Filgrastim & Pegfilgrastim – USA

On May 08, 2019, Federal Circuit affirmed district court’s decision that Sandoz’s biosimilar products do not infringe Amgen’s patents.

Amgen owns & markets filgrastim (Neupogen®) and pegfilgrastim (Neulasta®) products for treating neutropenia, a deficiency of white blood cells. Sandoz submitted BLA application to USFDA to market biosimilar version of Amgen’s product.  Amgen then  sued Sandoz for infringement. The court construed claims of U.S. Patents 6,162,427 and 8,940,878 and granted summary judgment of non-infringement of claim 7 of the ’878 patent to Sandoz. The ’878 patent discloses methods of protein purification by adsorbent chromatography. Claim 7 of US’878 patent relates to method of purifying a protein with sequential steps. The ’427 patent discloses methods of treating “diseases requiring peripheral stem cell transplantation.” Claim 1 of US’427 requires first administering G-CSF & thereafter disease treating effective amount of at least one chemotherapeutic agent.

The district court construed “disease treating-effective amount of at least one chemotherapeutic agent” in claim 1 of the ’427 patent as limited to “[a]n amount sufficient to treat a disease for which at least one chemotherapeutic agent is prescribed.” The court thereby rejected Amgen’s argument that the amount must be “sufficient to enhance the mobilization of stem cells.” Amgen thereafter stipulated to noninfringement of the ’427 patent contingent upon its right to appeal from the district court’s claim construction order. With respect to the ’878 patent, the district court construed limitations (f) and (g) of claim 7 (the “washing” and “eluting” steps) as separate steps and further clarified that the eluting step “must occur after the step of ‘washing the separation matrix.’ Since it is undisputed that Sandoz’s process only involves one step—applying the refold solution to the matrix, with no separate washing or eluting steps—the district court granted summary judgment that neither Zarxio® nor Sandoz’s proposed pegfilgrastim biosimilar infringes claim 7 of the ’878 patent.

US’878 patent

Claim 7 reads:

7. A method of purifying a protein expressed in a non-native limited solubility form in a non-mammalian expression system comprising:

(a) expressing a protein in a non-native limited solubility form in a non-mammalian cell;

(b) lysing a non-mammalian cell;

(c) solubilizing the expressed protein in a solubilization solution comprising one or more of the following: (i) a denaturant; (ii) a reductant; and (iii) a surfactant;

(d) forming a refold solution comprising the solubilization solution and a refold buffer, the refold buffer comprising one or more of the following: (i) a denaturant; (ii) an aggregation suppressor; (iii) a protein stabilizer; and (iv) a redox component;

(e) directly applying the refold solution to a separation matrix under conditions suitable for the protein to associate with the matrix;

(f) washing the separation matrix; and

(g) eluting the protein from the separation matrix, wherein the separation matrix is a non-affinity resin selected from the group consisting of ion exchange, mixed mode, and a hydrophobic interaction resin.

Upon appeal Federal Circuit reviewed district court’s claim construction de novo. Amgen contended that the district court misconstrued the “washing” and “eluting” claim limitations in both its claim construction and summary judgment decisions as requiring distinct solutions added to the matrix at different times. Instead, Amgen argued, the claims cover any number of solutions or steps as long as the functions of washing and eluting happen in sequence. Sandoz responds that the claim logically requires a series of steps & process claim is properly limited to a certain order of steps “‘when the claim language requires that the steps be performed in the order written, or the specification directly or implicitly requires’ an order of steps. Federal Circuit agreed with Sandoz & district court. It held that the washing and eluting steps of claim 7 require discrete solutions. Second, washing and eluting are consistently described in the specification as separate steps performed by different solutions.

Amgen next argued that the district court erred by rejecting its argument that Sandoz’s process infringes claim 7 through the doctrine of equivalents. Specifically, Amgen argued that Sandoz’s one-step, one-solution process is insubstantially different from the claimed three-step, three-solution process because it “achieves the same functions (washing and eluting), in substantially the same way (binding protein preferentially compared to contaminants, and then raising salt concentration to reverse protein binding) to achieve the same result (protein purification).” Sandoz responded that the district court properly analyzed Amgen’s argument and found that Sandoz’s one-step, one-solution process accomplishes purification in a different way from the claimed method and, as a result, is not equivalent. Federal Circuit again agreed with Sandoz and concluded that the district court correctly held that Sandoz’s one-step, one-solution process does not function in the same way as the claimed process. District court correctly held that, the claim recites a sequence of steps requiring application of “refolding,” “washing,” and “eluting” solutions, and our precedent prohibits us from overriding the natural language of claim 7 to extend these limitations to cover nearly any type of adsorbent chromatographic separation. The doctrine of equivalents applies only in exceptional cases and is not “simply the second prong of every infringement charge, regularly available to extend protection beyond the scope of the claims.” London v. Carson Pirie Scott & Co., 946 F.2d 1534, 1538 (Fed. Cir. 1991). Accordingly, the district court was correct to grant summary judgment that Sandoz does not infringe claim 7 under the doctrine of equivalents.

US’427 patent

Claim 1 reads:

1. A method of treating a disease requiring peripheral stem cell transplantation in a patient in need of such treatment, comprising

administering to the patient a hematopoietic stem cell mobilizing-effective amount of G-CSF;

and thereafter administering to the patient a disease treating-effective amount of at least one chemotherapeutic agent.

Amgen argued that the district court misconstrued the limitation of “disease treating-effective amount” of a chemotherapeutic agent in claim 1 of the ’427 patent as “an amount sufficient to treat a disease for which at least one chemotherapeutic agent is prescribed.” Specifically, Amgen asserted that the phrase only limits the amount of the chemotherapeutic agent administered and that the method of claim 1 encompasses “situations where the chemotherapeutic agent is prescribed only for stem cell mobilization rather than treatment of an underlying disease.” Sandoz responded that Amgen’s construction would read disease treatment out of the claim and collapse the claim’s textual distinction between a “stem cell mobilizing-effective amount” of G-CSF and a “disease treating-effective amount” of the chemotherapeutic agent. Federal Circuit agreed with Sandoz & held that “disease treating” requires that the chemotherapeutic agent be administered to treat an underlying disease. The claimed method therefore must be performed to treat an underlying disease. As the claim itself states, the “disease treating-effective amount” of a chemotherapeutic agent does precisely that. Court further said that Amgen’s construction would broaden claim 1 to cover administration of G-CSF and a chemotherapeutic agent solely for the purpose of mobilizing stem cells. Such a conclusion would require interpreting “disease treating” as “stem cell mobilizing,” but “[o]ur precedent instructs that different claim terms are presumed to have different meanings.” Finally, Federal Circuit held that the district court did not err in construing claim 1 of the ’427 patent & affirmed the Summary Judgment decision.