cassation appeal against the other appeal decision in which the same patent was revoked for lack of novelty, as requested by Actavis. Here, the Cour de cassation trod the easiest path and simply dismissed the cassation appeal in a distinct ruling by noting that the patent claims have now been definitely held invalid in view of the Teva ruling.

Too bad for us commentators, as the Actavis part of the lawsuit also involved some interesting legal points.

With that, as promised, I wish all readers happy holidays.


CASE REFERENCE: Cour de cassation, chambre commerciale, December 6, 2017, Merck Sharp & Dohme Corp. v. Teva Pharmaceutical Industries Ltd. & Teva santé, pourvoi No. 15-19726. 

One-two-three

Still warm from the press and courtesy of Matthieu Dhenne, come tidings of the fall of another important pharma IP, namely the Atripla SPC (Supplementary Protection Certificate).

Atripla is marketed as a pink tablet with “123” impressed on one side. It contains a combination of three anti-HIV drugs, namely efavirenz, emtricitabine and tenofovir.

The U.S. pharmaceutical giant Merck Sharp & Dohme Corp. (MSD) owns European patent No. EP 0582455, entitled “benzoxazinones as inhibitors of HIV reverse transcriptase“. The patent was filed on August 3, 1993.

Two SCPs were filed and granted in France based on the EP’455 patent, and on two successive marketing authorizations (MAs):

  • The first one, FR01C0012, was filed on April 10, 2001 and granted on May 18, 2001. It protected the active efavirenz per se. This SPC expired on November 20, 2013.
  • The second one, FR08C0021, was filed on May 27, 2008 and granted on November 20, 2009. It protects the triple therapy combination of efavirenz, emtricitabine and tenofovir (marketed as Atripla) and is set to expire on August 2, 2018.

On September 20, 2016, Mylan initiated legal proceedings against MSD in France, claiming that the FR’021 SPC is invalid. The Paris Tribunal de grande instance (TGI) issued its judgment on November 30, 2017.

The judgment is interesting both regarding the admissibility of the action and  the merits.

As far as admissibility is concerned, the nullity defendant claimed that Mylan was time-barred from requesting the nullity of the SPC.

As a first line of response, Mylan argued that the general statute of limitations in our Code civil, which provides a five-year limitation period for “personal or movable actions“, is not applicable to actions for nullity of an IP right. Unsurprisingly, the court disagreed, in keeping with recent case law at the first instance and appeal levels. The TGI made in particular reference to a trademark ruling by the Cour de cassation dated June 8, 2017. For the court, applying this ruling by analogy leads to the conclusion that an action for revocation of an SPC is indeed subject to the limitation period under ordinary law.

That being said, the real interesting point is the determination of the starting point for the five-year limitation period. Although there has been a lot of discussion (including on this blog) concerning the starting period for patent nullity cases, there has been no clear guidance for SPC nullity actions, as far as I am aware of.

MSD’s case was that the starting point for the limitation period was the publication of the SPC application. The court disagreed and set the following principles.

The starting point for the limitation period must be set to the day, determined in concreto, when Mylan knew or should have known, because it intended to market a generic version of the drug which received an MA on December 13 [2007], for the combination of [the] three actives, which is protected by the SPC, which represents an impediment for its business.

So, we all get the idea there – although a couple of words may be missing, which happens from time to time when your sentences are too long, and this is probably why my blog software keeps blaming me for using more than the recommended threshold of 25% of sentences containing more than 20 words.

The general principle of an in concreto assessment is in keeping with the TGI’s previous decisions in patent revocation cases. The court went on:

[…] Only the SPC matters as an impediment, and not the patent. 

One should not refer to the date of grant of the patent, since the validity of the patent is not challenged by Mylan, which acknowledges that the efavirenz active compound is the subject-matter of the invention protected by the EP’455 patent and then by the [FR’012] SPC which expired on November 20, 2013. 

Only the validity of the [FR’021] SPC […] is challenged […]. 

Thus the publication of the grant of the patent cannot be set as the starting point for the limitation period, as it would in fact require an unrealistic watch from stakeholders and is unrelated to the development of the project which gives standing to sue. 

Mylan’s standing does not derive from the publication of the title, be it the patent or the SPC, but from its concrete intent to market the same drug. 

In this case, they have to check that this intent to market the product does not infringe any IP, and if this is the case, to seek its revocation before launching. 

Watching patent or SPC registers cannot be required from stakeholders before they intend to develop a competing product. 

[…] In the present case, the first MA for Atripla […] was granted on December 13, 2007. In view of article R. 5121-28 of the Code de la santé publique, the generic company can only apply for an MA starting from the eighth year after the grant of the MA for the original drug, and cannot be granted one before ten years. 

Therefore, Mylan could not apply for an MA before December 13, 2015, and could not obtain it before December 13, 2017. As a consequence, the date at which Mylan’s standing can be taken into account is December 13, 2015, which is the date starting from which it could apply for an MA. Thus, Mylan is not time-barred as it had until December 13, 2020 to start legal action.

What is somewhat paradoxical is that the TGI calls for an in concreto appraisal but then defines what could possibly be a general rule for SPC cases, namely that the starting point for the limitation period is the date at which third parties may start applying for their own MAs.

We will need to wait for further cases to know for sure whether this is indeed a general rule or not.

Turning to the merits of the case, the discussion and the ultimate reasoning of the court are extremely similar to what can be found in the recent decision on Truvada, also reported on this blog a few weeks ago. 

Truvada is another anti-HIV drug based on the combination of tenofovir and emtricitabine. The SPC at stake in today’s decision relates to the combination of the same compounds, plus a third one, efavirenz. And the problems raised by this other combination are analogous.

According to article 3(a) of the SPC regulation (regulation (EC) No. 469/2009 of the European Parliament and of the Council), an SPC “shall be granted if, […] (a) the product is protected by a basic patent in force“.

How to determine whether a product can be considered as being “protected” by a basic patent has been the subject of intense litigation and numerous rulings from the CJEU, which are mentioned in the TGI’s judgment. Again, readers of this blog can refer to the Truvada post, which contains a short summary of the most important CJEU case law prepared by Lionel Vial.

CJEU case law on the interpretation of the SPC regulation: each ruling always leads to more referrals.

In the present case, none of the claims of EP’455 explicitly recites the combination of the three active compounds of the combination. Instead:

  • efavirenz is covered by a generic formula in claims 1 and 5 and is singled out in claims 2 and 12 (as well as in claims 8 and 9 but in combination with other drugs different from tenofovir and emtricitabine);
  • tenofovir and emtricitabine are not cited in the patent;
  • claims 7 and 16 relate to the combination of a generic formula (covering efavirenz), or of efavirenz specifically, together with a nucleoside analog;
  • tenofovir and emtricitabine belong to this category of nucleoside analogs.

According to the court, this is insufficient to consider that the combination of the three active compounds is protected by the EP’455 patent pursuant to article 3(a).

Says the court:

It turns out that the description never explicitly cites either tenofovir or emtricitabine which are not identified in the EP’455 patent, be it individually or collectively in a composition. And in addition the specific combination claimed as an active product “efavirenz + emtricitabine + tenofovir” is not implicitly but necessarily and specifically taught in the description, and no indication makes it possible for the skilled person to select emtricitabine and tenofovir as nucleoside analogs. 

In fact, if I understand correctly, emtricitabine and tenofovir were not even identified and known yet as anti-HIV drugs at the filing date of the EP’455 patent.

Furthermore, the court refused to consider the claims relied upon by MSD (reciting nucleoside analogs) as “functional claims” because “they do not describe the structure which should be present nor the function that the second and third products should have in this structure“.

For the sake of completeness, the court stated that even if the claims were considered as functional, the four-step test established by the Dutch patent office would then not be satisfied. Again, this same test was discussed in the previous Truvada post, so I will not describe it again here.

As a consequence, the SPC was found to be invalid under article 3(a).

By way of overkilling, the court added that the SPC was also invalid in view of article 3(c) of the SPC regulation, per which an SPC “shall be granted if, […] (c) the product has not already been the subject of a certificate“.

In this case, another SPC had been granted based on the same EP’455 patent, namely the efavirenz SPC. MDS relied on the Georgetown CJEU decision (C 484/12). According to this decision, article 3(c) does not preclude the grant of one SPC for a combination of active ingredients, and another SPC for a single active ingredient, based on the same patent.

Nevertheless, according to the TGI, Georgetown is only applicable if the mono and combo products are separate inventions.

In one brief paragraph, the court then held that:

the combination of efavirenz with emtricitabine and tenofovir does not represent a separate invention which may give the right to a second SPC. For this second reason, SPC [FR’021] is invalid under article 3(c) of the regulation. 

Those readers in favor of pan-European consistency (which probably means most readers of this blog) will be happy to know that the TGI’s decision mirrors a similar ruling in the UK handed down on March 21, 2017, per which the corresponding UK SPC was declared invalid by Mr. Justice Arnold.


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 1ère section, November 30, 2017, Mylan SAS v. Merck Sharp Dohme Corp., RG No. 16/14466.

A skinned patent

Prevailing as a patentee in France when your patent belongs to the chemical or pharmaceutical field is extremely difficult. I will in fact provide some figures on this matter soon.

More often than not, patents are skinned alive by the court – and, bad pun intended, even dermatology is not spared, as the present case shows.

Dermaconcept JMC is a French company active in the pharma / cosmetology business. It owns a French patent No. FR 2823671 as well as a European patent No. EP 1404327 claiming the priority of the French patent. Noreva-Led is their exclusive licensee, which markets the brand of products Actipur, for the treatment of acne skin and atopic dermatitis.

Together, they initiated legal proceedings against Laboratoire Bioderma in December 2014. Laboratoire Bioderma, later merged into Naos, was accused of infringing the above patents through their product Atoderm Intensive.

In May 2016, both patents were limited at the INPI (Institut National de la Propriété Industrielle) after record-breaking 8-day long proceedings. It is reasonable to assume that this limitation came as a reaction to Naos’ initial invalidity arguments.

The limitation was however apparently not good enough for the Paris Tribunal de grande instance (TGI), as the asserted claims were found invalid in spite.

The court started by throwing out claim 9 of the French patent.

In principle, when there are both a French patent and a European patent claiming the priority of the French patent, the effects of the former cease at the end of the opposition period (assuming that no opposition is filed against the European patent, as was the case here). See article L. 614-13 Code de la propriété intellectuelle (CPI). But this is traditionally believed to be true only insofar as both patents cover the same invention.

Here, claim 9 of the French patent is directed to

A method of cosmetic treatment characterized in that it consists in applying a composition based on nicotinic acid or nicotinic acid amide, and a sphingoid base according to any one of claims 2 to 7 on exposed areas, the composition being of the emulsion type.

As this claim is not present in the European patent, it survives in the French patent. Or rather, survived – until it got revoked by the court, that is.

Article L. 611-16 CPI is worded in a manner very similar to article 53(c) EPC, and it inter alia prohibits patents on methods of therapeutic treatment.

Referring to the description of the patent, the court noted that the composition at stake is meant to treat acne and atopic dermatitis, which are diseases of the skin.

Therefore, the method is not merely cosmetic but also therapeutic, since it does entail a therapeutic effect:

In this respect, the mere mention that the field of the claim is intended to cover only the cosmetic effect is not sufficient to shield this claim from the prohibition of article L.611-16 CPI, since the therapeutic effect is in fact inseparable, and actually is expressly presented as one of the advantages of the invention in the patent description. Therefore, the fact that this method produces an aesthetic effect on the skin, namely a fairer and smoother skin, is not sufficient to shield it from the prohibition of abovementioned article L.611-16 since this effect is only the consequence of the therapeutic treatment of the composition which reduces the presence of blackheads on the skin. 

The court also noted that a very similar claim was deleted from the European application before grant, as the European examiner had raised the same objection. I emphasize this, as it is not everyday that a French court feels bolstered by the opinion of an EPO examiner.

A butterfly batch – the ideal treatment for skin disorders.

Next up were claims 1 and 10 of the French part of the European patent – as limited in front of the INPI – which are respectively a product claim and a Swiss-type claim.

Claim 1 reads as follows:

A dermatological composition useful for the treatment of atopic dermatitis, characterized in that it comprises, in combination, nicotinamide (vitamin PP), and at least one sphingoid base selected from phytosphingosine, tetraacetylphytosphingosine, N-acetylphytosphingosine, and phytosphingosine hydrochloride. 

Claim 10 is directed to:

The use of nicotinamide (vitamin PP), and of a sphingoid base according to claim 1, for preparing a medicinal product for the treatment of atopic dermatitis.

Both claims fell for lack of inventive step.

The closest prior art was found to be a Procter and Gamble (“P&G“) PCT application No. WO 99/47114. Claim 1 of the P&G reference discloses a skin moisturizing composition comprising a vitamin B3 compound and a ceramide pathway intermediate or precursor thereof. Other passages of the document disclose that the vitamin B3 compound can be selected from a list comprising nicotinamide, and that the ceramide intermediate or precursor can be selected from a list comprising some sphingoid bases, including e.g. sphingosine.

Interestingly, the P&G reference does not explicitly mention phytosphingosine or its derivatives, recited in claim 1 of the European patent. As far as I understand, phytosphingosine is a compound which is different from sphingosine.

But the P&G reference contains the following statement:

Ceramide pathway intermediates or precursors are discussed in detail in U. S. Patent 5,578,641 to Simon et al. and U. S. Patent 5,610,040 to Smeets et al., both of which are herein incorporated by reference. 

And it turns out that phytosphingosine is recited as a preferred ceramide pathway intermediate in US 5,578,641.

The court considered that the teaching of this U.S. patent completes the explicit teaching of the P&G reference, so that:

The [P&G reference], the purpose of which is to provide a composition activating and increasing the rate of ceramide synthesis and to provide improved methods of skin moisturizing […] already discloses the composition mentioned in claim 1 of the EP’327 patent, with the additional remark that […] the synergistic effect of the combination was already known. 

In other words, the court relied on the incorporation by reference of US 5,578,641 in the P&G reference in order to determine its overall teaching.

As a next step, the court stated:

It remains to be determined if it was obvious for the skilled person to use this combination to solve the problem at stake, i.e. treat atopic dermatitis.

Thus, the only difference between the claims at stake and the teaching of P&G was the fact that the composition is used for treating atopic dermatitis.

This means that the court fully took into account the therapeutic purpose recited in product claim 1 (“a dermatological composition useful for the treatment of atopic dermatitis“) as well as in Swiss-type claim 10 (“for preparing a medicinal product for the treatment of atopic dermatitis“). 

This finding is rather logical but not so straightforward given the (past?) tendency of French courts to come up with unconventional claim constructions especially when therapeutic inventions are at stake.

Going back to the final step of the inventive step reasoning, the court noted that atopic dermatitis, as set forth in the patent in suit, is known as being related to an alteration of the barrier function of the skin.

The P&G reference itself mentions that the composition improves said barrier function.

The court then turned to a secondary reference, Korean patent application No. KR 2000-0024485, specifically concerned with the treatment of atopic dermatitis. It is explained in the document that atopic dermatitis is related to skin dryness, wherein skin moisturizing is significantly reduced, which impairs the barrier function. The Korean document adds that nicotinamide increases lipid synthesis in the skin, therefore supporting the barrier function of the skin and curbing atopic dermatitis.

The court thus concluded:

It can be derived from this that the skilled person, knowing the effects of the combination comprising a vitamin B3 compound and a ceramide precursor on skin moisturizing, looking for a way to alleviate the effects of atopic dermatitis, and knowing that the latter is characterized by skin dryness and impairs the barrier function thereof, but also that nicotinamide strengthens this barrier function and that its combination with an intermediate or precursor of ceramide synthesis produces an amplified effect on the ceramide synthesis properties of vitamin B3 compounds, would use this same combination for the treatment of atopic dermatitis without exercising any inventive step. 

Claims 1 and 10 were thus declared invalid, and the infringement claims were not examined.

Whether the judges got it right or not, at least the decision looks well reasoned and in line with European case law.  

One reservation, though, is that there is no discussion in the judgment as to whether P&G was a proper starting point for the inventive step reasoning at all, despite the fact that the claimed therapeutic purpose was not mentioned in the document.

This point may not have been raised by the nullity defendants. And it may not be a big deal anyhow. It can be surmised that a similar reasoning of lack of inventive step could have been made starting from the Korean application (which is concerned with atopic dermatitis) and combining it with P&G.


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 2ème section, July 7, 2017, Dermaconcept JMC & Laboratoires Nora-Led v. Naos, RG No. 15/00069.