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England and Wales High Court (Patents Court) Decisions
You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Takeda UK Ltd v F Hoffmann-La Roche AG (Rev 1)  EWHC 1911 (Pat) (17 July 2019)
Cite as:  WLR(D) 476,  EWHC 1911 (Pat),  Bus LR 2681
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BUSINESS AND PROPERTY COURTS OF ENGLAND AND WALES
INTELLECTUAL PROPERTY LIST (ChD)
The Rolls Building
7 Rolls Buildings
London EC4A 1NL
B e f o r e :
| Takeda UK Limited
|- and -
|F. Hoffmann-La Roche AG
Richard Meade QC,William Duncan and Thomas Jones (instructed by Marks & Clerk) for the Defendant
Hearing dates: 12th -14th, 17th - 21st, 23rd - 27th June 2019
Crown Copyright ©
Mr Justice Birss :
|The skilled person and the common general knowledge||29|
|The patent and claim construction||51|
Monoclonal antibody of human IgG1 or IgG3 type being glycosylated with a sugar chain at Asn297,
said antibody being characterized in that the amount of fucose within said sugar chain, related to the sum of G0, G1, G2 without mannose 4 and mannose 5 as 100% and as analyzed by Liquid Chromatography/Mass Spectrometry (LCMS) peptide map analysis is at least 99%
and in addition the amount of NGNA within said sugar chain, related to the sum of G0, G1, G2 without mannose 4 and mannose 5 as 100% and as analyzed by Liquid Chromatography/Mass Spectrometry (LCMS) peptide map analysis, is 1% or less,
and the amount of N-terminal alpha 1,3 galactose within said sugar chain related to the sum of G0, G1, G2 without mannose 4 and mannose 5 as 100% and as analyzed by Liquid Chromatography/Mass Spectrometry (LCMS) peptide map analysis is 1% or less.
2. Antibody according to claim 1, characterized in that the amount of NGNA is 0.5% or less.
3. Antibody according to claims 1 or 2, characterized in that the amount of N-terminal alpha 1,3 galactose is 0.5% or less.
4. Antibody according to claims 1 to 3, characterized in that the antibody is a chimeric, humanized or human antibody.
5. CHO cell line DSM ACC 2795.
6. Use of an antibody according to claims 1 to 4 for the manufacture of a medicament.
7. Pharmaceutical composition comprising an antibody according to claims 1 to 4.
8. Use of a CHO cell according to claim 5 for the recombinant production of a monoclonal antibody according to claims 1 to 4.
9. Method for the recombinant production of a monoclonal antibody according to claims 1 to 4 in a CHO cell according to claim 5.
i) Lack of novelty over:a) International Patent Application WO 2005/040221 A1 published 6th May 2005 ("Bihoreau");b) The article by Shinkawa et al entitled "The Absence of Fucose but Not the Presence of Galactose or Bisecting N-Acetylglucosamine of Human lgGl Complex-type Oligosaccharides Shows the Critical Role of Enhancing Antibody-dependent Cellular Cytotoxicity" (2003) in the Journal of Biological Chemistry, Vol.278, No.5, Issue of January 31, pp 3466-3473, 2003;c) The article by Ferrara et al entitled "The Carbohydrate at Fc?RIIIa Asn-162 An Element Required for High Affinity Binding to Non-Fucosylated IgG Glycoforms" published in The Journal of Biological Chemistry Vol.281, No.8 pp.5032-5036d) A prior use by the company Novartis of chimeric monoclonal antibody known as basiliximab (trade name Simulect). This was advanced in the EPO opposition and supported by declarations given the numbers D57, D58 and D59.
ii) Lack of inventive step:a) On the basis of lack of technical contribution;b) Bihoreau;c) Simulect;
iii) Insufficiency:a) Ambiguity in that the skilled person cannot identify what calculation is required by the claims;b) Ambiguity in that the skilled person cannot know whether they are carrying out the right test to find out if they are within the claims;c) A breadth of claim argument linked to lack of technical contribution;d) A classic insufficiency argument linked to deposited cell line DSM ACC 2795.
i) "99%-Roche" means 99% calculated using the method advanced by Roche as its primary case on construction of claim 1.
ii) "99%-Takeda" means 99% calculated using the method advanced by Takeda as its primary case on construction of claim 1.
iii) "99%-TRM" means 99% calculated using the method advanced by Roche as a modified version of the Takeda method. It is Roche's fall back alternative case for the construction of claim 1.
iv) "99%-Shields" means 99% calculated by the method used in a seminal common general knowledge paper called Shields.
The skilled person and the common general knowledge
i) The use of monoclonal antibodies as therapeutic agents;
ii) How to make antibodies for therapy and for research relating to therapy;
iii) The biochemistry of antibodies - particularly glycosylation, its nature and importance, the various monosaccharides and oligosaccharide structures encountered;
iv) Immunology and in particular antibody effector functions; and
v) Techniques for analysing glycosylation.
The patent and claim construction
"According to the invention 'amount' means the amount of said sugar within the sugar chain at Asn297, related to the sum of G0, G1, G2 (without mannose(4 and 5) as 100% and as calculated in example 3."
" The term "antibody" encompasses the various forms of antibodies including but not being limited to whole antibodies, antibody fragments, human antibodies, humanized antibodies and genetically engineered antibodies as long as the characteristic properties according to the invention are retained. Therefore an antibody according to the invention contains at least a functionally active (FcR binding) Fc part of lgG1 or lgG3 type comprising glycosylated Asn297."
Patent Example 3
|Relative amount of glycosylation variants||Relative amount of glycosylation variants||Relative amount of glycosylation variants||Relative amount of glycosylation variants||Relative amount of glycosylation variants||Relative amount of glycosylation variants|
|Clone No.||G0 [%]||G1 [%]||G2 [%]||NonFuc[%]||Man1 [%]|
Patent Example 4
"As reference standard of an antibody showing "no ADCC" is used an (monoclonal) antibody against KLH (keyhole limpet hemocyanin) or an lgG mixture isolated from about 35.000 donors ("Redimune"). A 75% fucose free antibody against IGF-IR was used as positive control. An antibody according to the invention showed a TDA release which is within 3xSD of the TDA release of the standard antibody (Fig.1)."
What is an antibody within claim 1?
99% amount of fucose
Vedolizumab fucose level
Vedolizumab functionally active (FcR binding) Fc region
(1) An invention shall be considered to be new if it does not form part of the state of the art.
(2) The state of the art shall be held to comprise everything made available to the public by means of a written or oral description, by use, or in any other way, before the date of filing of the European patent application.
"1.9 [ ] the appellant submitted that it would not be reasonable to consider that a product falling under granted claim 1 which was in the public's hands before the filing date of the patent in suit could be held not to anticipate the subject-matter of said patent. However, this is the conclusion reached in view of the condition which is derivable from decision G 1/92 (as explained in sections 1.3 and 1.4 above), namely that in order to be part of the prior art pursuant to Article 54(2) EPC, a public prior use must also amount to an enabling disclosure. A similar conclusion was already reached e.g. in T 977/93 (OJ EPO 2001, 84: sections 3, 4, 11 and 13 of the reasons), T 370/02 (sections 8.6 to 8.8 of the reasons), T 2045/09 (sections 29, 31 and 32-38 of the reasons) and T 23/11 (sections 2.1 to 2.5 of the reasons). The same line of argumentation was also adopted in T 301/94 (sections 3.3 to 3.5 of the reasons), albeit the conclusion in that case was that the alleged public prior use was part of the prior art because it could be reproduced without undue burden. Therefore, the appellant's argument is not persuasive."
"1.7 [ ] the appellant argued that it would not have been difficult for the skilled person to prepare a composition having the features of the public prior use product which were specified in claim 1. However, this is not the issue at stake. Rather, in order for the product to be state of the art, the question is whether or not the skilled person would have been in a position to prepare the product as such, i.e. a sample identical to RigidexฎP450xHP60 in all its properties (not only those specified in claim 1, but exhibiting e.g. also the same properties as indicated in [a prior art datasheet]). It was however not shown by the appellant that this was the case. [ ]"
"1.4 [ ] Where it is possible for the skilled person to discover the composition or the internal structure of the product and to reproduce it without undue burden, then both the product and its composition or internal structure become state of the art."
"To verify the combined effect of bisecting GlcNAc with Fuc, LEC10 cells, a variant CHO cell line overexpressing GnTIII (12), were used to produce chimeric anti-CD20 monoclonal IgG1. In oligosaccharide analysis, bisecting GlcNAc-binding fucosylated oligosaccharides were the majority on LEC10-produced anti-CD20 IgG1 (74% of bisecting GlcNAc and 100% Fuc; data not shown). In the ADCC assay, LEC10-produced IgG1 showed only severalfold enhancement of ADCC compared with RituxanTM (Fig 5B)."
"611. In giving her evidence the question asked of Professor Bertozzi was, correctly, "what, if anything, does the Patent make by way of a technical contribution over Bihoreau". Professor Parren on the other hand was asked to comment on what the skilled team "would do, if anything, if presented with the teaching of Bihoreau". The evidence he gives is therefore based on an incorrect premise."
Obviousness lack of technical contribution
i) Disclosing that CHO cells can be obtained having fucosylation of >99%;
ii) Disclosing the idea of increasing fucose for a therapeutically useful purpose;
iii) Disclosing the idea that increasing fucose to 99%+ would reduce ADCC to background.
Disclosing that CHO cells can be obtained having fucosylation of >99%
Disclosing the idea of increasing fucose for a therapeutically useful purpose
Disclosing the idea that increasing fucose to 99%+ would reduce ADCC to background
Lack of technical contribution - conclusion
i) A free standing issue, added during trial, relating to the rival approaches to calculating the amount of fucose;
ii) A kind of classic "it can't be done" kind of argument which is really a squeeze;
iii) A claim breadth argument which is a counterpart of the technical contribution case;
iv) An ambiguity type insufficiency concerned with how the skilled person works out whether a product is within the claim or not.
The rival approaches to calculating the amount of fucose
The classic "it can't be done" argument
Claim breadth as a counterpart of the technical contribution case
Ambiguity type insufficiency
|Nano LCMS /
|Nano LCMS /
|Total non-fuc without Man||8.6