Celltrion Inc v Genentech, Inc & Anor [2025] EWHC 174 (Pat) (30 January 2025)
Genentech and Novartis have successfully defended the validity of their patent for a formulation of omalizumab in a revocation action brought by Celltrion.
The decision of HHJ Hacon was handed down on 30 January 2025. Celltrion sought to revoke the patent on grounds including lack of novelty, lack of inventive step and insufficiency. Celltrion admitted its biosimilar product, Omlyclo®, infringed the patent, if it was held valid. Omlyclo is the first omalizumab biosimilar approved in Europe.
This judgment covers a lot of ground but this article will focus on the issues of primary interest, namely the issues concerning the construction of ranges within the patent claims and Celltrion’s lack of novelty arguments which included an alternative argument that the doctrine of equivalents should extend to novelty.
Background
Asthma is an inflammatory lung disease which affects the airways of the lungs, leading to wheezing, coughing, chest tightness and shortage of breath. According to the World Health Organisation, asthma currently affects approximately 262 million people globally, with the UK having a particularly high prevalence of the disease. One cause of asthma is an allergy which triggers inflammation of the lung airways. Common allergens include dust mites, pollen and allergens produced by animals, often pets. These allergens cause the immune system of an affected individual to overact, thereby producing a type of antibody called Immunoglobulin E (“IgE”).
Omalizumab is a monoclonal antibody (designated rhuMAB E25), designed to treat asthma. It is an anti-IgE antibody which works by binding to IgE thereby reducing or eliminating the allergic reaction triggered. In the UK, omalizumab is marketed by Novartis under the brand name Xolair®. In Europe, Xolair® is available in two forms: a vial containing a powder and solvent that are made up into a solution for injection which must be administered by a doctor; and as a prefilled syringe containing a solution for injection which is suitable for administration at home.
Genentech and Novartis’ patent, EP 3 805 248 (“EP248”), claims a pharmaceutical liquid formulation of omalizumab with stated constituents. The claims of the patent are product claims, each in respect of a solution containing omalizumab with a stated formulation. Claim 1 of EP248 concerns a pharmaceutical formulation of anti-IgE antibody rhuMAB E25, characterised in that the formulation is about 150g/L of the anti-IgE antibody in 0.02M histidine, 0.2M arginine-HCl, 0.04% polysorbate 20, pH 6. Claim 2 claims a formulation according to Claim 1, wherein that formulation is substantially free from aggregates.
Construction
The Judge’s consideration of construction concerned five ‘ingredients’ of the claims: liquid, temporal stability of the formulation, about 150g/L anti-IgE antibody, 0.04 polysorbate 20, and histidine.
Liquid
It was common ground between the parties’ experts that the formulation of the patented claims must be a liquid. However, Celltrion argued that a lyophilised formulation which has been reconstituted into a liquid fell within the claims. Novartis and Genentech argued the claims were limited to a formulation made up as a liquid and remaining as such. The Judge agreed with Novartis and Genentech on the basis that the skilled team would have expected that a formulation in liquid form which had been reconstituted from lyophilised material would have been described in that way and none of the processes set out in EP248 involved lyophilisation.
Temporal stability
Celltrion argued that neither the description of EP248 or its claims disclosed anything in respect of the temporal stability of the claimed formulation. However, the parties’ agreed statement of common general knowledge (“CGK”) provided that the skilled team would have understood that a liquid formulation that would have been manufactured as a liquid and therefore stored, transported and administered in liquid form. It followed therefore that the formulation must be sufficiently stable in the period between manufacture and administration to remain suitable for administration. The Judge found, based on the evidence, that the skilled team would expect the formulation in claim to be stable for at least 6 months, possibly much longer.
‘About’ 150g/L anti-IgE antibody
There was dispute between the parties in relation to the scope of ‘about’ in respect of the 150 g/L of the antibody stated within Claim 1. Celltrion argued that conventional rounding provided for variation in range of +/- 5 g/L and that the inclusion of the word ‘about’ in the claim adds further flexibility in the range so as to include 125 g/L. The evidence of Celltrion’s experts was that the skilled team would have been seeking to achieve the highest concentration of antibody possible in order to minimise the volume to be injected into the patient and that EP248 discloses a particularly high concentration. The Judge accepted Genentech and Novartis’ argument and found that the flexibility, if any, to be given to a number in a patent claim is always fact dependent. HHJ Hacon said that the inclusion of the word ‘about’ or something similar preceding a stated figure assumed some variation of that figure. The Judge found that the rounding convention was likely to provide a good guide as to the degree of flexibility that the skilled team would have taken EP248 to mean i.e. a range of between 145-155 g/L.
0.04 polysorbate 20
Celltrion made a similar argument in relation to the quantity of the polysorbate disclosed in the claim on the basis it was arbitrary. The Judge found that skilled team would have understood the patentee to have intended a limitation to the claim by stating a figure of 0.04% and would have treated it accordingly. Again, the Judge was of the view that to the extent that there was any flexibility, it would not have gone beyond the usual rounding convention.
Histidine
There was also a dispute in relation to the meaning of the word ‘histidine’ in the claim. Histidine is an amino acid and would be added to the other contents in claim 1 of EP248 in the form of a salt, the most common of which is histidine-HCl. The salt would dissociate in part in solution leaving histidine as a free base and the counteracid existing in equilibrium. At pH 6 the histidine and counteracid act as a buffer to resist small changes in pH. Genentech and Novartis’ position was that the histidine has to be histidine-HCl because arginine-HLC is also included, and both will partially dissociate in solution. If some other salt were used, it would impact the molarity of arginine-HCl by producing some lesser molarity.
Celltrion argued that claim 1 is a claim to a recipe and that 0.2M histidine and 0.2M arginine-HCl are two ingredients to be added to make the whole. Therefore, what happens in respect of the free base amino acids and their counterirons in solution has no relevance to the claim.
The Judge agreed with Genentech and Novartis and found that if the claim is to a recipe then it is a recipe for the contents of the solution, not merely a list of ingredients to be ‘tipped in’. Therefore, the histidine ingredient must be histidine-HCl.
Celltrion’s novelty and anticipation by an equivalent argument
Celltrion cited a single piece of prior art in support of its lack of novelty claim, a PCT application with publication no. WO 2004/091658 A1, of which Genentech was the proprietor (“Liu”). Liu was published post priority so was available only in respect of novelty. Liu discloses an earlier or parallel stage of Genentech’s antibody formulation research. The focus of the invention claimed in Liu is the discovery that arginine, arginine-HCl specifically, is particularly suitable for highly concentrated liquid protein or antibody formulations. The summary of the invention in Liu provided that: “… the present invention concerns highly concentrated antibody formulations arginine-HCl (50-200 mN) and polysorbate (0.01% – 0.1%) having a pH of 5.5-7.0, a viscosity of 50 cs or less and osmolarity from 200 mOsm/kg – 450 mOsm/kg.” Further, the description identifies two IgE antigens, including rhuMAbE-25 (shortened to E25 later in the description), namely omalizumab. Polysorbates are also among the surfactants stated to be suitable for the formulation disclosed in Liu.
Liu identified two specific formulations. The difference between one of the examples in Liu, Example 2, and claim 1 of EP248 is that Example 2 refers to concentration of polysorbate 20 of 0.02% and claim one refers to concentration of polysorbate 20 of 0.04%.
Because of the Judge’s findings on construction i.e. that the concentration of polysorbate 20 in claim 1 would be treated by the skilled team as stated at 0.04%, and to the degree there was any flexibility, the figure would not encompass 0.02%.
Overlapping ranges, lists and selection
Following his findings on construction, the Judge considered whether Liu’s disclosure of a formulation with alternative polysorbates (at least five), each having a range of concentrations, taken with the disclosed elements of Example 2 i.e. 150 mg/ml E25, anticipated claim 1. With regard to overlapping ranges or lists, or the selection from a range or list, the Judge found that relevant test was whether the prior art would lead the skilled person to ‘seriously contemplate’ use of the specific value for the element as claimed in the patent. Citing Jacob LJ in Dr Reddy’s (Dr Reddy’s Laboratories (UK) Ltd v Eli Lilly & Co Ltd [2009] EWCA 1362), the Judge found that in order to be novelty destroying an ‘individualised description’ of the later claim compound or class of compounds was required.
The Judge explained that the EPO Guidelines provides a summary of what constitutes an individualised description, providing that a sub-range selected from a broader numerical range of prior art will be considered novel provided that it meets two criteria: (i) the selected sub-range is narrow compared to the known range; and (ii) the selected sub-range is sufficiently far removed from any specific examples disclosed in the prior art. The Guidelines provide that the meaning of ‘narrow’ and ‘sufficiently far removed’ needs to be decided on a case by case basis.
The Judge found that in circumstances where there may be selection from two or more lists, if the nature and degree of interdependence is not clear to the skilled person then any doubt in this regard may suggest that the prior art does not anticipate the claimed invention. The Judge also considered other factors may be potentially relevant, including the extent of overlap with a prior art range and statement of preference in the prior art which point towards the claimed invention.
The Judge found that the relevant selection in EP248 is both from a range of between 0.01%-0.1% and from a list of polysorbates with at least five alternatives. In relation to concentration, the Judge found that the skilled team would interpret the range as a series of alternatives in integers of 0.01% i.e. 10 in all. The Judge held that the correct analysis is not simply a numbers game and that the prior art must provide an individualised description of the invention as claimed, including the relevant value of the element in dispute, in order to deprive the invention of novelty.
In the result, the Judge found that the selection in this case was one of at least 50 alternatives and the skilled team would not have thought of the interrelationship between the range of concentrations of polysorbate and the type of polysorbate. Furthermore, there were no indicated preferences in Liu. As such, the Judge found that claim 1 of EP248 was novel over Liu.
Anticipation by equivalent – an Angora cat?
Celltrion advanced an alternative argument on lack of novelty that the scope of a claim must be the same when assessing validity as its is for infringement, which includes equivalents of the invention as construed on a normal construction. If not, all patentees would have the ability to be an Angora cat: very small, cuddly and docile with smooth hair when validity is challenged yet very large when infringement is alleged with bristling fur, teeth and claws bared and flashing eyes.
The Judge considered the English case authorities, citing Mr Justice Meade’s statement in Optis Cellular Technology LLC v Apply Retail UK Ltd [2021] 1939 (Pat) in relation to whether equivalence is available to broaden the scope of a claim as the target for an anticipation attack, or only applicable to infringement. Mr Justice Meade expressed a view in Optis that, given its importance, that issue would require the consideration of the Court of Appeal and likely the Supreme Court.
HHJ Hacon held that because he was concerned with novelty only, the Angora cat was therefore ‘tamed’ with no teeth or eyes blazing. This was because although the scope of the claim is wider when assessing infringement, for all practical purposes, the scope of the claim that can be asserted against the world goes no wider than its scope when assessing novelty under section 2 of the Patents Act 1977. In doing so, the Judge found that the Formstein defence has now become part of English law, subject to a contrary ruling by the Court of Appeal or Supreme Court.
The Judge then went on to review the Case Law of the EPO Boards of Appeal and EPC Contracting States and considered the impracticality of national Intellectual Property Offices considering equivalents of the invention claimed in a patent application during examination and prosecution given the lack of harmony in approach to equivalents in different jurisdictions. Following that consideration, the Judge found that the equivalents of a claimed invention are not relevant to the assessment of the novelty of the claim. HHJ Hacon held that while there may be ‘some pedantic satisfaction’ in making the scope of a claim the same from the perspective of both novelty and infringement, this was outweighed by the practicality considerations. He therefore found that Celltrion’s alternative argument had no basis in English law.
More to come
An application for permission to appeal the UK court’s decision is still pending but the UK is not the only forum for this dispute.
There are ongoing proceedings between the parties in The Netherlands and also before the UPC concerning the same or related patents. The UK Court decision follows the decision of the Dusseldorf Local Division of the UPC to refuse an application made by Novartis and Genentech for a preliminary injunction for imminent infringement of the patent. Despite Celltrion obtaining a marketing authorisation Omlyclo®, in May 2024, the Dusseldorf Local Division found that there was insufficient evidence that Celltrion had taken more than regulatory steps and had not engaged in price negotiations or made applications for reimbursement. Genentech and Novartis’ application for provisional measures was therefore refused.
The entire UK judgment can be read here.
The UPC judgment in respect of the application for provisional measures is available here.
