Court says no to Ono

Owing to my colleague and excellent friend Lionel Vial, it is SPC month on Patent my French!

After tackling the recent Halozyme judgment a couple of weeks ago, Lionel now goes one-on-one with Ono.

As promised last week, we are back to discuss the second of the third recent supplementary protection certificate (SPC) appeal decisions rendered on refusals of the French patent office (INPI).

This week’s decision, which was rendered by the Paris Cour d’appel on January 19, 2021, discusses not one but two articles (aren’t we lucky) of Regulation (EC) No 469/2009 (the “SPC regulation”): 3(a) and 3(c).

SPC application FR15C0088 was filed on December 15, 2015 by Ono Pharmaceutical Co. Ltd and Professor H., whom we are told in the decision is a Nobel prize winner, on the basis of (i) marketing authorization EU/1/15/1014 in the name of Bristol-Myers Squibb Pharma EEIG and of (ii) European patent EP 1537878 (which will give you the full name of Professor H. if you are curious or if you don’t know the names of all Nobel prize winners by heart). EP 1537878 was filed on July 2, 2003 and granted on September 22, 2010. The product forming the subject-matter of the SPC is nivolumab (Opdivo®), a human monoclonal antibody which blocks the PD-1 receptor and is indicated in the treatment of certain cancers.

Since the decision begins with article 3(c) of the SPC regulation, let’s do the same.

The SPC application was rejected on March 2, 2018 pursuant to article 3(c) of the SPC regulation because a SPC had already been granted to Ono Pharmaceutical Co. Ltd for nivolumab.

The SPC in question is FR15C0087, also filed on December 15, 2015, granted on January 6, 2017, and held by Ono Pharmaceutical Co. Ltd and E. R. SQUIBB & SONS, L.L.C on the basis of European patent EP 2161336.

The INPI based its decision in particular on the judgment of the CJEU of September 3, 2009 in case C‑482/07 (AHP Manufacturing), which notably provides that “it should be pointed out that the first sentence of Article 3(2) [of Regulation (EC) No 1610/96, i.e. the phytosanitary SPC regulation] precludes the grant, to the holder of more than one patent for the same product, of more than one SPC for that product. However, the second sentence of Article 3(2) allows such a grant to two or more holders of different patents for the same product. It is thus apparent that the special condition for the grant of two or more SPCs for the same product is that the relevant applications emanate from different holders of basic patents” (see paragraph 25 of the judgement).

Faithful readers will immediately be reminded of a previous decision discussed here on this blog, in which the Cour d’appel sustained the decision of the INPI to reject a SPC applied by Medivir AB for simeprevir pursuant to article 3(c) in view of a previous SPC for the same product held by Medivir AB and Janssen Sciences Ireland UC.

The INPI therefore appears to be consistent in considering that the different holders of a same SPC or SPC application should not be considered as a single entity but individually.

Is it also the case of the Cour d’appel?

In the appeal proceedings, Ono and Professor H. notably argued that the case law of the General Court of the European Union (EU) allows the EU judge who cannot find elements in the EU law which would allow her/him to specify the content and scope of an EU provision by an autonomous interpretation to rely on national law. In the present case, pursuant to French civil law ruling co-ownership, the “holder” within the meaning of the SPC and phytosanitary SPC regulations would thus refer to all the persons holding property rights on a patent, so that the two basic patents (and the corresponding SPCs) would be held by different holders.

The Cour d’appel ruled as follows:

In this regard, the reference made by the appellants to the rules of civil law relating to co-ownership to argue that the holders of the EP 336 and EP 878 patents are not the same – the co-ownership consisting of the ONO and SQUIBB & SONS companies, holders of the EP 336 patent, being in this regard different from the co-ownership consisting of the ONO company and Pr. H., holders of the EP 878 patent – so that the conditions of Article 3(2) (second sentence) of regulation (EC) 1610/96 are fulfilled, is inoperative. The rules governing patent co-ownership are specifically defined by articles L. 613-29 to L. 613-32 of the Code de la propriété intellectuelle. Article L. 613-30 expressly provides that the ordinary law governing co-ownership resulting from the civil code does not apply to co-ownership of a patent application or a patent. Article L. 613-29 provides that “Each of the co-owners may use the invention for its own benefit, provided the other co-owners are indemnified (…)”. It follows therefrom that ONO, which is a co-owner of both the EP 336 and EP 878 patents and which may use them alone under the conditions set forth in article L. 613-29 of the Code de la propriété intellectuelle, is a “holder” of these patents within the meaning of article 3(2) of previously cited regulation No. 1610/96.

The decision of the INPI was therefore sustained.

Here, we are of the opinion that the reasoning of the Cour d’appel might miss a point. Indeed, article L. 613-32 of the Code de la propriété intellectuelle provides that articles L. 613-29 to L. 613-31 apply in the absence of contractual provisions stating otherwise and that co-owners may decide otherwise at any time through a co-ownership agreement.

As such, before reaching its conclusion, the Cour d’appel should have checked whether co-ownership agreements had been set up between Ono & Squibb on the one hand, and between Ono & Professor H. on the other hand, and if both these agreements allowed Ono to use the patents for its own benefit, without requiring any authorization from the other parties.

Perhaps this missing piece in the reasoning of the Cour d’appel will be addressed by the Cour de cassation (the French Supreme court) in the future.

An Easter egg was supposed to be hidden in this post, but it went missing.

Notwithstanding, this may be irrelevant for the outcome of this case, as the rejection was also based on article 3(a) of the SPC regulation.

Claim 3 of the basic patent was relied on for the purpose of the SPC application:

Anti-PD-1 antibody which inhibits the immunosuppressive signal of PD-1 for the use in cancer treatment.

The INPI considered that while claim 3 did “implicitly” cover nivolumab, it could not be interpreted in the light of the description of the basic patent as relating “necessarily” and “specifically” to this active ingredient within the meaning of the judgement of the CJEU in case C‑493/12 (Eli Lilly), as the description of the patent did not contain any indication, such as a concrete embodiment or any other teaching allowing to specifically individualise nivolumab.

The appellants argued that nivolumab necessarily relates to the invention covered by the patent, because it implements the technical contribution brought by the basic patent. The appellants further argued that nivoluab was specifically identifiable by the person skilled in the art because patent EP 878 teaches all the necessary elements to identify the antibodies forming the subject-matter of claim 1, and describes in detail the steps for producing an anti-PD-1 antibody and how to screen these antibodies to identify those which inhibit the immunosuppressive signal of PD-1; as such, the person skilled in the art could obtain, at the filing date of the EP 878 patent, through routine operations, all the antibodies fulfilling the function recited by the EP 878 patent, including nivolumab.

The Cour d’appel essentially relied on the judgement handed by the CJEU on April 30, 2020 in case C‑650/17 (Royalty Pharma) to reach its decision.

The Royalty Pharma judgement provides:

1. Article 3(a) of Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the supplementary protection certificate for medicinal products must be interpreted as meaning that a product is protected by a basic patent in force, within the meaning of that provision, if it corresponds to a general functional definition used by one of the claims of the basic patent and necessarily comes within the scope of the invention covered by that patent, but is not otherwise indicated in individualised form as a specific embodiment of the method of that patent, provided that it is specifically identifiable, in the light of all the information disclosed by that patent, by a person skilled in the art, based on that person’s general knowledge in the relevant field at the filing date or priority date of the basic patent and on the prior art at that date.

2. Article 3(a) of Regulation No 469/2009 must be interpreted as meaning that a product is not protected by a basic patent in force, within the meaning of that provision, if, although it is covered by the functional definition given in the claims of that patent, it was developed after the filing date of the application for the basic patent, following an independent inventive step (emphasis added by the Cour d’appel).

The Cour d’appel agreed with the appellants that nivolumab is implicitly and necessarily within the scope of the invention covered by the basic patent. However, it came to a different conclusion as to whether nivolumab is specifically identifiable.

The Cour d’appel considered that the preparation of monoclonal antibodies requires more than routine operations. The fact that 3 years were necessary for Ono to file the EP 336 patent which specifically relates to nivolumab was a sound indication that an independent inventive step was needed from the EP 878 patent to arrive at nivolumab.

The decision of the INPI based on article 3(a) of the SPC regulation was therefore also sustained.

For our part, we are not certain that the article 3(a)-test should be applied in the same manner to functionally-defined antibodies on the one hand and small molecules on the other hand.

Indeed, given a protein target, it is generally considered that the level of difficulty for identifying small molecule inhibitors is higher than for antibody inhibitors. As such, this difference should also be reflected in the standard to apply for determining if a product is specifically identifiable from a patent specification. In this regard, it should be noted that the Royalty Pharma judgement arose from a small molecule case (sitagliptin). In contrast, the Eli Lilly judgement arose from a monoclonal antibody case (tabalumab). Accordingly, perhaps monoclonal antibody SPCs should be assessed on the basis of the Eli Lilly judgement, without applying the “independent inventive step” test added by the Royalty Pharma judgment, which should be reserved to small molecules, at least until the CJEU clearly states that this latter test is of universal application for functionally-defined products. In this regard, it should be noted that the UK intellectual property office did grant a SPC for nivolumab based on the EP 878 patent on June 25, 2018 (before the Royalty Pharma judgement was handed).

We will be back soon with the last of the three SPC appeal decisions rendered on refusals of the INPI, with yet another article 3(a)/Royalty Pharma case.

Thank you Lionel. Any decent SPC post is supposed to end with the expression of a wish for – or fear of – a future CJEU referral, and I am quite happy that this one is no exception.


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 1, January 19, 2021, Ono Pharmaceutical Co. Ltd. et al. v. Directeur général de l’Institut national de la propriété industrielle, RG No. 18/10522.

Easy as ACD

Even for those who know the ABCs of patent law, mastering the ACDs of SPC law may seem a daunting task. I am talking about article 3(a), 3(c) and 3(d) of the SPC regulation of course, a never-ending source of legal headaches. 

I am happy to once again host a contribution from SPC enthusiast Lionel Vial, reporting on the first of a series of three recent judgments. With his explanations, I am sure everything will look as easy as ACD.

Today we discuss the first of three recent decisions of the Cour d’appel (appeal court) of Paris rendered on appeal against decisions of the French patent office (INPI) to reject three SPC applications in view of Articles 3(a), 3(c) and 3(d) of the SPC Regulation (Regulation (EC) No 469/2009):

Date of the decision Parties SPC Product Article of the SPC regulation applied Main CJEU decisions applied Outcome
15/12/2020 Halozyme Inc. 15C0053 Trastuzumab and recombinant human hyaluronidase 3(d) C-631/13 (Arne Forgsen) SPC rejection sustained
19/01/2021 Ono Pharmaceutical Co. Ltd & Prof. H 15C0088 Nivolumab 3(a) & 3(c) C-482/07 (AHP Manufacturing) & C-650/17 (Royalty Pharma) SPC rejection sustained
09/02/2021 Wyeth LLC & the General Hospital Corporation 16C1004 Osimertinib 3(a) C-650/17 (Royalty Pharma) SPC rejection sustained
The ABC mouse is right: SPC law does feel like the teacher playing a joke on the class.

In the first case, Halozyme Inc. had applied for a SPC (FR15C0053) for a combination product of trastuzumab and recombinant human hyaluronidase on the basis of a marketing authorization (MA) granted on 26 August 2013.

The combination is indicated in the treatment of breast and gastric cancer. Trastuzumab is a monoclonal antibody targeting HER2 thereby inhibiting the proliferation of human tumor cells that overexpress HER2. Recombinant human hyaluronidase increases the dispersion and absorption of co-administered drugs when administered subcutaneously, by catalyzing the hydrolysis of hyaluronan, a constituent of the extracellular matrix.

A previous MA for trastuzumab was granted on 28 August 2000.

Problem: the summary of the product characteristics of the MA of 2013 mentions trastuzumab as the sole active ingredient and hyaluronidase is listed among the excipients.

As a consequence, the INPI rejected the SPC application on 7 March 2018 on the basis of Article 3(d) of the SPC Regulation, considering that recombinant human hyaluronidase was not an active ingredient having a therapeutic action of its own but that it was an excipient, as provided in the summary of the product characteristics of the MA. As such, hyaluronidase did not qualify as a product within the meaning of the SPC regulation, the product being none other than the active ingredient shown in the MA, i.e. trastuzumab, which had already been granted a MA in 2000.

Halozyme appealed the decision of the INPI in particular on the ground that, based on judgement C-631/13 (Arne Forgsen) of the CJEU, it was of no consequence that hyaluronidase was presented as an excipient in the MA, since the SPC regulation does not provide that a SPC should be only granted for active ingredients presented as such in the corresponding MA. Instead, it should be verified, based on all pertinent factual and scientific elements, whether the ingredient at stake could be considered an active ingredient. In this regard, recombinant human hyaluronidase should be considered as an active ingredient, since it has a therapeutic action on the organisms of patients allowing treating breast cancer.

As a reminder, judgement C-631/13 notably provides that:

Article 1(b) of Regulation No 469/2009 must be interpreted as meaning that a carrier protein conjugated with a polysaccharide antigen by means of a covalent binding may be categorized as an “active ingredient” within the meaning of that provision only if it is established that it produces a pharmacological, immunological or metabolic action of its own which is covered by the therapeutic indications of the marketing authorization, a matter which it is for the referring court to determine, in the light of all the facts of the dispute in the main proceedings. (emphasis added).

This is what the Court decided:

It results from the foregoing that it appears from the “summary of the product characteristics” of the MA that the active ingredient of the medicinal product is trastuzumab, that hyaluronidase is an excipient, and that no other element contained in the MA justifies that hyaluronidase alone, or associated to trastuzumab, would produce a pharmacological, immunological or metabolic action of its own which is covered by the therapeutic indications of the MA (emphasis added).

[…]

It follows that, in the combination of trastuzumab and recombinant human hyaluronidase, forming the subject-matter of the SPC at stake, only trastuzumab is the active ingredient, while a MA has already been granted for trastuzumab alone. Therefore the invoked MA is not the first MA for the product pursuant to article 3(d) of the regulation. Accordingly, the director of the INPI rightly decided that the SPC application did not comply with the requirements of the regulation and that it had to be rejected.

Even though the appeal was eventually rejected, it should be noted that the Cour d’appel did consider other parts of the MA than the summary of the product characteristics to assess the action of hyaluronidase and establish whether it could be considered as an active ingredient.

Accordingly, there is still some hope for combination SPCs in France when one of the ingredients of the combination is not mentioned as an active ingredient in the summary of the product characteristics of the MA, provided, of course, that data showing a therapeutic action of its own within the indications of the MA is available.

To be continued with the second of the three decisions!


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 1, December 15, 2020, Halozyme Inc. v. Directeur Général de l’INPI, RG No. 18/14332.

No (cross) product liability

I am not sure I have ever seen a bioinformatics patent lawsuit in France before the case reported on today: this may well be a first.

It is therefore particularly interesting to see how our judges grappled with such an exciting and complex topic. And the short answer is: pretty well it would seem!

The Codexis group is a leader in the field of biocatalysts. In particular, Codexis Mayflower Holdings LLC owns European patent No. EP 1761879, filed in June 2005 and claiming a priority of June 2004. The patent was granted in August 2013 and was not opposed.

Claim 1 of the patent is the following (the wording which will be important for the discussion below has been emphasized):

A computer-implemented method for identifying amino acid residues for variation in a protein variant library in order to affect a desired activity, said method comprising:
(a) receiving data characterizing a training set of a protein variant library, wherein the data provides activity and sequence information for each protein variant in the training set;
(b) from the data, developing a sequence-activity model that predicts activity as a function of amino acid residue type and corresponding position in a protein sequence,
wherein the sequence-activity model includes one or more non-linear terms, each representing an interaction between two or more amino acid residues in the protein sequence,
and wherein the sequence-activity model can distinguish amino acid residues that have a significant impact on the desired activity from those that do not; and
(c) using the sequence-activity model to identify one or more amino acid residues at specific positions that are predicted to impact the desired activity for variation to impact the desired activity,
(d) wherein at least one of the non-linear terms is a cross-product term comprising a product of one variable representing the presence of one interacting residue and another variable representing the presence of another interacting residue, and
(e) wherein developing said sequence-activity model comprises selecting one or more cross-product terms from a group of potential cross-product terms, wherein the selected cross-product terms are those cross-product terms representing true structural interactions that have a significant impact on activity.

Unusually, the main defendant is an individual, and even more unusually, a university Professor, Mr. O.

Mr. O happens to teach biochemistry, molecular biology and bioinformatics in Nantes; he was blamed by Codexis for his personal website offering a tool for predicting protein sequences, called ProSAR. Furthermore, Mr. O is a vice-president of the company Peaccel, which provides services to biotech and pharma companies, and which uses the ProSAR software.

The issue, as you have probably guessed, is that Codexis deemed that the ProSAR software infringes its EP’879 patent.

In 2015, Codexis had an internet bailiff’s report, and then an infringement seizure at the professor’s home (!) carried out. The source code for ProSAR was seized and placed under seal. Codexis then formally initiated infringement proceedings against Mr. O and his company. The defendants filed a nullity counterclaim.

In 2016, an expert was appointed by the judge in charge of case management to analyze the source code and provide a comparison with the patent claims. The expertise was concluded in a matter of months.

In 2018, the Paris TGI issued its decision on the merits, rejecting both the nullity counterclaim and the infringement main claim.

Codexis appealed, Mr. O and Peaccel counter-appealed, which now leads us to the judgment rendered by the Paris Cour d’appel on January 15, 2021. This second judgment fully confirmed the first instance decision.

Starting with the validity discussion, one first item of contention was whether the priority claim was valid.

Indeed, Codexis’ inventors had originally filed a U.S. provisional application in 2002, followed by three successive continuation-in-part applications CIP1, CIP2 and CIP3 in 2003 and 2004. The EP’879 claims priority to the third one, CIP3.

Whenever patent attorneys see “continuation-in-part” and “European priority claim” in a same sentence, they smell blood in the water.

And indeed, the infringement defendants argued that CIP3 is not the first application for the claimed invention, as the first application is rather CIP2. As a result, they said, the priority is invalid, since only a “first application” can give rise to a priority right under article 87 EPC.

This argumentation must sound perfectly clear to EQE candidates, but it may not be an easy objection to deal with for a court of law. However, in this case, the court nicely set out the test to be applied:

It must therefore be first determined whether the subject-matter of the main claim 1 of the EP’879 patent and of dependent claims 2, 3, 7, 10 and 12 can be directly and unambiguously derived by the skilled person from the teaching of application CIP2, or from only the parts of application CIP3 not present in application CIP2. 

Then, the court noted that the patentee did not dispute that features (a) to (d) were directly and unambiguously derivable from CIP2. On the other hand, they did not believe that feature (e) could be derived from the passages cited by the defendants. As a result, CIP3 was acknowledged as the first application for the invention, and the priority was found valid. Too bad for the defendants, as the application CIP2 itself was published between the priority date and filing date of the patent.

Mr. O and Peaccel further raised objections of lack of novelty based on two articles published in 2001.

The first article, “W et al.“, apparently disclosed a method similar to that of claim 1, but applied to peptides, and not proteins as required by the claim.

Let’s take a step back to molecular biology 101: peptides and proteins (also referred to as polypeptides) both designate polymers comprising amino acid residues. But the term “peptide” generally refers to a short polymer, whereas a “protein” is a long polymer. Paragraph [0024] of the patent mentions a “typical” minimum number of amino acid residues of 30, 50 or 100 in a protein. In W et al., only three amino acids were present in the analyzed peptides.

The defendants insisted that the allegedly infringing software ProSAR works on both peptides and proteins, and that the internet bailiff’s report and expertise proceedings were actually conducted based on a test peptide of only ten amino acid residues, but this was considered irrelevant to the issue of novelty by the court.

From a peptide to a protein… to a living organism? Would the modelling still work then?

As to the defendants’ argumentation based on the second article , “L. et al.“, it was found to be so lacking that the court did not even bother to address it in detail:

The object of this publication differs from that of the EP’879 patent since it does not disclose a computer-implemented method to identify amino acid residues for variation in a protein variant library in order to affect a desired activity, but a method for rationally designing a medicament, […] as not contradicted by the very partial translation of the L et al. article filed [by the defendants]. [They] unsuccessfully attempted to combine various excerpts from incomplete sentences […] [so that] it is not necessary to reply in detail to this technical argumentation. 

Next, inventive step.

Starting from the first article W et al. as the closest prior art, Mr. O argued that the disclosed process was obvious to adapt from short peptides to actual proteins. The court was not convinced, as the proposed secondary reference related to a different process of protein engineering without features d) and e) of claim 1.

A second inventive step challenge also starting from a document directed to peptide engineering failed for similar reasons.

The patent was thus upheld. Let’s now turn to the issue of infringement.

Mr. O first argued that the analysis of the software relied upon by the plaintiff was based on a ten-amino acid test peptide – and thus not a protein. However, the court rejected the argument, since the software clearly works similarly with peptides and proteins. Squeeze-type arguments do not always work, and in this case the peptide/protein squeeze raised by the defendants left the judges unimpressed.

But another defense hit the mark, both in first instance and on appeal. Features d) and e) of claim 1 make reference to “a cross-product term comprising a product of one variable representing the presence of one interacting residue and another variable representing the presence of another interacting residue”In the ProSAR tool, a different calculation is performed, based on quadratic, term-to-term products.

Codexis’ technical expert acknowledged that there is a well-accepted mathematical definition of “cross-product” (“produit vectoriel” in French) but then submitted that a broader interpretation of this expression should be adopted in view of the description of the patent, which would cover any non-linear term expressing the interaction of two residues in the polypeptide. The court did not agree that a definition of cross-product different from the conventional one could be found in the patent.

The identification of this difference between ProSAR and claim 1 of the patent was not offset by other contextual arguments, such as allegedly incriminating statements made by Mr. O that he had been inspired by articles published by Codexis. The identified difference was sufficient to conclude that there was no literal infringement.

Codexis had another shot, based on the doctrine of equivalents. They claimed that the quadratic terms in the ProSAR software are equivalent to the cross product of EP’879.

Again, the court was unsympathetic to this view:

[…] Therefore, the equation of step 6 of the expert report and the one of paragraph [0101] of the description of the patent are neither identical, nor mathematically equivalent, and it can thus not be stated […] that the ProSAR tool is identical to the cross-product of the patent in terms of function and effect. 

Thus, it is not demonstrated by Codexis that the selection of quadratic terms implemented in the ProSAR tool fulfils the same function as the selection of terms of the cross-product in the patented method, namely the identification of interactions between acid amino residues which have an impact on activity, in order to achieve a same result, namely predicting the activity of new variants. The expert report does not confirm […] that the sole purpose of the genetic algorithm implemented in the ProSAR tool is to allow an efficient selection of non linear terms. 

It is slightly unfortunate that the judgment does not contain a more detailed discussion on this last aspect. Assessing infringement by equivalence in France requires determining what the function of the allegedly equivalent means is, but this determination is seldom straightforward. In the present case, based on the judgment itself, it is not easy to understand what the exact respective roles of the term-to-term product and the cross-product are in the process – and why.

Other than that, the quality of this ruling seems quite remarkable, given the high complexity of the technical field.


CASE REFERENCE: Cour d’appel de Paris, pôle 5 chambre 2, January 15, 2021, Codexis Mayflower Holdings LLC & Codexis Inc. v. Bernard O. & SASU Peaccel, RG No. 18/15295.