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First biologic decision under PMNOC Regulations: Amgen’s prohibition application dismissed

Authored byUrszula Wojtyra

On November 10, 2015, the Federal Court dismissed Amgen’s application for an order prohibiting the issuance of a notice of compliance (NOC) to Apotex for its proposed filgrastim product, which relied on a comparison to Amgen’s NEUPOGEN: Amgen Canada Inc v Apotex Inc, 2015 FC 1261. This is the first decision on a subsequent entry biologic (SEB) product in an application brought under the Patented Medicines (Notice of Compliance) Regulations. Apotex was successful in its allegation of obviousness.

Filgrastim is a granulocyte colony-stimulating factor. It is a 175 amino acid protein produced by recombinant DNA technology. Amgen markets filgrastim under the brand name NEUPOGEN, which is approved for a number of indications, including decreasing the incidence of infection in cancer patients receiving myelosuppressive chemotherapy. NEUPOGEN was first approved in Canada in 1992.

Amgen sought an Order prohibiting the Minister of Health from issuing an NOC to Apotex until expiry of Patent No. 1,341,537. The 537 patent was filed in 1986 and issued in 2007. As an “Old Act” patent, the 537 patent will expire 17 years after issuance, July 31, 2024. Apotex served its notice of allegation in October 2012, alleging that it would not infringe the 537 patent and that the patent was invalid on a number of bases. The parties agreed to extend the prescribed 24-month statutory stay until 60 days after the hearing of the application.

The Court laid out Amgen’s development story of the 537 patent based on what is set out in the patent itself and evidence from various Amgen researchers. In brief, the Court found that Dr. Welte from the Sloan-Kettering Institute, unrelated to Amgen, had partially purified a naturally occurring protein from a human cell line, which he called a pluripotent hematopoietic colony-stimulating factor or pluripotent CSF. Dr. Welte’s purification and characterization of the pluripotent CSF, including some of its biological activity in in vitro assays, was published 5 months before the priority date of the 537 patent. According to the Court, the goal of the inventor of the 537 patent at Amgen was to take the naturally occurring protein reported by Dr. Welte and to create, by recombinant means, a protein having some or all of the amino acid sequence and some or all of the biological properties of that protein, in order to make sufficient quantity for further research. The Court was satisfied that the inventor of the 537 patent accomplished what he had set out to do.

By the time of hearing, only claim 43 was at issue and Apotex maintained three grounds of invalidity: lack of novelty, obviousness and inutility. Claim 43 reads as “A polypeptide defined by the amino acid sequence” followed by a particular 175 amino acid sequence beginning with a methionine amino acid. Commenting that claim 43 did not set out any physical parameters of the protein, or define or limit the process by which the protein is made, the Court construed claim 43 as follows:

Claim 43 is directed to a polypeptide having an amino acid sequence beginning with a Met (methionine) with the remainder of the sequence having some or all of the sequence and some or all of the biological properties of the natural factor identified by Dr. Welte.

Apotex relied on a publication co-authored by Dr. Welte (the Welte paper ) for both its allegations of obviousness and lack of novelty.

Novelty: The Court held Apotex’s allegation of lack of novelty not justified. Under the old Patent Act, a patent is invalid if the invention was known or used by another person, if this other person disclosed or used the invention in such a manner that the invention became available to the public. Apotex argued that the Welte paper had isolated and purified the natural pluripotent CSF, characterized it in several ways although without revealing the amino acid sequence, and that a patent should not issue for identification of a property of a known substance. However, the Court agreed with Amgen that the claimed product was not identical to the natural protein disclosed by the Welte paper for two reasons:

  1. the polypeptide of claim 43 begins with methionine, a result of the recombinant means to make the polypeptide, which is absent from the naturally occurring protein; and
  2. the amino acid sequence following the methionine is quite possibly but not certainly the sequence of the natural product.

Obviousness: In light of the Welte paper and the known techniques used by Amgen, the Court held that claim 43, as construed above, was obvious. The Court was not persuaded by Amgen’s arguments that what was done was inherently unpredictable, or that there were many choices, each with the risk of failure, along the path of making the recombinant protein and determining the protein sequence. The Court reasoned that the work done by Dr. Welte (identifying the critical protein, isolating it, purifying it, and charactering it in several respects, albeit not the amino acid sequence) may well be considered an invention. However, the Welte paper also presented a motivation to others to make the protein in larger quantities, and the Court held that this is exactly what Amgen did. The Court reasoned that while Amgen may have done so by an inventive process that may be patentable (noting there are several claims in the patent directed to processes), the end-product, as claimed in claim 43 without any process limitations, is not itself inventive.

In its obviousness analysis, the Court referred to a recent publication of a diagram showing a progression from “creative work” through to “robotic work”, opining that “creative work” is necessary to deserve patent protection. In this case, the “steps [undertaken by Amgen] were routine in the sense that they were carried out by skilled persons operating with the science as it was known at the time” and thereby amounted to “skilled work” rather than “creative work”.

Utility: The Court followed recent jurisprudence which indicates that depending on the proper construction, a promise in a patent may apply to only some claims, and that an unfulfilled promise does not necessarily render the whole patent invalid. While the 537 patent contained language regarding pharmaceutical use, claim 43 did not claim any particular use. Rather, the Court construed the promise of the patent as “to create a manufactured protein having some or all of the amino acid structures, and some or all of the biological properties of the natural protein,” and this promise had been demonstrated by the product of claim 43. The Court therefore found Apotex’s inutility allegation unjustified.

To date, Apotex has not received its NOC; accordingly it is unclear whether Apotex’s regulatory submission is (or will be) in an approvable state. If approved, subject to any intervening SEB approvals, Apotex’s filgrastim product would be the fifth* subsequent entry biologic approved in Canada (after OMNITROPE, 2009, REMSIMA/INFLECTRA, 2014 and BASAGLAR, 2015).

(*Correction: An earlier version had not referred to BASAGLAR, which was approved in September 2015).

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