Upcoming Mallesons seminarsU.S. pharmaceutical patent infringement decision - Amgen Inc v Hoechst Marion Roussel Inc and Transkaryotic Therapies Inc
Introduction
On 19 January 2001, U.S. District Court Judge, William Young, ruled that Transkaryotic Therapies Inc and Hoechst Marion Russel Inc (now Aventis Pharmaceuticals Inc) (collectively “TKT”) infringed three of five patents protecting the anaemia drug, Epogen, produced by Amgen Inc (“Amgen”). All of the patents in issue share a common disclosure and
identical specifications. Only their claims differ.
Epogen is a version of natural erythropoietin (“EPO”), a protein which acts by boosting the number of red blood cells in patients undergoing kidney analysis. It is made by inserting a human gene into hamster ovary cells which then produces EPO. TKT produced a yet to be marketed drug, Gene-Activated Erythropoietin, which also acts by boosting the number of red blood cells. However, it differs from Epogen in the manner in which it is manufactured. It acts by activating silent genes in human cells by inserting a promoter into the human’s gene sequence that then directs the cell to generate HMR4396, an EPO.
Claim Construction
The Court decided the claim construction issues at a separate hearing from the infringement claim, as there was a risk that if they were heard together, the Court might dispose of the case by narrowly construing the claims.
In determining the meaning of terms, the Court took the ordinary meaning approach, so that the words of the patent claims were the most important tool for determining the construction of the claims. For example, the Court was asked to interpret the meaning of “vertebrate cells” in the Amgen patent claims. Amgen argued that vertebrate cells are “cells originating from an animal having a backbone”, while TKT argued that vertebrate cells are “non-human cells that originate from an animal having a backbone”. The Court held that the term “vertebrate” is widely known and has a precise scientific meaning, and a human is regarded as a vertebrate. Therefore the Court accepted Amgen’s construction of “vertebrate cells”.
The Law - Patent Infringement
Proof of infringement may be made out pursuant to either the literal infringement theory or the doctrine of equivalents. In determining whether a product has literally infringed a patent claim, the Court first construes the claims to determine the scope of the claims and then compares the claim to the alleged infringing product. If the alleged infringing product does not meet each of the claims, the product does not literally infringe the patent. Even if there is no literal infringement, a product can infringe a patent in the U.S. on application of the doctrine of equivalents. If there are only insubstantial differences between the patent claims and the alleged infringing product, then that product may infringe the patent.
‘080 Patent
- an erythropoietin glycoprotein having the in vivo biological activity of causing bone marrow cells to increase the production of red blood cells; and
- a pharmaceutical composition comprising a therapeutic amount of such glycoprotein.
The glycoprotein is further limited because it must comprise “the mature erythropoietin amino acid sequence of Fig. 6”, which was construed by the Court to mean “the fully realised form of the amino acid sequence of Figure 6” of the patent specification. Figure 6 sets out the DNA sequence of human EPO, covering a sequence of 166 amino acids. The Court found that the language of the patent specification equated the amino acid sequence of mature human EPO with the specifically enumerated 166 amino acid sequence. Because the asserted claims were limited explicitly by the meaning of Figure 6, the specific amino acid sequence was significant. As a result, to literally infringe the ‘080 Patent, HMR4396 (human EPO produced by TKT’s gene-activation technology) had to contain a glycoprotein comprising the full amino acid sequence in Figure 6. The amino acids labelled 1 - 165 in Figure 6 are exactly the same as those contained in HMR4396. However, HMR4396 has only 165 amino acids. What was not known at the time of drafting the ‘080 patent was that arginine (the 166th amino acid) was cleaved off prior to the secretion of the protein from the cell. Because of the presence of amino acid 166 in Figure 6, the court found that HMR4396 did not literally infringe the ‘080 patent. However, the Court found that HMR4396 still performs in substantially the same way and achieves the same result as an erythropoietin glycoprotein containing 166 amino acids. The Court found that the lack or presence of this arginine did not make the substances materially different. Importantly, the lack of an arginine did not affect the in vivo biological activity of the EPO product. Therefore, the Court found that the ‘080 patent was valid, and was infringed by TKT.
‘422 Patent
The parties did not dispute the relevant facts regarding infringement of the ‘422 Patent. On the basis of their claim construction decision, the Court found that TKT literally infringed Amgen’s ‘422 Patent.
‘698 Patent
The ‘698 patent is a process patent that recites a series of steps that if followed by one skilled in the art, will produce an identified result. There are a number of distinctions between TKT’s process and that of Amgen. In order to make Epogen under the ‘698 patent, Chinese hamster ovary cells are transfected with a vector that contains both vital promoter DNA and the human EPO gene. The human EPO DNA is exogenous because it has been removed from the cell in which it originated, placed in a vector and reintroduced into a host cell. On the other hand, HMR4389 is made by manipulating the human EPO gene where it naturally resides in human cells. Therefore the human EPO is expressed in a human rather than a hamster cell.
Under the ‘698 patent, the promoter DNA inserts into a different location from TKT’s promoter, relative to the gene being expressed. The Court found that because of these two distinctions, TKT was entitled to a judgment of non-infringement on the ‘698 patent both literally and under the doctrine of equivalents.
‘349 Patent
Amgen claimed that TKT’s R223 cells, which are cells used to produce EPO, infringed Amgen’s patent in relation to vertebrate cells used to produce EPO. The Court found that the ‘349 patent was valid and all the claims except one were infringed. The claim that was not infringed was a process patent for the production of EPO and was not infringed for the same reasons as the ‘698 patent was not infringed. TKT attempted to distinguish its cells on the basis of the origin of the human EPO DNA contained therein. Amgen inserts the EPO DNA by transfection into a non-human host, whereas KT’s human cell already contains the human EPO DNA. This factual distinction was immaterial because the claim language of the ‘349 patent is not limited by the origin of the EPO DNA.
‘933 Patent
Amgen claimed that TKT infringed one independent and two dependent claims of the ‘933 patent. The independent claim stated that the invention was a non-naturally occurring EPO ... “having glycosylation which differs from that of human urinary erythropoietin”. Amgen showed that TKT’s product differed from all but one human urinary EPO. However, the Court found that because TKT’s product did not differ from all human urinary EPO, TKT did not literally infringe the patent. Further, the Court found that Amgen’s evidence was also insufficient to show an infringement under the doctrine of equivalents. Inequitable conduct TKT argued that Amgen’s patents ought to be declared unenforceable because they were obtained as a result of inequitable conduct. To prove this, TKT had to show:
- that the patentee withheld material information from the patent examiner or submitted false material information; and
- that the patentee did so with the intent to deceive or mislead the examiner into allowing the patent.
TKT contended that Amgen’s representatives withheld a urinary EPO clinical study. The Court found that although Amgen could have drawn more attention to this study, they did disclose it. Amgen did not submit actual scientific data relating to the study to the Patent Office nor did they extensively describe the study. However, the findings of the study were generally referred to. Most importantly, the Court found that Amgen did not deliberately hide the study from the Examiner. The Court concluded that there was no intent to deceive. Accordingly, TKT failed to prove that Claim 1 of the ‘422 patent ought not be enforced because of inequitable conduct by Amgen. TKT also argued that the ‘933 patent is unenforceable because Amgen misrepresented some material data and withheld other experimental data relating to glycosylation differences between recombinant and human urinary EPO. The Court found that Amgen complied with its duty of candour with respect to this data and that even if Amgen had withheld this information, such withholding would not give rise to inequitable conduct because TKT failed to prove that the data was material or that it was withheld with an intention to deceive. TKT further contended that the ‘422 and ‘349 patents should be rendered unenforceable because Amgen failed to disclose that its human host cell experiments performed with 239 cells were unsuccessful in producing high levels of EPO. TKT argued that Amgen failed to disclose these experiments because they would cast doubt on its assertion that its invention would extend to all mammalian cells, including human cells. The Court found that that the purpose of these experiments were not as TKT’s argument implies and therefore were not material to whether Amgen, as a matter of equitable conduct, could pursue cell and pharmaceutical claims that included human cells.
TKT also argued that the ‘349 and ‘422 patents should not be enforced because Amgen withheld from the Patents Office that the patents were the subject of litigation that went to the issue of the patentability of the patents themselves. The Court found that this was not all Amgen’s fault. According to the law, the clerk is required to give notice to the Commissioner, “setting forth so far as known the names and addresses of the parties, name of inventor and the designating number of the patent upon which the action has been brought.” The clerk gave notice but only referred to three of the five patents. More importantly, TKT did not demonstrate that Amgen possessed an intent to deceive the Patent Office. In summary, TKT did not prove any inequitable conduct on the part of Amgen, and the Court found that Amgen never intended to deceive the Patent Office.
Conclusion
The finding by the Court that TKT infringed three out of five of Amgen’s patents relating to Epogen effectively blocks TKT from selling their competing product. TKT has stated that they plan to appeal this decision.
Sally Ting
Solicitor
T +61 7 3244 8037
sally.ting@mallesons.com