Amgen's Neupogen® Patent Invalidated For Obviousness

In Amgen v Pfizer, 2020 FC 522, the first trial decision under the amended Patented Medicines (Notice of Compliance) Regulations (the “PM(NOC) Regulations”), the Federal Court dismissed the action by the plaintiffs, Amgen Inc. and Amgen Canada Inc. (collectively “Amgen”), brought pursuant to subsection 6(1) of the PM(NOC) Regulations for a declaration that Pfizer Canada ULC’s (“Pfizer”) filgrastim biosimilar product, NIVESTYM, will infringe certain claims of Canadian Patent No. 1,341,537 (the “537 Patent”). The 537 Patent is listed on the Patent Register in respect of Amgen’s drug, NEUPOGEN®, a biologic used to treat neutropenia.

Prior to this action, Amgen had brought an application under the pre-2017 PM(NOC) Regulations against Apotex Inc., where Justice Hughes held that Apotex’s allegation that the 537 Patent was invalid on the basis of obviousness was justified ( Amgen v Apotex, 2015 FC 1261 (the “Apotex Decision”)). Apotex was represented by the Goodmans IP Team, including Andrew Brodkin, Richard Naiberg and Jordan Scopa.

While the Amgen v Pfizer decision addressed a number of different issues, including abuse of process, judicial comity, validity, material misrepresentation, insufficiency and the prior use defence, the central issue was obviousness. The Federal Court found in favour of Pfizer, holding that the claims of the 537 Patent asserted by Amgen were obvious and therefore invalid.

The 537 Patent

The 537 Patent is titled “Production of Pluripotent Granulocyte Colony-Stimulating Factor” and relates to a naturally occurring protein that stimulates colonies of neutrophils. This naturally occurring protein (or “polypeptide”) is to be recombinantly produced (i.e., produced in a laboratory through DNA technology).

Construction of the Asserted Claims

The Court construed claims 43-47 (the “Asserted Claims”) as follows:

• Claim 43 pertains to a polypeptide with the specified sequence of 175 amino acids.
• Claim 44 pertains to a recombinant DNA molecule that instructs cellular machinery to synthesize a specified sequence of 175 amino acids, namely the Claim 43 polypeptide. The DNA molecule can have variations in its sequence because the genetic code is degenerate, meaning that most of the amino acids are encoded by more than one codon (i.e., a triplet of deoxyribonucleotides in the DNA). “Recombinant” means sections of DNA from different sources, joined together in a laboratory.
• Claim 45 pertains to an expression vector, which is a recombinant DNA molecule that can drive synthesis of a specified sequence of 175 amino acids, namely the Claim 43 polypeptide, when inside an appropriate host cell. The DNA molecule can have variations in its sequence for the same reasons as in Claim 44.
• Claim 46 pertains to a living cell that contains the expression vector of Claim 45, introduced using genetic engineering techniques in such a way that the cell can express the Claim 43 polypeptide.
• Claim 47 pertains to a process for making the Claim 43 polypeptide that has granulocyte colony-stimulating activity. The process involves inserting the expression vector of Claim 45 into a living cell, reproducing that cell, and purifying the polypeptide away from other host cell proteins.

Obviousness

Under the Old Patent Act, obviousness is assessed as of the invention date, rather than the claim date. The Court concluded that Amgen was entitled to rely on the August 23, 1985 priority date.

The Court relied on the analytical framework for assessing obviousness as explained by the Supreme Court of Canada in Apotex v Sanofi-Synthelabo, 2008 SCC 61 (the “Plavix Decision”) as follows (emphasis added):

1. (a) Identify the notional “person skilled in the art”; (b) Identify the relevant common general knowledge of that person;
2. Identify the inventive concept of the claim in question or if that cannot readily be done, construe it;
3. Identify what, if any, differences exist between the matter cited as forming part of the “state of the art” and the inventive concept of the claim or the claim as construed;
4. Viewed without any knowledge of the alleged invention as claimed, do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?

Skilled Person and Common General Knowledge

The Court noted that the parties described themselves as being in general agreement as to the background scientific knowledge the skilled person would have had as of August 23, 1985. The skilled person was a team consisting of a molecular biologist, a hematologist and a protein biochemist.

Inventive Concept/Subject Matter of the Claims

The Court referred to guidance provided by the Federal Court of Appeal in Ciba Specialty Chemicals Water Treatments Ltd v SNF Inc, 2017 FCA 225 at paras 72-77, that uncertainty regarding ascertaining the “inventive concept” of a claim can be eliminated by “simply avoiding the inventive concept altogether and pursuing the alternate course of construing the claim”, which is expressly contemplated by steps 2 and 3 of the analytical framework set out in the Plavix Decision (see emphasis above).

The Court noted that the differences between the parties’ respective positions on claim construction were inconsequential for purposes of the obviousness analysis, and adopted the constructions described above as the inventive concepts of the Asserted Claims.

The Court noted that it did not adopt the inventive concept of Claim 43 as held by Justice Hughes in the Apotex Decision, which had included a reference to the biological properties of the polypeptide despite those properties appearing nowhere in the language of Claim 43. Only the inventive concept of Claim 47 was held to include the biological properties of the polypeptide, as those properties are expressly referred to in the language of Claim 47.

State of the Art

The Court adopted Dr. Van Etten’s list of prior art documents as representing the state of the art. Dr. Van Etten testified on behalf of Pfizer.

Differences Between State of the Art and Inventive Concept of the Claims (or the Claims as Construed)

With respect to Claim 43, the Court adopted Dr. Van Etten’s articulation of the differences between the state of the art and the inventive concept (or the claim as construed). Dr. Van Etten identified Welte 1985 to be the key piece of prior art and concluded that the only differences between the recombinant protein and the natural protein identified in Welte 1985 are:

1. identifying the amino acid sequence for naturally occurring HpG-CSF; and
2. adding an N-terminal methionine residue to that sequence to enable recombinant expression in E. coli.

The Court held that, for Claims 44-46, they add to Claim 43 only known, general DNA tools (recombinant DNA, expression vector, and transformed host cell) needed to make the recombinant protein of Claim 43.

The additional differences between the state of the art and the inventive concept of Claim 47 are:

1. the general process steps of growing a host cell and then expressing and purifying the recombinant protein of Claim 43; and
2. the purified protein having granulocyte colony-stimulating activity.

Whether such Differences would be Obvious to the Skilled Person

The Federal Court found it appropriate to apply the “obvious to try” test, outlined in the Plavix Decision:

1. The motive factor. Is there a motive provided in the prior art to find the solution the patent addresses?
2. The self-evident factor. Is it more or less self-evident that what is being tried ought to work? Are there a finite number of identified predictable solutions known to persons skilled in the art?
3. The extent of effort factor. What is the extent, nature and amount of effort required to achieve the invention? Are routine trials carried out or is the experimentation prolonged and arduous, such that the trials would not be considered routine?

In order to prove that the invention was “obvious to try”, Pfizer was only required to prove, on a balance of probabilities, that it was more or less self-evident to try to obtain the invention.

The motive factor was in Pfizer’s favour because there was a specific motivation in 1985 to make a recombinant G-CSF.

With respect to the self-evident factor, the Court provided a number of comments:

• This factor does not ask whether success is certain, rather an amount of uncertainty is permitted in the analysis and there is no need to have certainty that the “try” in the obvious to try will be successful.
• The Plavix Decision teaches that the existence of a finite number of identified predictable solutions known to the skilled person favours a finding that the alleged invention was obvious to try.
• The possibility of error, and the possibility that such error is not or cannot be properly identified contributes to the risk that the project will not succeed. However, the skilled person is not risk averse and would not be discouraged from attempting the G-CSF project by known potential problems with identifiable solutions.

Ultimately, the Court concluded that the skilled person would find it self-evident that the steps leading to the Claim 43 polypeptide ought to work, which favoured a finding that Claim 43 was obvious to try.

Lastly, with respect to the extent of effort factor, the Court found that Amgen’s expert, Dr. Speicher, erred by interpreting the skilled person to exclude individuals in the top 10-20% in ability. Indeed, the Court found that Dr. Speicher should not have concluded that prior art published by extraordinary individuals does not inform what was routine and within the capabilities of the skilled person. The Court held that one does not automatically exclude from the analysis the work or publications of leaders in the field. What matters is how that work or those publications inform the question of whether the skilled person could have bridged the obviousness gap (without applying inventiveness, which the skilled person does not possess). It is, after all, inventiveness rather than skill that the skilled person lacks.

Ultimately, the Court concluded that the extent, nature and amount of effort required to achieve the Claim 43 polypeptide would have been within the skilled person’s capabilities as of August 1985, and that any potential challenges they would encounter could be addressed with skill and did not require inventiveness.

Conclusions on Obviousness

Based on the evidence, the Court was satisfied on a balance of probabilities that it was more or less self-evident to try to obtain the Claim 43 polypeptide, and therefore Claim 43 was invalid for obviousness. The Court held that Claims 44 to 46 relied on the same arguments that were considered in relation to Claim 43 and there was no evidence that these Claims added anything inventive. While the Court did conclude that Claim 47 had further differences, there was nothing additionally inventive about Claim 47 that was not addressed in the arguments relating to Claim 43.

The Court therefore concluded that all of the Asserted Claims were invalid for obviousness and dismissed Amgen’s action.

Authors: Jordan Scopa and Jaclyn Tilak