HC 1999 No. 03241
Strand, London, WC2A 2LL
B e f o r e :
| HOECHST MARION ROUSSEL and others||Claimants|
|- and -|
| KIRIN-AMGEN INC. and others ||Defendants|
Mr. Antony Watson QC and Mr. Andrew Waugh QC and Mr. Tom Hinchliffe and Mr. Colin Birss (instructed by Messrs. Taylor Joynson Garrett) for the Defendants/Patentees.
Hearing dates : 4,5,6,7,8,19,20,21 February 2002
Crown Copyright ©
Mr. Justice Neuberger:
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.
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.
A GENERAL OVERVIEW OF THE FACTS
“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.”
“A recombinant polypeptide [having a similar structure to naturally occurring human EPO and with the biological properties of human EPO] and characterised by being the product of eucaryotic expression of an exogenous DNA sequence and which has higher molecular weight by SDS-PAGE from erythropoietin isolated from urinary sources.”
This closing characterisation or limitation was dependent on the teaching of the three paragraphs in Example 10.
a. Includes the first and third of the three paragraphs in Example 10;
b. Excludes from Example 10 the second of the three paragraphs;
c. Includes a claim, Claim 19, to “a recombinant polypeptide” which has appropriately defined sequences and biological properties “being the product of eucaryotic expression of an exogenous DNA sequence and which has higher molecular weight by SDS-PAGE from erythropoietin isolated from urinary sources”;
d. Includes Claims 20 to 25 which are effectively contingent on Claim 19.
THE PARTIES’ CONTENTIONS
a. The first paragraph of Example 10 described COS rEPO as having a “slightly larger” apparent molecular weight than urinary EPO, whereas there is not and never has been any evidence available to Amgen to support this;
b. The first paragraph of Example 10 described CHO rEPO (and indeed COS rEPO) as having a higher apparent molecular weight than urinary EPO, whereas Amgen knew that urinary EPO had a variable apparent molecular weight which was sometimes equal to that of CHO rEPO (and was sometimes equal to and sometimes greater than, that of COS rEPO);
c. The carbohydrate analysis of recombinant EPO as described in the second paragraph was demonstrably inaccurate.
I shall refer to these errors as error (a), error (b), and error (c) respectively.
The Statutory framework
“(1) If the validity of a patent is put in issue in proceedings for infringement… and it is found that the patent is only partially valid, the Court… may, subject to sub-section (2) below, grant relief in respect of that part of the patent which is found to be valid and infringed.
(2) Where in any such proceedings it is found that a patent is only partially valid, the Court… shall not grant relief by way of damages, costs or expenses, except where the plaintiff… proves that the specification for the patent was framed in good faith and with reasonable skill and knowledge, and in that event the Court… may grant relief in respect of that part of the patent which is valid and infringed, subject to the discretion of the Court… as to costs or expenses and as to the date from which damages should be reckoned.”
“(1) Subject to the following provisions of this Act, the court… may on the application of any person… revoke a patent for an invention on (but only on) any of the following grounds, that is to say –
(c) the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art;
(4) An order under this section may be an order for the unconditional revocation of the patent or, where the court… determines that one of the grounds… has been established, but only so as to invalidate the patent to a limited extent, an order that the patent should be revoked unless within a specified time the specification is amended under section 75…”
“In any proceedings… in which the validity of the patent is put in issue the Court… may, subject to section 76 below, allow the proprietor of the patent to amend the specification of the patent in such manner, and subject to such terms as to advertising the proposed amendment and as to costs, expenses or otherwise, as the Court… thinks fit.”
“If the grounds for revocation only affect the European patent in part, revocation shall be pronounced in the form of a corresponding limitation of the said patent. If the national law so allows, the limitation may be effected in the form of an amendment to the claims, the description or the drawings.”
Partially valid patents: introduction
Partially valid patents: the cases before 1999
“If it was the law in 1919 that a patent with an invalid claim was invalid until amended, then it is no longer the law. The Court has power to grant relief in respect of a partially valid patent without requiring amendment.”
He reached that decision based on his earlier decision in Hallen Co. –v- Brabantia (UK) Limited  FSR 134 at 138, and on the reasoning of the Court of Appeal in C. Van der Lely  RPC 54.
“[S]ection 63… has swept away the old rule that the presence of an invalid claim rendered the whole patent invalid. Instead, such a patent is now treated as “partially valid”, and provided that the specification for the patent was framed in good faith and with reasonable skill and knowledge, the Court may grant relief in respect of the valid claims found to have been infringed.”
“In such a case it can grant relief without requiring amendment or may direct that it be amended to its satisfaction. Thus, if a claim specifies more than one invention, it may grant relief in respect of one of those inventions even though the other invention is invalid.”
“The defendants submitted that this is a case where the Court should not exercise its discretion so as to allow the amendment. Counsel did not shrink from the conclusion that he said resulted, namely that the patent should be revoked, thereby depriving the plaintiffs of any patent protection for the invention that I held had been made.”
“Clearly such a finding would be harsh and would only seem to provide justice if there are very exceptional circumstances.”
Further, in a subsequent passage in the judgment at  FSR 463 Aldous J said this:
“In cases of deletion, a patentee will not be deprived of the fruits of his invention unless there are very compelling reasons to do so.”
Partially valid patents: the law since 1999
“The discretion as to whether or not to allow amendment is a wide one and the cases illustrate some principles which are applicable to the present case. First, the onus to establish that amendment should be allowed is upon the patentee and full disclosure must be made of all relevant matters. If there is a failure to disclose all the relevant matters, amendment will be refused. Secondly, amendment will be allowed provided the amendments are permitted under the Act and no circumstances arise which would lead the court to refuse the amendment. Thirdly, it is in the public interest that amendment is sought promptly. Thus, in cases where a patentee delays for an unreasonable period before seeking amendment, it will not be allowed unless the patentee shows reasonable grounds for his delay. Such includes cases where a patentee believed that amendment was not necessary and had reasonable grounds for that belief. Fourthly, a patentee who seeks to obtain an unfair advantage from a patent, which he knows or should have known should be amended, will not be allowed to amend. Such a case is where a patentee threatens an infringer with his unamended patent after he knows or should have known of the need to amend. Fifthly, the court is concerned with the conduct of the patentee and not with the merit of the invention.”
As he pointed out, that passage was accepted by the Court of Appeal in Hsiungs’ Patent  RPC 497.
“Section 63 is concerned with a case where the patent is partly valid as is Article 138(2); whereas section 75 permits amendment to validate an invalid patent. That difference was exposed in Van der Lely N.V. –v- Banfords Limited  RPC 54” (paragraph 36).
“We did not hear argument on the amendments sought by OGT, but on their face they appear to be of the kind designed to validate an invalid patent rather than to limit the patent to a part which is valid. Thus it would seem that the court would have to exercise its discretion under section 75 when considering the amendments. If the amendments had been of the kind which reflected the fact that one claim was valid, then section 63 could apply provided that the claim was infringed. In those circumstances the word “may” in section 63 might be construed in a permissive sense to give effect to the word “shall” in Article 138(2).”
The contention that the Court of Appeal took the view that, by enacting section 63, the legislature gave effect to the first sentence of Article 138(2) is reinforced by the apparent equating of the two provisions in paragraph 41 of the judgment at  RPC 322.
Partially valid patents: conclusion
Discretion to allow or refuse amendment
Damages, expenses and costs: if section 63(2) does not apply
“[It] is for a defendant to establish that special conditions exist before terms will be imposed or a patentee will be deprived of part of his damages. A patentee who has made an invention, disclosed it to the public in his specification and established that his specification was framed in good faith and with reasonable skill and knowledge is entitled to the full rewards provided by the law unless some special circumstances exist.”
“[I]t will remain the fact that the defendant has infringed a valid claim, and that the plaintiff ought not to be deprived of his right to damages in respect thereof without good reason. If the presence of the invalid claims has induced the defendant to act as he did, then it would be unjust to order him to pay damages prior to the date on which the invalidity of the claims was established. If, on the other hand, the presence of the invalid claims has had no effect upon the defendants’ conduct, then ordinarily it would not be just to deprive the plaintiff of any part of his damages.”
Damages, costs and expenses: section 63(2)
“[I]t is my view that section 63(2) imposes upon a plaintiff a duty to prove on the balance of probabilities two things: first that the specification was framed in good faith. That requires a plaintiff to prove that the specification was framed honestly with a view to obtaining a monopoly to which, on the material known to him, he believed he was entitled. Secondly, that the specification was framed with reasonable skill and knowledge. The words “skill and knowledge” are a composite phrase relating to the competence employed in framing the specification and require the specification as framed to be in the form in which a person, with reasonable skill in drafting patent specifications and a knowledge of the law and practice relating thereto, would produce.”
“I did not have in mind the possibility that the draftsman may not have been properly instructed on the details of the invention. In such a case, a patentee cannot be in a better position than the patentee who properly instructs the draftsman.”
“Where an amendment of the specification… has been allowed under any of the provisions of this Act, no damages shall be awarded in proceedings for an infringement of the patent committed before the decision to allow the amendment unless the Court… is satisfied that the specifications of the patent as published was framed in good faith and with reasonable skill and knowledge.”
THE ISSUES OF FACT AND INFERENCE
Error (a) in 1984
“Recombinant monkey and human EPO produced by COS cells have the same molecular weight as native urinary EPO [Goldwasser’s [urinary] EPO]. This result indicates that the recombinant EPO is glycosylated to the same extent as the native protein.”
(1) If one confines oneself to Goldwasser uEPO, then:(a) the statement in Example 10 that COS rEPO had a “slightly larger” apparent molecular weight than pooled urinary EPO is incorrect: they ran the same on SDS-PAGE;(b) the statement that CHO rEPO had a higher apparent molecular weight than urinary EPO is correct.
(2) If one includes Lot 82 uEPO and/or Therapeutics uEPO, then:(a) the statement about the performance of COS rEPO remains inaccurate;(b) the statement about CHO rEPO is no longer reliable, because it has the same apparent molecular weight as some urinary EPOs.
Error (a): 1994
“By Western analysis, the recombinant and human urinary EPO migrate identically.”
In the highly respected New England Journal of Medicine (Vol 316, page 73) in a paper of which Dr Egrie was also one of the authors, there was this:
“In addition, the carbohydrate portion… of the natural urinary and recombinant hormones are indistinguishable…”
That meant that the two types of EPO must have the same apparent molecular weight, because, virtually by definition, the polypeptide backbone of the two EPOs was the same, and Mr Borun would or should have understood this. In her evidence in the Interference Proceedings, Dr Egrie specifically confirmed that she stood by her views in these papers.
“Dr Egrie… found that COS cell-expressed recombinant EPO and the pooled human urinary EPO migrated identically on SDS-PAGE, while CHO cell-expressed recombinant EPO moved differently…”
“It must always be remembered that it is the task of the patent agent to exercise his skill to apply to obtain as wide a coverage for the invention which is disclosed to him by the inventor as the state of the art known to him at the time of the application would reasonably warrant.”
Want of good faith
Amendment or revocation
Damages, costs and expenses
“[W]e have been looking in detail at one claim and one short passage in a long and complex specification. In my view, the skill in drafting overall was of the highest order and to end up with only the present areas of concern is to my mind, highly creditable.”
“[T]here appears… to be no certainty of getting a particular rEPO glycosylation pattern. The glycosylation patent for uEPO would also appear to depend on the time of day, and physiological status of the patient from whom it is obtained. rEPO thus appears to share with uEPO the characteristic that the carbohydrate composition is to a considerable degree a matter of chance.”
They also went on to make express reference to Amgen’s submissions to the FDA.
“The basis for this restriction was simply given by reference to the first paragraph of Example 10.”
As already mentioned, it seems to me that if error (a) had been excised from Example 10, but error (b) had remained, the Appeal Board would have had no good reason for reaching a different conclusion from that which they reached.