Patents - Celltrion v Genentech

Omalizumab structure
Authors Manav Segal, Jeffrey R Stokes, Thomas B. Casale Licence CC BY 2,5
Source Wikimedia Commons

Jane Lambert

Patents Court (HH Judge Hacon) Celltrion Inc v Genentech, Inc and another [2025] EWHC 174 (Pat) (30 Jan 2025)
 

This was an action by Celltrion Inc ("Celltrion") for the revocation of European patent (UK)  3 805 248 B1 for a "Process for concentration of antibodies and therapeutic products thereof" ("the patent") held by Genentech Inc ("Genentech") and Novartis AG ("Novartis") and a counterclaim by Genentech and Novartis against Celltrion and its UK subsidiary for infringement.  The action and counterclaim were tried by His Honour Judge Hacon between 24 Oct 2024 and 1 Nov 2024.  The learned judge delivered judgment on 30 Jan 2025 (see Celltrion Inc v Genentech, Inc and another [2025] EWHC 174 (Pat) (30 Jan 2025)).  By para [193] of his judgment, he found that the patent was valid and infringed.

The Patent

The judge said that the patent's title was misleading because all of its 6 claims were for a product, each a solution containing omalizumab with a stated formulation.  The specification explained means for making the claimed formulations.  The judge explained in the introduction to his judgment that asthma is an inflammatory disease of the airways of the lungs, leading to wheezing, coughing, chest tightness and shortness of breath.  A frequent cause is an allergy that triggers the inflammation, such as dust mites, pollen and allergens produced by pets.  The body produces an antibody called Immunoglobulin E ("IgE"), which causes an allergic reaction.  Omalizumab is an anti-IgE antibody that binds to IgE, reducing or eliminating the reaction.  The disputed claims are as follows:

"1. 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.
2. The formulation of claim 1, wherein the formulation is substantially free from aggregates."

The Issues

Celltrion sought the revocation of the patent on grounds of anticipation, obviousness, implausibility, insufficiency and added matter. Celltrion and its subsidiary admitted that if the patent were valid, it would be infringed. The judge dealt with the claim for revocation first.

Anticipation

S.72 (1) (a) of the Patents Act 1977 provides for the revocation of a patent if the invention is not a patentable invention. One of the conditions for the grant of a patent is that the invention is new (see s.1 (1) (a) of the Act).   S.2 (1) states that an invention shall be taken to be new if it does not form part of the state of the art.   

State of the Art

The state of the art is defined by s.2 (2) as "all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way."  

S.2 (3) further provides:

"The state of the art in the case of an invention to which an application for a patent or a patent relates shall be taken also to comprise matter contained in an application for another patent which was published on or after the priority date of that invention, if the following conditions are satisfied, that is to say -
(a)    that matter was contained in the application for that other patent both as filed and as published; and
(b)    the priority date of that matter is earlier than that of the invention."

Lack of Novelty

In General Tire & Rubber Company v Firestone Tyre & Rubber Company Limited, [1972] RPC 457, the Court of Appeal said:

"If the prior inventor’s publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee’s claim if carried out after the grant of the patentee’s patent, the patentee’s claim will have been shown to lack the necessary novelty, that is to say, it will have been anticipated. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor’s publication will inevitably result in something being made or done which, if the patentee’s patent were valid, would constitute an infringement of the patentee’s claim, this circumstance demonstrates that the patentee’s claim has in fact been anticipated."

Prior Art

Celltrion argued that PCT Application WO 2004091658 A1 for High Concentration Antibody and Protein Formulations, invented by Jun Liu and Steven Shire ("Liu"), anticipated the invention. It alleged that Liu had identified two IgE antigens which provide a specific aspect of the claimed invention, one of which was omalizumab. Liu disclosed a formulation of 150mg/ml E25 20mM Histidine-HCI 200 mM Arg-HCI 0.02% Polysorbate 20 pH 6.0. The only difference between that formulation and claim 1 of the patent was that in Liu, the concentration of polysorbate 20 is 0.02% whereas in the patent in suit, the concentration was 0.04%. The judge held that the skilled addressee would not interpret 0.04% to include 0.02%. Liu also showed a range of other polysorbate concentrations and alternative types of polysorbate.  The issue was whether Liu's disclosure of a formulation with alternative polysorbates, each having a range of concentrations, anticipated claim 1 of the patent.

Whether the Patent was Anticipated

His Honour referred to the Court of Appeal's judgment in Jushi Group Co Ltd v OCV Intellectual Capital, LLC [2018] EWCA Civ 1416, which concerned a formulation for a type of glass strand used in the reinforcement of plastic and other materials. The prior art disclosed a range of values for each of several constituents, and the same was true of the formulation claimed in the patent. Even though the two ranges overlapped, the Court of Appeal held that there was no anticipation.   In the present case, there were 50 alternatives.  The skilled addressees would not have thought that there was an interrelationship between the range of concentrations of polysorbate and the type of polysorbate, and there were no indicated preferences in Liu.  Judge Hacon concluded that the patent was novel over Liu.

Doctrine of Equivalents

Celltrion submitted that the Supreme Court's judgment in Actavis UK Ltd v Eli Lilly & Co  [2017] Bus LR 1731, [2017] RPC 21, (2017) 157 BMLR 96, [2018] 1 All ER 171, [2018] 2 All ER (Comm) 1, [2017] UKSC 48 required a patent to be revoked for lack of novelty if a prior publication would have infringed the patent under the doctrine of equivalents. It argued that there can be no varying scope of a single patent claim because ss.2 and 3 of the Patents Act 1977 require validity to be assessed by reference to the invention. The invention is defined in s.125 (1), which states that the extent of protection conferred by a patent shall be determined by reference to the claim. S.125 (3) provides that the Protocol on the Interpretation of art.69 of the European Patent Convention shall apply for the purposes of s.125 (1). The scope of protection afforded by a claimed invention must therefore be the same as the scope of the invention when considered under ss.2 and 3. It follows that when applying ss.2 and 3, the assessments of validity and obviousness must be done not just by reference to the invention claimed and interpreted according to a normal construction, but also by reference to equivalents to the invention. If an equivalent lacks novelty or is obvious over the prior art, the patent is invalid.

Mr Justice Arnold had rejected that contention in Generics (UK) Ltd v Yeda Research and Development Co Ltd [2017] EWHC 2629 (Pat) as did Mr Justice Meade in Optis Cellular Technology LLC v Apply Retail UK Ltd [2021] 1939 (Pat), at [252]:

"In addition to raising how equivalence should be pleaded, the present case raises the issue of whether, as a matter of law, equivalence is available to broaden a claim as the target for an anticipation attack, or only applied to infringement. This is an extremely important point for UK patent law. It seems certain to need the consideration of the Court of Appeal and very probably the Supreme Court. When it is first ruled on in a case where it is decisive to the result, it will need to be fully argued, including with reference to the law of other EPC jurisdictions and with regard to how and whether people can be prevented from practising the prior art, or if not, how and why not."

Judge Hacon observed at para [80] of his judgment in Celltrion that the correct view on the relevance of equivalents in relation to novelty is connected closely with that in relation to inventive step.

The judge considered para 4.5. Taking equivalents into account of the Case Law of the EPO Boards of Appeal (10th ed., 2022), the judgments of the German, Dutch and French courts and the examination guidelines of the Spanish Patent and Trade Mark Office.  He concluded at [107]:

"In my judgment, the equivalents of a claimed invention are not relevant to the assessment of the novelty of the claim. I agree with the courts of the Netherlands. There may be some pedantic satisfaction to be had in making the scope of a claim identical from the perspective of both novelty and infringement, but this is outweighed by practical difficulties that would follow in the train of that view of the law. And there is no practical injustice inherent in the view that equivalents of the invention are irrelevant to an assessment of novelty."

He rejected Celltrion's alternative argument that claim 1 of the patent lacks novelty because of equivalents of the invention, stating that the argument had no basis in English law.

Obviousness

Another condition for the grant of a patent is that the invention involves an inventive step (s.1 (1) (b) of the Act).  S.3  provides:

"An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which forms part of the state of the art by virtue only of section 2 (2) above (and disregarding section 2 (3) above)."

Lord Hodge said at para [58] of his judgment in Actavis Group PTC EHF and others v ICOS Corporation and another  [2019] Bus LR 1318, [2019] RPC 9, [2019] UKSC 15, (2019) 167 BMLR 1, [2020] 1 All ER 213:

"These statutory provisions mandate the court to assess whether an invention is obvious by having regard to the state of the art at the priority date of the invention. If the invention is not obvious to the skilled person at that date, section 3 deems the invention to involve an inventive step."

He added at [60]:

"In addressing the statutory question of obviousness in section 3 of the 1977 Act it is common for English courts to adopt the so-called Windsurfing/Pozzoli structure which asks these questions:

'(1) (a) Identify the notional ‘person skilled in the art’;
(b) Identify the relevant common general knowledge of that person;
(2) Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
(3) Identify what, if any, differences exist between the matter cited as forming part of the ‘state of the art’ and the inventive concept of the claim or the claim as construed;
(4) Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?'
(Pozzoli SPA v BDMO SA [2007] EWCA Civ 588; [2007] FSR 37, para 23 per Jacob LJ)"

Skilled Addressee

The judge noted at para [8] of his judgment that the "person skilled in the art" would be a team consisting of a clinician and a formulator of medications.

Common General Knowledge

His Honour mentioned in para [22] that the parties had agreed a joint statement of common general knowledge, which he referred to in various passages of his judgment.

Inventive Concept

The judge construed claim 1 of the patent between paras [19] and [41].  He concluded that it was a claim to a formulation of a liquid solution. If it were to be treated as a recipe, then it was a recipe for the contents of the solution, not a list of the ingredients before they are tipped in. It followed that the arginine-HCl must have a molarity of 0.2M, and therefore, the histidine ingredient added was histidine-HCl.

Differences between the Prior Art and the Inventive Concept

Celltrion relied on a paper by Kentaro Shiraki and others entitled Biophysical effect of amino acids on the prevention of protein aggregation which appeared in the Journal of Biochemistry Volume 132, Issue 4, October 2002, Pages 591–595.  The learned judge summarized the paper between para [111] and para [113] of his judgment:

"[111] Proteins fold into their native structure spontaneously. Under certain conditions they may unfold and refold. During either, undesirable protein aggregation may occur. Professor Shiraki and his colleagues tested the effect of 15 alternative amino acids for their effect on preventing aggregation, primarily using the protein lysozyme as a model system. Arginine exhibited the best results with lysozyme and other proteins:

'These results indicated that Arg has the most significant effect on the prevention of aggregation of various kinds of proteins despite differences of pI and molecular weight.'
(pI is the pH value at which the molecule carries no electrical charge).

[112] The discussion at the end of the paper includes these observations:

'(i) The addition of Arg at 200 mM improves heat-induced protein aggregation. … (ii) The addition of Arg at 200 mM also improves dilution-induced aggregation from the denatured form. However, dilution-induced aggregation is related to the balance of folding competition … (iv) Keeping protein concentration low is one of the easiest ways to minimize protein aggregation. Previous reports have suggested that optimum refolding yields can be expected in the range of 10-50 µg/ml.'

[113] Three tests are described. The experts agreed that the most relevant of these involved heat-induced aggregation at 98 [degrees] C."

His Honour said that it would have been reasonable for the skilled team to expect that a modification of the lyophilized form of omalizumab with arginine would arrive at a liquid formulation of omalizumab which was both sufficiently stable and suitable for administration to patients as a treatment for asthma. However, it would not have been obvious to try a formulation with about 150 g/L omalizumab or with 0.04% polysorbate 20. The evidence indicated that the skilled team would have had no reason to depart from the information contained in the label for the lyophilized form of omalizumab marketed as 'Xolair' for those components, or at least not such as to arrive at the figures of claim 1. No expectation in relation to the claim 1 formulation would have arisen one way or the other.

Would the Steps between the Prior Art and the Claim have been Obvious?

It followed that claim 1 of the patent would not have been obvious over Professor Shiraki's paper.

Implausibility

I discussed the concept of plausibility in Plausibility - Generics (UK) Ltd and others v AstraZeneca AB on 29 July 2025 and also in a presentation and handout that I delivered to a big Birmingham law firm on 23 Oct 2023 (see Plausibility - A Review of the English and EPO cases 7 Aug 2025 NIPC Training).

The judge noted at para [174] that the invention claimed was "an incredibly narrow invention." Celltrion argued that identifying the mere idea of a concentration of 150 g/L omalizumab in a formulation was not a technical contribution that justified a patent.  It submitted that the disclosure said to justify the invention claimed must be assessed by reference to the 5 questions identified by Mr Justice Birss at para [207] of his judgment in Takeda UK Ltd v F. Hoffman-La Roche AG [2019] WLR(D) 476, [2019] RPC 18, [2019] EWHC 1911 (Pat), [2019] Bus LR 2681] EWHC 1911 (Pat):

"In relation to each disclosure there are five questions to answer: Is it disclosed in the patent? Is it plausible? Is it true? Is it a technical advance? Does it support claims of the breadth they are?"

Judge Hacon addressed each of those questions between [183] and [186] and concluded at [187] that claim 1 was not obvious on the ground that the invention claimed made no technical contribution to the art.

Insufficiency

S.14 (3) of the Patents Act 1977 requires a specification of an application to disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the art.   If it does not, s.72 (1) (c) entitles the Patents Court or the Comptroller-General of Patents, Designs and Trade Marks to revoke the patent for the invention.  Celltrion's argument on insufficiency depended on claim 1 covering formulations with histidine salts other than histidine-HCl. As the judge had found that it did not, the attack of insufficiency fails.

Added Matter

Another ground for the revocation of a patent is that the matter disclosed in the specification of the patent extended beyond that disclosed in the application for the patent, as filed (see s.72 (1) (d)). Celltrion argued that the claims of the PCT application WO 2006/031560 A2  contained only process claims and that so far as products were concerned, the disclosure was limited to formulations made by the processes disclosed. Taking claim 1 for example, Celltrion argued that the new matter disclosed in the patent was that the product could be made by means other than those disclosed in the application.  

The argument failed because the summary of the invention in the PCT application began as follows:

"In general terms, the present disclosure generally relates to processes for concentrating proteins, such as processes for concentrating antibody preparation, pharmaceutical formulations containing such a preparation, and there [sic] use human therapy or animal therapy."

The reader was thus told that what followed would include the disclosure of formulations as such.  The formulation of claim 1 was disclosed three times.

Infringement

As infringement was admitted, subject to the validity of the patent, the judge did not need to try the counterclaim.

Comment

There are a lot of issues in this judgment, some of which are quite novel.  The question of whether the doctrine of equivalents applies to anticipation is one example.  The argument over whether the invention made a technical contribution is another.  Anybody wishing to discuss this case can call me on 020 7404 5252 during normal UK office hours or send me a message through my contact form at any time.