The latest chapter in the long-running dispute between Amgen and Sandoz over Sandoz's Zarxio® biosimilar to Amgen's Neupogen® biologic drug came to a close last week when the Federal Circuit affirmed grant of summary judgment against Amgen in Amgen Inc. v. Sandoz Inc.

To recap, Amgen's Neupogen® product (filgrastim) is "a recombinant analog of granulocyte-colony stimulating factor ('G-CSF'), a naturally-occurring human glycoprotein that stimulates the production of neutrophils and stem cells and their release into the bloodstream."  It is used to treat patients with a deficiency of white blood cells (neutropenia), typically caused by treatment with certain cancer chemotherapeutic agents.  In 2014, Sandoz filed an abbreviated biologic license application (aBLA) under the provisions of § 351(k) of the Public Health Service Act (42 U.S.C. § 262(k)) for approval of its Zarxio® biosimilar.  However, Sandoz refused to comply with provisions of the Biologic Price Control and Innovation Act (BPCIA) requiring a biosimilar applicant to disclose its application and any relevant manufacturing information to reference product sponsor Amgen.  Amgen brought suit but the District Court denied Amgen's motion for preliminary injunction, ruling that such disclosure was not mandatory (see "Gotta Dance? Apparently Not -- A Biosimilar Update").  Amgen appealed to the Federal Circuit, who in a fractured decision agreed with Sandoz (see "Amgen v. Sandoz" and "Federal Circuit Decides Amgen v. Sandoz (in an opinion that will make neither party happy)"). The Supreme Court granted certiorari and also agreed with Sandoz (see "Sandoz Inc. v. Amgen Inc. (2017)").  And upon remand to the Federal Circuit, Amgen lost any chance of obtaining an injunction on the ground that the state law claims (unfair competition among them) asserted by Amgen were preempted by the BPCIA, which contained no provision for an injunction under these circumstances.  During this time, the FDA had approved Zarxio® and Sandoz was marketing the Neupogen® biosimilar (see "Sandoz' NEUPOGEN® Biosimilar Now on the Market").

Amgen pursued its patent case on the merits, asserting U.S. Patent Nos. 6,162,427 and 8,940,878.  The '427 patent is directed to methods for treating patients in need of peripheral stem cell transplantation; Amgen asserted claim 1 in the District Court action:

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.

The '878 patent is directed at protein purification methods using adsorbent chromatography; claim 7 was at issue before the District Court:

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.

Central to the issues on appeal was the District Court's claim construction, where the Court construed "disease treating-effective amount of at least one chemotherapeutic agent" in claim 1 of the '427 patent to be limited to "[a]n amount sufficient to treat a disease for which at least one chemotherapeutic agent is prescribed," rejecting Amgen's asserted construction that the amount must be merely sufficient to mobilize stem cells regardless of its effect on the underlying disease.  Under this construction, Amgen stipulated Sandoz did not infringe claim 1 of the '427 patent pending appeal to the Federal Circuit.

The District Court construed the terms relating to the "washing" and "eluting" steps of the method claimed in the '878 patent (specifically, subparts (f) and (g)) as being separate steps that required the washing step to be performed before the eluting step.  Again, under this construction Amgen conceded it could not prevail on infringement because Sandoz performed these steps concurrently with step (e) (regarding application of the refolding solution).  This appeal followed.

The Federal Circuit affirmed, in an opinion by Judge Lourie joined by Judges O'Malley and Reyna.  Regarding construction of the claims of the '878 patent, the panel credited Sandoz's argument that the claim "logically requires a series of steps," citing (as did Sandoz) Mformation Technologies, Inc. v. Research in Motion Ltd., 764 F.3d 1392, 1398–1400 (Fed. Cir. 2014) ("a process claim is properly limited to a certain order of steps 'when the claim language, as a matter of logic or grammar, requires that the steps be performed in the order written, or the specification directly or implicitly requires' an order of steps").  The Federal Circuit, like the District Court, rejected Amgen's argument that washing and eluting could be performed simultaneously, for example, under circumstances where "washing may occur toward the bottom of the matrix at the same time that elution occurs toward the top."  The Court's reasoning was based in part on the ordered (and sequentially lettered) steps (a) through (g), which "logically" implies they be performed in sequence.  This ordered performance of the steps was also consistent with how the process was described in the specification.

Having determined that the District Court's construction was correct as a matter of law (and thus that Sandoz process did not literally infringe claim 7 of the '878 patent), the Federal Circuit then considered infringement under the doctrine of equivalents.  Using language that arguably was at least in part responsible for energizing the Supreme Court to review more closely the Federal Circuit's stewardship of the Court's patent jurisprudence (inter alia, in Warner-Jenkinson v. Hilton Davis Chemical Co. and Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co. almost a generation ago), the panel dismissed Amgen's doctrine of equivalents argument saying "[t]he 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,'" citing its pre-Warner Jenkinson precedent in London v. Carson Pirie Scott & Co., 946 F.2d 1534, 1538 (Fed. Cir. 1991).  More correctly (and less provocatively), the panel based its decision on the sound reasoning that "Sandoz does not infringe claim 7 under the doctrine of equivalents because its one-step, one-solution purification process works in a substantially different way from the claimed three-step, three-solution process" recited in Amgen's claims.

The opinion also rejected Amgen's argument that the District Court abused its discretion in not denying or postponing summary judgment under Federal Rule of Civil Procedure 56(d) because Sandoz "intends" (undisputedly), sometime in an uncertain future, to change its purification protocol to (perhaps) an infringing one but has provided neither Amgen nor the FDA with details of its plans.  As the Court held in Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc., 731 F.3d 1271, 1279–80 (Fed. Cir. 2013), while district courts cannot ignore amendments to ANDA or aBLA applications in determining whether there is (artificial) infringement under § 271(e)(2), they also have "a broad mandate to render a 'just, speedy, and inexpensive' decision," citing In re Micron Tech., Inc., 875 F.3d 1091, 1100 (Fed. Cir. 2017) (quoting Dietz v. Bouldin, 136 S. Ct. 1885, 1891 (2016)).  The opinion discounted Amgen's argument that failure to postpone judgment would deny them of a remedy if Sandoz changed its process to an infringing one, on the grounds that Amgen could pursue a remedy for infringement to the extent that principles of res judicata and collateral estoppel were not violated, citing Bayer AG v. Biovail Corp., 279 F.3d 1340, 1349–50 (Fed. Cir. 2002).  Under the circumstances before the Court in this case (particularly because the possible changes Sandoz might make would still not result in an infringing process), the Federal Circuit held the District Court did not abuse its discretion in declining to postpone entry of summary judgment.  This aspect of the decision highlights a disparity in information first encountered when Sandoz refused to disclose either its aBLA or manufacturing information under Paragraph 2 of the BPCIA (42 U.S.C. § 262 (l)(2)).  The District Court (expressly), the Federal Circuit, and the Supreme Court evinced their presumption that all requisite information could be obtained during discovery in an ensuing lawsuit (disregarding the disadvantage their interpretation of the statute propagated regarding which patent(s) a reference product sponsor such as Amgen should sue on in the absence of this information).  Again, here, the Federal Circuit presumes that Amgen will be able to obtain the information necessary to file a well-pleaded complaint in the event Sandoz begins practicing an infringing version of its purification method, without addressing Amgen's argument that there is a possibility that they will not have and will not be able to obtain the information, under circumstances where the Court had at least some leverage to obtain binding representations from Sandoz that this information would be made available should that time come.

Turning to the '427 patent, the panel also affirmed the District Court's construction of the term "disease treating-effective amount of at least one chemotherapeutic agent" to be limited to "[a]n amount sufficient to treat a disease for which at least one chemotherapeutic agent is prescribed."  The Federal Circuit rejected Amgen's argument that the amount need not be effective to treat the underlying disease but only be sufficient to mobilize stem cells in blood or bone marrow.  The opinion based this construction on the preamble ("A method of treating a disease") and (according to the Court) "neither the claim nor the specification lends support to Amgen's interpretation."  Under Amgen's construction, the claim would encompass activities directed solely at mobilizing stem cells, which would require the "disease treatment" to correspond to stem cell mobilization per se.  There is no basis for this interpretation in the panel's view, and thus the Court affirmed the District Court's grant of summary judgment.

Amgen Inc. v. Sandoz Inc. (Fed. Cir. 2019)
Panel: Circuit Judges Lourie, O'Malley, and Reyna
Opinion by Circuit Judge Lourie