Kirin-Amgen Inc. v Transkaryotic Therapies Inc. (No.2)

Hearing dates: 4,5,6,7,8,19,20,21 February 2002

Approved Judgment

I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.

Mr. Justice Neuberger

Mr. Justice Neuberger:

INTRODUCTION

This is an application by Kirin-Amgen Inc. and others ("Amgen"):

a. For the amendment of European Patent (UK) Number 148,605 ("the Patent") by deleting Claims 19 to 25 inclusive therefrom;

b. For a determination that Amgen is entitled to recover damages, costs and expenses from Hoechst Marion Roussel Limited ("HMR") notwithstanding the amendment of the Patent.

HMR oppose both parts of the application, and contend that the Patent should be revoked.

I have considered the Patent on a number of occasions, and in particular in a judgment given on 11 ^th April 2001. In that judgment, I concluded that, subject to the question of amendment which now has to be considered, the Patent was valid, and that various parties, including HMR, infringed it.

The Patent relates to a protein called erythropoietin, or EPO for short, which is produced in healthy mammals in small, but vital, quantities. Its function is to stimulate the production of red blood cells which carry oxygen from the lungs to other parts of the body. The ability to synthesise EPO artificially has substantial commercial and therapeutic implications. Dr Fu-Kuen Lin, who was a member of a research team employed by Amgen, appears to have been the first person to have obtained the amino acid sequence of human EPO, and the DNA sequence of the human EPO gene. He also appears to have been the first person to have used human EPO DNA to enable artificial manufacture, or "expression", of EPO in certain types of cell, in particular the Chinese Hamster Ovary cell, or CHO cell, and the COS Monkey cell, or COS cell.

Naturally occurring human EPO is only obtainable in minute quantities; it can be extracted from urine, and hence is known as urinary EPO, or uEPO. Artificially expressed EPO such as that obtained in accordance with the work of Dr Lin, is known as recombinant EPO, or rEPO. Human EPO is a glycoprotein, i.e. a protein (or polypeptide) with carbohydrate units, or residues, attached. It is during the process of being expressed in a mammalian cell (whether in a human cell naturally or artificially, or in a COS cell or CHO cell artificially) that human EPO becomes glycosylated—i.e. carbohydrate residues become attached to the polypeptide chain, or backbone.

Much of the technical background necessary to understand the issues in the main action (as discussed in the judgment of 11 ^th April 2001 at paragraphs 41 to 131) is not germane to the more limited issues raised on these applications. However, one technique that should be mentioned is SDS-PAGE (discussed at paragraphs 122 to 131 of the earlier judgment). It is a method of assessing the relative molecular weights of different proteins, based on how far they migrate along a gel which is subject to an electric field. The further a protein proceeds along the gel in a particular time, the higher its apparent molecular weight. "Apparent", because it is a somewhat imprecise exercise, the mobility depending not only on weight, but also on the shape and electric charge of the protein.

The Patent as eventually granted contained a Description which ran to over 20 pages of closely printed material interspersed with another 20 pages of tables of polypeptide and DNA sequences. The Description included the following:

a. An introduction which explained that the invention "relates generally to the manipulation of genetic materials and, more particular, to recombinant procedures making possible the production of polypeptides possessing part or all of the primary structural conformation [of EPO]";

b. Over two pages describing "manipulation of genetic materials";

c. Over three pages explaining why EPO is "a polypeptide of interest";

d. A "brief summary" which effectively reproduced the claims, and then went on to explain how vertebrate cells, and in particular COS cells and CHO cells could be transfected with artificially made EPO DNA, which could then be used to express recombinant EPO;

e. A detailed description, which contained twelve Examples, effectively setting out the procedures involved in the claimed invention. In particular, Example 10 explained how CHO cells and COS cells could be transfected with the human EPO gene in a way which enables recombinant EPO to be expressed in substantial quantities.

There were 31 Claims in the Patent, as eventually granted. Claims 1 to 11 were to various DNA sequences. Claims 12 to 18 were to cells which had been transfected so as to be enabled to express EPO (and two of the Claims respectively referred to a transfected COS cell and a transfected CHO cell). Claims 19 to 26 were to various different types of recombinant polypeptide, i.e. to EPO which had been effectively manufactured substantially in accordance with the teaching of the Patent. Claims 20 to 25 were dependant on Claim 19. Claims 27 to 29 were process claims, and Claims 30 and 31 were claims to pharmaceutical composition substantially in accordance with the teaching of the Patent.

A more detailed description of the contents of the Patent is contained in paragraphs 132 to 183 of my earlier judgment.

A GENERAL OVERVIEW OF THE FACTS

The first application for a United States Patent was made on behalf of Amgen on 13 ^th December 1983, and the three other relevant subsequent applications were made on 21 ^st February, 28 ^th September, and 30 ^th November 1984. (While not of central relevance to the present applications, Amgen made a fifth application on 23 ^rd October 1987). Amgen's application for a European Patent was first filed on 12 ^th December 1984, claiming a priority date by reference to the four earlier US applications. The US Patent applications, like the European Patent application were substantial documents, running to well over twenty thousand words, and including many tables (of amino acid sequences and DNA sequences), Examples, figures, and Claims.

As I have mentioned, Example 10 of the Patent was concerned with describing the artificial expression of human EPO in COS cells and in CHO cells which had been transfected with human EPO DNA constructed according to the teaching of the Patent. After the third US application had been made, three paragraphs were added to the end of Example 10 in the fourth US Patent application (made on 30 ^th November 1984).

The three paragraphs (which I shall refer to as the first, second and third paragraphs respectively) at the end of Example 10 of the fourth US Patent application and of the European Patent application were in the following terms:

"A preliminary attempt was made to characterise recombinant glycoprotein products from conditioned medium of COS-1 and CHO cell expression of the human EPO gene in comparison to human urinary EPO isolates using both Western blot analysis and SDS-PAGE.These studies indicated that the CHO-produced EPO material had a somewhat higher molecular weight than the COS-1 expression product which, in turn, was slightly larger than the pooled source human urinary extract. All products were somewhat heterogeneous. Neuraminidase enzyme treatment to remove sialic acid resulted in COS-1 and CHO recombinant products of approximately equal molecular weight which were both nonetheless larger than the resulting asialo human urinary extract. Endoglycosidase F enzyme (EC 3.2.1) treatment of the recombinant CHO product and the urinary extract product (to totally remove carbohydrate from both) resulted in substantially homogeneous products having essentially identical molecular weight characteristics" (emphasis added).

"Purified human urinary EPO and a recombinant, CHO cell-produced, EPO according to the invention were subjected to carbohydrate analysis according to the procedure of Ledeen, et al.Methods in Enzymology, 83(Part D), 139–191 (1982) as modified through use of the hydrolysis procedures of Nesser, et al., Anal.Biochem., 142, 58–67 (1984). Experimentally determined carbohydrate constitution values (expressed as molar ratios of carbohydrate in the product) for the urinary isolate were as follows: Hexoses, 1.73; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.93; Fucose, 0; and N-acetylgalactosamine, 0.Corresponding values for the recombinant product (derived from CHO pDSVL-gHuEPO 3-day culture media at 100 nM MTX) were as follows: Hexoses, 15.09; N-acetylglucosamine, 1; N-acetylneuraminic acid, 0.998; Fucose, 0; and N-acetylgalactosamine, 0. These findings are consistent with the Western blot and SDS-PAGE analysis described above" (emphasis added).

"Glycoprotein products provided by the present invention are thus comprehensive of products having a primary structural conformation sufficiently duplicative of that of a naturally-occurring erythropoietin to allow possession of one or more of the biological properties thereof and having an average carbohydrate composition which differs from that of naturally-occurring erythropoietin."

Claim 40 included in each of the US Patent applications (which was effectively the predecessor of Claim...