In Amgen Inc., v. Hoechst Marion Roussel, Inc. (Now Aventis) and Transkaryotic Therapies, Inc., (05-1157), the Court of Appeals for the Federal Circuit affirmed a District Court’s decision that Transkaryotic Therapies Inc. (TKT) and Aventis Pharmaceuticals Inc. infringe Amgen’s erythropoietin (EPO) patent estate. The court’s decision upheld the validity of two of Amgen’s EPO patents and the infringement by TKT of three patents and 12 claims, including a patent that does not expire until 2015.

The current appeal reviewed the District Court’s findings on the infringement and validity of two patents with claims to the production of erythropoietin, the infringement of one product patent under the doctrine of equivalents, and the validity of one product patent. The Federal Circuit found the production patents valid and infringed (U.S. Patent Nos. 5,618,698 and 5,756,349). The court reversed the District Court’s determination that TKT infringed Amgen’s U.S. Patent No. 5,621,080 under the doctrine of equivalents, and remanded to the District Court for further consideration of the remaining validity issue on one of the other product patents (U.S. Patent No. 5,955,422).

The patents at issue are directed to recombinant DNA technology relating to the production of the hormone erythropoietin (“EPO”). All five patents share a common specification and descend from Application No. 06/561,024, filed on December 13, 1983.

EPO, which is a naturally occurring hormone, stimulates the production of red blood cells in the bone marrow through a process called erythropoiesis. Thus, the production of EPO is useful in treating blood disorders characterized by low hematocrit, which is a low ratio of red blood cells to total blood cells. Amgen markets and sells its EPO product under the brand name “Epogen.”

This case has a sorted history dating back to 1997 when Amgen brought a declaratory judgment action against Hoechst (now Aventis) and Transkaryotic Therapies (“TKT”) alleging that TKT’s Investigational New Drug Application (“INDA”) for an EPO product infringed the five patents.

In what is known as Amgen I, the district court held the claims of the ’080, ’349, and ’422 patents valid and infringed with the exception of claim 7 of the ’349 patent and held the ’698 and ’933 patents not infringed. In Amgen II, the CAFC vacated and remanded the case to the district court to construe the term “therapeutically effective amount” in claim 1 of the ’422 patent and then determine whether certain claims are anticipated or obvious or if they are infringed. In Amgen III, the district court entered judgment in favor of Amgen. They’re now back for Round IV.

The patents at issue in this case relate to recombinant DNA technology for the production of EPO. In the invention of the five patents, prior to production of a protein from the mRNA with the sequence coding for EPO, the mRNA sequence is spliced to remove introns and to connect exons. After splicing, the mRNA is translated into the 166-amino acid protein shown in Figure 6 of the common specification of the patents.

Prior to secretion from the cell, the 166-amino acid EPO protein undergoes cleaving. In this process, the final amino acid in the sequence shown in Figure 6 of the ’422 patent, arginine, is cleaved off, leaving a 165-amino acid protein. This 165-amino acid protein is then secreted as mature human EPO by the cell. HMR and TKT collaborated to develop a drug known as HMR4396. HMR4396 consists of human EPO produced from TKT’s R223 cell line.

The ’422 patent claims: “A pharmaceutical composition comprising a therapeutically effective amount of human erythropoietin and a pharmaceutically acceptable diluent, adjuvant or carrier, wherein said erythropoietin is purified from mammalian cells grown in culture.”

On remand, the district court construed “therapeutically effective amount” in claim 1 of the ’422 patent to require that the claimed EPO increase hematocrit and also be useful in healing or curing certain classes of patients, e.g., patients generally requiring blood transfusions.

Amgen argued that the district court correctly interpreted the term since only amounts of EPO producing effects—particularly increased hematocrit—that counteract these anemia-like diseases are “therapeutically effective.”

The CAFC held that:

In Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en banc), we stated that claim construction must begin with the words of the claims themselves. Id. at 1312. A claim term has “the meaning that the term would have to a person of ordinary skill in the art. . . .” Id. at 1313. This meaning is ascertained “in the context of the entire patent, including the specification.” Id. In particular, we stated in Phillips that “we must look at the ordinary meaning in the context of the written description and the prosecution history.” Id. (quoting Medrad, Inc. v. MRI Devices Corp., 401 F.3d 1313, 1319 (Fed. Cir. 2005)). When dealing with technical terms, we noted, a court should look to “the words of the claims themselves, the remainder of the specification, the prosecution history, and extrinsic evidence concerning relevant scientific principles, the meaning of technical terms, and the state of the art.” Id. (quoting Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111, 1116 (Fed. Cir. 2004)).

We think the district court made an artificial distinction between the first four effects listed in column 33, lines 11-22, stimulation of reticulocyte response, development of ferrokinetic effects, erythrocyte mass changes, and stimulation of hemoglobin, and the fifth effect, an increase in hematocrit. The specification lists all five effects after stating that “any or all” of them may be an effect of therapy with the claimed invention. Thus, this section of the specification supports the construction that the ’422 patent encompasses a pharmaceutical composition which produces “any or all” of the five listed effects.

This doesn’t seem to take into account the fact that increasing hematocrit is the mechanism in all of the patient treatments listed.

In looking at infringement under the doctrine of equivalents of the ’080 patent, the CAFC disagreed that Amgen met its burden of showing that the reason for the addition of the reference to the “amino acid sequence of FIG. 6” was merely tangential to the alleged equivalent stating:

We must reject Amgen’s argument that the sole reason for the amendment requiring EPO with 166 amino acids was to limit the ’080 patent to human EPO and that therefore the amendment was merely tangential to a 165-amino acid equivalent … claim 1 contains no limitation pertaining to human or non-human EPO. Claim 1 of the ’933 patent, which covers both human and non-human EPO, also lacks any limitation concerning the amino acid sequence of the claimed EPO product. Accordingly, claim 1 of the ’933 patent broadly encompasses EPO with any amino acid sequence, which would include amino acid sequences differing from that set forth in Figure 6.

Finally, we think that if the patentee had wished only to limit the claims to human EPO, the patentee could have done so by continuing to use the adjective “human” when referring to EPO in the third preliminary amendment; instead the patentee chose to further narrow the claims in the third preliminary amendment by making reference to the specific sequence in Figure 6 rather than human EPO.

Chief Judge Michel, dissenting-in-part, summed up things thusly:

This litigation has already dragged on for almost ten years, yet the end is nowhere in sight. … When will it end? Ironically, the patents in dispute may expire before this litigation concludes.

Moreover, since the majority holds that other asserted patents are not invalid and are literally infringed by HMR 4396, (and here I agree), the district court likely will enter an injunction precluding appellants from marketing HMR 4396 until the expiration of at least the ‘698 and ‘349 patents. Prolonging this litigation seems futile when, in the end, an injunction will likely issue regardless of how “therapeutically effective” is construed or whether claim 1 of the ‘422 patent is invalid.

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