Amgen Inc. v. Pfizer Canada ULC

Amgen Inc. v. Pfizer Canada ULC
Court (s) Database
Federal Court Decisions
Date
2020-04-16
Neutral citation
2020 FC 522
File numbers
T-741-18
Decision Content
Date: 20200416
Docket: T-741-18
Citation: 2020 FC 522
Ottawa, Ontario, April 16, 2020
PRESENT: The Honourable Mr. Justice Southcott
BETWEEN:
AMGEN INC. AND AMGEN CANADA INC.
Plaintiffs/
Defendants by Counterclaim
and
PFIZER CANADA ULC
Defendant/
Plaintiff by Counterclaim
PUBLIC JUDGMENT AND REASONS
I. OVERVIEW 3
II. BACKGROUND 5
III. THE ASSERTED CLAIMS 9
IV. ISSUES 10
V. FACT WITNESSES 11
A. Mr. Thomas Boone (Amgen Witness) 12
B. Dr. Krisztina Zsebo (Amgen Witness) 15
C. Dr. Hsieng Lu (Amgen Witness) 17
D. Ms. Anita Hammer (Amgen Witness) 22
E. Ms. Sheila Ahmed (Pfizer Witness) 23
F. Dr. Goran Valinger (Pfizer Witness) 23
VI. EXPERT WITNESSES 24
A. Dr. Richard Van Etten (Pfizer Expert) 25
B. Dr. Mark Hermodson (Pfizer Expert) 33
C. Dr. Steven Boxer (Pfizer Expert) 36
D. Dr. Stanley Maloy (Amgen Expert) 40
E. Dr. David Speicher (Amgen Expert) 48
F. Dr. James Griffin (Amgen Expert) 53
VII. ABUSE OF PROCESS 58
VIII. JUDICIAL COMITY 63
IX. CLAIM CONSTRUCTION - THE SKILLED PERSON 65
X. CLAIM CONSTRUCTION - ANALYSIS 67
XI. OBVIOUSNESS – DATE OF INVENTION 70
A. Priority Date from the 959 Application 71
B. Evidence Establishing the Invention was Achieved by August 23, 1985 85
XII. OBVIOUSNESS – ANALYSIS 98
A. Legal Principles 98
B. The Skilled Person and their Common General Knowledge 99
C. Inventive Concept 103
D. State of the Art 108
E. Differences Between State of the Art and Inventive Concept of the Claims 109
F. Whether Differences would be Obvious to the Skilled Person 111
G. Conclusion on Obviousness 165
XIII. SECTION 53 - MATERIAL MISREPRESENTATION 166
XIV. INSUFFICIENCY 172
XV. PRIOR USE 177
XVI. COSTS 186
I. OVERVIEW
[1] This decision relates to an action by the Plaintiffs, Amgen Inc. and Amgen Canada Inc. [collectively, Amgen], against Pfizer Canada ULC [Pfizer], and a related counterclaim by Pfizer. Amgen brings this action pursuant to section 6(1) of the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 [Regulations], after being served with a Notice of Allegation by Pfizer pursuant to section 5(3) of the Regulations.
[2] Amgen Inc. is the current owner of Canadian Patent No. 1,341,537 [the 537 Patent]. Amgen Inc. has authorized Amgen Canada Inc. to list the 537 Patent on the Patent Register against Amgen’s biologic drug NEUPOGEN, which the latter markets, sells, and distributes in Canada. The drug substance in NEUPOGEN and disclosed in the 537 Patent is generically known as filgrastim. Pfizer has filed with the Minister of Health a New Drug Submission [NDS] for the issuance of a Notice of Compliance [NOC] for its filgrastim biosimilar NIVESTYM. Pfizer’s NDS refers to NEUPOGEN as a reference biologic drug for the purposes of regulatory approval.
[3] Amgen’s claim in this action alleges the making, constructing, using, selling, offering for sale, importing or exporting of NIVESTYM in accordance with Pfizer’s NDS would infringe certain claims of the 537 Patent. Pfizer’s defence and counterclaim allege the 537 Patent is invalid and void, due to obviousness of the asserted claims, insufficiency of the 537 Patent’s disclosure, and alleged misrepresentations to the Canadian Intellectual Property Office [CIPO]. Pfizer also asserts that, even if the patent is valid, it is protected against allegations of infringement by the defence of prior use.
[4] Some of the evidence adduced at trial is subject to a Confidentiality Order dated December 11, 2019 [the Confidentiality Order], in order to protect commercially sensitive confidential information of the parties. A draft confidential decision was therefore sent to the parties on April 6, 2020 to allow them to propose any redactions required for the issuance of the public version of the decision. Amgen proposed redactions to protect a non-party’s private health information and to protect the dates and durations of certain steps in the invention process, which Amgen considers commercially sensitive information. Pfizer does not object to redaction of the private health information but does oppose the other redactions.
[5] In the course of exchanging written submissions on this issue, Pfizer pointed out that several of the proposed redactions relate to a date that is accessible to the public in the file history for the 537 Patent. Amgen agreed and withdrew its request that this date be redacted. With respect to the remaining proposed redactions, Pfizer disputes Amgen’s assertion that these dates could affect its patent rights in other jurisdictions. Pfizer submits that Amgen is motivated by strategic litigation considerations and not by confidentiality interests in commercially sensitive information. Amgen responds, inter alia, that wishing to protect information because of litigation considerations would not diminish the confidential nature of the information.
[6] I agree with Amgen’s position. It has consistently treated the information at issue as confidential, including obtaining the Confidentiality Order and redacting the information from the publicly filed versions of its fact witness affidavits. While a party with which it is in litigation in another jurisdiction may be able to obtain this information though the discovery process, it will presumably then be protected by a version of the implied undertaking rule or by a protective agreement or order. As the proposed redactions will not affect the intelligibility of the decision, I am satisfied that the redactions appropriately balance the interests of protecting confidential information and the public interest in open and accessible court proceedings. As such, two versions of this decision, one public and the other confidential, will be issued simultaneously.
[7] For the reasons explained in detail below, I find that the claims of the 537 Patent asserted by Amgen are obvious and therefore invalid. I do not find the 537 Patent as a whole invalid due to misrepresentation or insufficiency. I also find that, if the claims asserted by Amgen had been valid, Pfizer would not have been protected by the defence of prior use.
II. BACKGROUND
[8] The Plaintiff, Amgen Inc., is a corporation incorporated and existing under the laws of the State of Delaware with its principal place of business in Thousand Oaks, California. Amgen Inc. is a biotechnology company and is the current owner of the 537 Patent. The Plaintiff, Amgen Canada Inc. [Amgen Canada], is a corporation incorporated and existing under the laws of the Province of Ontario and located in Mississauga, Ontario. Amgen Canada is also a biotechnology company and markets, sells and distributes various biologic drugs in Canada, including the filgrastim drug NEUPOGEN. Filgrastim is used to treat neutropenia (a disorder wherein the body cannot produce sufficient levels of white blood cells called neutrophils), which can develop as a result of damage to the body’s hematopoietic system (the system responsible for production of blood cells).
[9] The Defendant, Pfizer, is a corporation incorporated under the laws of Canada and has its head office and principal place of business in Kirkland, Québec. Like Amgen Canada, Pfizer sells pharmaceutical products including biologic drugs in Canada.
[10] The 537 Patent is entitled “Production of Pluripotent Granulocyte Colony-Stimulating Factor.” It issued on July 31, 2007 from Canadian Patent Application No. 516,737 [the 737 Application], filed on August 25, 1986. The 537 Patent claims priority to US Patent Application No. 768,959 [the 959 Application], filed on August 23, 1985, and US Patent Application No 835,548 [the 548 Application], filed on March 3, 1986. Only the 959 Application is relevant to this proceeding, for reasons outlined below. Because of the dates surrounding this patent, the governing legislation in this action is the Patent Act, RSC 1984, c P-4 as it read immediately before October 1, 1989 [the Old Act]. The 537 Patent will expire on July 31, 2024. Amgen describes the patent as relating to a hematopoietic growth factor, made using recombinant genetic technology.
[11] By way of general scientific background relevant to this description, a hematopoietic growth factor is, in this case, a protein, which stimulates the growth of blood cells. A protein is composed of a string of amino acids. There are 20 different amino acids found in proteins of mammalian species. A recombinant protein is one produced in a laboratory through DNA technology. This involves, inter alia: (a) combining the DNA that codes for the target naturally occurring protein with another piece of DNA, a process called cloning that forms recombinant DNA; (b) inserting that recombinant DNA into a host cell, referred to as transforming the cell; and (c) replicating the transformed host cell to form a colony of such cells, which express the target protein because of the presence of the protein’s DNA.
[12] The 537 Patent refers to the target protein, i.e. the naturally occurring protein to be recombinantly produced, as “human pluripotent granulocyte colony-stimulating factor” or “hpG-CSF”. A colony-stimulating factor [CSF] is a hematopoietic growth factor that stimulates the growth of progenitor cells into colonies. Progenitor cells develop from stem cells and in turn form mature blood cells. There are different categories of progenitor cells, which in turn develop into particular categories of mature cells. Granulocytes (the G in hpG-CSF) are one category of mature white blood cell that matures from relevant progenitor cells. As noted above, the protein to which the 537 Patent relates stimulates colonies of neutrophils, which are a type of granulocyte.
[13] The remaining term in the name the 537 Patent employs for the subject protein is “pluripotent.” The meaning of this term, particularly in the context of the 537 Patent’s disclosure, is controversial between the parties. As will be explained in greater detail later in these Reasons, the prior art describes the target protein as “pluripotent”, meaning in that context that it stimulated growth of multiple lineages of mature blood cells from progenitor cells. However, either before or after the filing of the patent application (a point about which the parties disagree), it was discovered that this protein stimulates only the growth of granulocytes, not other cell lineages. The protein subsequently became known as granulocyte colony-stimulating factor [G-CSF]. Other than where this controversy is engaged (in the analyses of the misrepresentation and insufficiency allegations), these Reasons use the terms “hpG-CSF” and “G-CSF” interchangeably.
[14] While the 537 Patent sets out 82 claims, Amgen’s allegations of infringement assert only Claims 43 though 47 [the Asserted Claims]. Subject to the defences it has pleaded, Pfizer admits that the making, constructing, using or selling of filgrastim would infringe the Asserted Claims. As such, the outcome of this action turns on Pfizer’s allegations of invalidity, all based on provisions of the Old Act, and the prior use defence.
[15] Pfizer’s alleges three bases for invalidity: (a) the Asserted Claims are obvious; (b) Amgen has made wilfully misleading and untrue material allegations to CIPO, contrary to s 53 of the Old Act; and (c) the 537 Patent does not sufficiently disclose the alleged invention, contrary to s 34 of the Old Act. The prior use provision of the Old Act is s 56, although, for reasons that will be explained later, Pfizer relies on the common law to invoke that defence.
[16] As a preliminary matter, this proceeding also raises an issue surrounding the interaction between an action under s 6(1) of the current Regulations and an application under the former Regulations related to the same patent. In 2012, Amgen brought such an application in Court File No. T-2072-12, seeking a prohibition order against the Minister of Health to prevent an NOC from issuing to Apotex Inc. [Apotex] for its filgrastim biosimilar [the Apotex Application]. In Amgen Canada Inc v Apotex Inc, 2015 FC 1261, Justice Hughes dismissed the Apotex Application, finding Amgen had not shown Apotex’s obviousness allegation in relation to Claim 43 of the 537 Patent was unjustified [the Apotex Decision]. Pfizer now argues this Court should adopt certain factual and legal findings of the Apotex Decision based on principles of abuse of process and/or judicial comity.
[17] Each of the parties supported its positions on the various issues in this action through the evidence of expert witnesses. Each expert presented a report and was cross-examined at trial. All experts were qualified at trial without objection, with the articulation of the experts’ respective areas of qualification agreed between the parties. While Pfizer objected to various portions of Amgen’s experts’ evidence in advance of trial, including objections as to admissibility, the parties agreed the Court would receive the evidence and submissions on its admissibility at trial and adjudicate those objections in this Judgment and Reasons. Pfizer further advised during closing argument that it was pursuing objections to the expert evidence only as outlined in its closing submissions (all of which go to weight).
[18] The parties also introduced evidence through fact witnesses. By agreement, they adopted a process whereby the witnesses’ direct evidence was presented in affidavit form, to be supplemented at the trial by a “warm up” examination-in-chief, followed by cross-examination. One of Amgen’s witnesses, Dr. Hsieng Lu, was examined in advance of trial, with the video recording of the examination played and entered into evidence during trial.
III. THE ASSERTED CLAIMS
[19] The Asserted Claims in the 537 Patent read as follows:
43. A polypeptide defined by the amino acid sequence:
Met Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro [Claim 43 Sequence].
44. A recombinant DNA encoding a polypeptide defined by the amino acid sequence: Claim 43 Sequence
45. An expression vector comprising a DNA sequence encoding a polypeptide defined by the amino acid sequence: Claim 43 Sequence
46. A transformed host cell comprising an expression vector comprising a DNA encoding a polypeptide defined by the amino acid sequence: Claim 43 Sequence
47. A process for the preparation of a human granulocyte-colony stimulating factor (G-CSF) comprising transforming a host cell with an expression vector containing a DNA sequence encoding the amino acid sequence: Claim 43 Sequence, culturing said transformed host cell and collecting the granulocyte colony-stimulating factor expressed by said transformed cell.
IV. ISSUES
[20] By the time of trial, the parties had significantly narrowed the issues originally identified in the pleadings and agreed on a Joint Statement of Issues. With some re-ordering/re-grouping and minor changes in their articulation, I adopt those issues as follows:
Abuse of Process / Judicial Comity:
Abuse of Process: Is it an abuse of process for Amgen to relitigate factual and legal issues determined by Justice Hughes in the Apotex Decision?
Judicial Comity: If it is not an abuse of process, should this Court nevertheless follow the legal findings and/or factual findings from the Apotex Decision by reason of judicial comity?
Skilled Person: Who is the person skilled in the art to whom the 537 Patent is addressed [the Skilled Person]?
Claim Construction: How should the Asserted Claims be construed?
Obviousness:
(a) Date of Invention: Is August 23, 1985 the invention date of each of the Asserted Claims by virtue of the 959 Application? Or, was the subject matter of each of the Asserted Claims invented by no later than August 23, 1985?
(b) Obviousness Analysis: Was each of the Asserted Claims obvious as of the date of invention?
Validity:
Material Misrepresentation: Is the 537 Patent void pursuant to section 53 of the Old Act?
Insufficiency: Is the disclosure of the 537 Patent insufficient pursuant to section 34 of the Old Act?
Prior use defence: Is Pfizer exempt from liability for infringement by reason of section 56 of the Old Act?
V. FACT WITNESSES
[21] The following is a brief summary, identifying the background and role of each fact witness and the areas to which their evidence relates. While particular details of the evidence will be considered later in the Reasons, in analysing the issues to which it relates, I will include in this summary some detail intended to provide an overall factual framework. The following also identifies my general observations as to the reliability of the individual fact witnesses’ evidence.
A. Mr. Thomas Boone (Amgen Witness)
1. Evidence in Brief
[22] The first and lengthiest witness to give evidence on behalf of Amgen was Mr. Thomas Boone. Mr. Boone is a molecular biologist and protein chemist. In the 1970s, he received a Bachelor of Science degree in genetics and then two Masters of Science degrees, in genetics and soil science. Mr. Boone started working at Amgen Inc. in September 1981 as a Research Associate under Dr. Lawrence Souza (the named inventor on the 537 Patent) and reported to him for several years. He retired from Amgen in 2009 as its Vice President of Protein Sciences, the group within Amgen that focus on expressing, purifying, and developing proteins that can be used in human beings. Mr. Boone now owns his own consulting company, which consults for many companies including Amgen.
[23] From 1981 through 1984, Mr. Boone worked as a Research Associate for Amgen, developing protocols and techniques for gene cloning and DNA sequencing, and working on projects focused on specific proteins. In this role, he developed experience in research strategies and molecular biology techniques involved in gene cloning, as well as experience with protein purification, both at the initial stage of isolating a naturally occurring protein and at the later stage of purifying a genetically engineered protein.
[24] Mr. Boone first joined Amgen’s G-CSF project in late 1984. He was involved in this project through the clinical introduction of Amgen’s genetically engineered G-CSF in late 1986 and continued to work with the protein into the early 1990s. He explains that the “kicking-off point” for this project was a discovery made by a group of scientists at the Sloan-Kettering Institute [SKI] who were investigating the protein secreted by the “5637” human bladder carcinoma cell line. Dr. Karl Welte and other scientists at SKI had observed that a protein preparation derived from the conditioned culture medium of 5637 cells had a stimulatory effect on blood cell precursors in certain types of in vitro assays. (While not expressly noted in Mr. Boone’s affidavit, the parties agree that this discovery was subsequently published in an article by Dr. Welte and others at SKI, entitled “Purification and biochemical characterization of human pluripotent hematopoietic colony-stimulating factor,” in the March 1985 edition of the Proceedings of the National Academy of Sciences [Welte 1985]).
[25] Mr. Boone explains that the objective of Amgen’s G-CSF project was to attempt to clone the DNA for this protein and to design a process for expressing a genetically engineered (or recombinant) version of the protein, having the same biological activity as the naturally occurring variant. In his affidavit, he provides detailed explanations of Amgen’s process for attempting to produce the recombinant protein, broken down into the following five stages:
obtaining an adequately purified sample of the naturally occurring G-CSF protein;
identifying a partial amino acid sequence of the protein;
making a set of useful probes designed to bind to the cDNA (meaning complementary DNA) that encoded the identified partial amino acid sequence of the protein;
identifying the gene (i.e. DNA sequence) that encodes the protein, by creating a cDNA library for the 5637 cell line and employing the probes to attempt to hybridize (i.e. bind) one of the probes to the targeted cDNA in the library;
expressing a recombinant version of the G-CSF protein and purifying it in such a way that it retains at least some of the biological activities of the naturally occurring G-CSF protein.
[26] By the time Mr. Boone first joined the G-CSF project in late 1984, others on the Souza team had attempted throughout 1984 to obtain a partial amino acid sequence for the target protein by analysing samples of the conditioned medium that had been sent to Amgen by SKI, with which Amgen was collaborating. However, as adequate amino acid sequencing had not been achieved using the SKI samples, Dr. Souza decided Amgen would attempt to culture the 5637 cells itself to create its own conditioned medium and then purify the relevant protein to undertake further sequencing efforts. This in-house work involved modifications to SKI’s original culturing and purification protocols as set out in Welte 1985. Mr. Boone was not directly involved in producing the conditioned medium. His work with the Souza team began with helping to purify Amgen’s in-house samples.
[27] Mr. Boone’s affidavit details the challenges and uncertainties at the various stages of the G-CSF project. He emphasizes the very real possibility that the project would fail. Those challenges will be explained and considered later in these Reasons.
(a) General Observations on Reliability
[28] Pfizer submits the Court should treat Mr. Boone’s evidence with caution, arguing he is a paid advocate who has provided inconsistent and unreliable evidence. While Amgen no longer employs Mr. Boone, Pfizer notes he has worked with different Amgen legal teams on litigation involving the 537 Patent for years. Pfizer asserts that, while Mr. Boone is the witness Amgen has chosen to tell its invention story, he does not have first-hand knowledge of much of the evidence he seeks to provide to the Court. Pfizer also asserts that, by comparing Mr. Boone’s current evidence with that which he provided in past proceedings, it is apparent he has both stretched and curated his evidence to favour Amgen’s position.
[29] In support of this last assertion, Pfizer notes that Mr. Boone’s affidavit in the Apotex Application described Amgen’s changes to Dr. Welte’s purification protocol simply as “refinements”, while his current affidavit describes those changes as “significantly re-worked”. As another example, Pfizer refers to Mr. Boone’s evidence regarding the purification and proper folding of the recombinant G-CSF, which he describes as “[…] a difficult challenge for us to overcome in August 1985.” Pfizer points out that [REDACTED].
[30] My overall impression of Mr. Boone was that he attempted to testify accurately and honestly. At times, he was less than direct in answering cross-examination questions, but I interpreted this as wanting to ensure precision in his answers, rather than as being difficult. That said, Pfizer’s points about Mr. Boone’s subjective characterization of Amgen’s work do resonate with me. Subject to concerns regarding evidence about which he does not have sufficient knowledge (which I will consider when addressing specific aspects of his evidence), I am inclined to treat his factual evidence surrounding Amgen’s work as reliable. However, I will treat his characterizations of that work with more caution.
B. Dr. Krisztina Zsebo (Amgen Witness)
1. Evidence in Brief
[31] Dr. Krisztina Zsebo is a biochemist who worked at Amgen Inc. from April 1984 to 1992. She received a Bachelor of Science degree in biochemistry in 1977, a Masters degree in biochemistry and biophysics in 1980, and a PhD in comparative biochemistry, with a minor in molecular biology, in 1984. Dr. Zsebo then joined Amgen as a Research Scientist. During her time at Amgen, she worked on the characterization, cloning, and/or recombinant expression of G-CSF and other factors. After the G-CSF project, she led the development of a stem cell factor, which was a hematopoietic growth factor like G-CSF. When Dr. Zsebo left Amgen in 1992, she was the Associate Director, Product Development for that stem cell factor. She is currently the Chief Executive Officer, Director, and Co-founder of a biotechnology company established in 2018.
[32] Dr. Zsebo believes her involvement with the G-CSF project began sometime in April 1985. She states she was heavily involved in the project and explains she was asked to provide information about that work, particularly the in vitro testing of the recombinant protein. Dr. Zsebo describes her involvement in the following aspects of the project:
Beginning around April 1985, she joined the Souza team that had been working on culturing 5637 cells and helped Joan Fare, a research associate on that team, to produce the conditioned medium from which the target protein was purified;
She conducted various in vitro tests, of both the purified target protein and Amgen’s E. coli expressed, recombinant version of the protein, to characterize the protein and to confirm that the team had recombinantly produced the correct protein. This involved setting up and running a number of in vitro biological assays, as well as determining the carbohydrate structure (or glycosylation) of the protein by identifying its apparent molecular weight;
She helped to express a different version of the recombinant protein in mammalian cells (as opposed to E. coli cells); and
She assisted Dr. Arthur Cohen, an Amgen research scientist specializing in the pharmacology of drug candidates, with in vivo testing of the E. coli expressed recombinant protein.
2. General Observations on Reliability
[33] While Dr. Zsebo is not presently an Amgen employee, Pfizer notes she has acted as a consultant for Amgen in previous proceedings, including the Apotex Application. Notwithstanding that she may have an ongoing business relationship with Amgen, I identified no indications of bias or advocacy in her testimony. Dr. Zsebo struck me as a precise and straightforward scientist, and I found no basis to question her credibility. I remain conscious of arguments raised by Pfizer as to particular areas of her evidence that are not reliable, and I will take those into account when analysing her evidence in greater detail later in these Reasons.
C. Dr. Hsieng Lu (Amgen Witness)
1. Evidence in Brief
[34] Dr. Hsieng Lu is a protein biochemist who worked at Amgen Inc. in its protein sequencing group from September 1984 until his retirement on December 31, 2013. Dr. Lu graduated with a Bachelor of Science in agricultural chemistry in 1970, a Masters of Science in 1975, and a PhD in biochemistry in 1981. Protein sequencing was an important part of his thesis work, and he worked on several sequencing projects during his doctoral work from 1979 to 1981. From 1982 to 1984, Dr. Lu completed post-doctoral work, focusing on the study of protein structure, protein function, and protein sequencing.
[35] When Dr. Lu joined Amgen in 1984, he was the second research scientist to be recruited to its protein sequencing group. He joined another research scientist, Dr. Por Lai, who had already been working on the amino acid sequencing component of the G-CSF project. He ultimately worked on the project with both Dr. Lai and two research assistants in the 1984 to 1986 timeframe.
[36] Dr. Lu explains the key responsibilities of the protein sequencing group were to determine the purity of protein samples provided to them and to try to determine the amino acid sequence of the protein of interest in each sample. With respect to cloning projects, the goal of the group was to determine, unambiguously, enough of the amino acid sequence of a protein of interest to permit Amgen’s molecular biologists to attempt to clone the protein. Dr. Lu explains the equipment and process through which this work was conducted.
[37] In the period from March 1984 to late June 1985, Amgen’s protein sequencing group tried to sequence the target G-CSF protein five separate times—three times using samples provided by SKI and twice using a protein sample independently purified by Amgen researchers—before Dr. Souza was satisfied his team had a sufficiently long and unambiguous amino acid sequence to proceed with the cloning project. By the time Dr. Lu joined the group in September 1984, the three unsuccessful sequencing efforts (or runs) using the SKI samples had already taken place.
[38] Dr. Lu states he was personally involved, with Dr. Lai, in the fourth and fifth runs using the sample purified in-house at Amgen. His involvement in the fourth run began on May 24, 1985, when the protein sequencing group received a sample that had been partially purified by Mr. Boone from protein secreted by cells cultured in-house at Amgen. He and Dr. Lai performed the final purification stage, employing a High Performance Liquid Chromatography [HPLC] system. Dr. Lu states that, from the fourth sequencing run, they were able to obtain a sequence of 31 amino acids, most of which they were certain they identified correctly. However, Dr. Souza was not satisfied they could proceed with the cloning effort, and he directed the protein sequencing group to attempt another run on the same sample.
[39] Therefore, in late June 1985, Amgen performed another sequencing run, using approximately 50% more of the sample than in the previous run. In addition to the increased amount of the sample, for the fifth sequencing run, the protein sequencing group decided to reduce the sample with ß-mercaptoethanol to remove the protein's secondary structure. That is, they unfolded the protein under reducing conditions, with the hope of improving the effectiveness of the process (called Edman degradation) by which they cleaved individual amino acids from the protein chain, allowing them to call additional amino acids. Dr. Lu also states that, after weighing the pros and cons of using polybrene, which could sometimes make sequencing calls more difficult due to the presence of impurities, Dr. Lai made the judgment call to use polybrene at each cycle of the Edman degradation to try to improve the identification of the amino acids of interest.
[40] Dr. Lu explains they were then able to determine the identity of 44 amino acids before the chromatograms became too difficult to interpret. Based on the results of this fifth run, Dr. Souza was satisfied the amino acid sequence was sufficiently long and unambiguous that he could rely on it to move forward to the next steps of the cloning project. In his affidavit, Dr. Lu describes Dr. Souza and Mr. Boone selecting from this fifth run sequence a particular span of amino acids to design oligonucleotide probes. He also describes the sequencing group’s uncertainty as to their results in the fifth run. In his view, Amgen was lucky that Dr. Souza chose the particular span that he did, as it later turned out that there were errors elsewhere in this fifth run sequence.
2. General Observations on Reliability
[41] Pfizer questions the level of first-hand involvement by Dr. Lu in the G-CSF project and the reliability of the recollections he claims to have of events that took place almost 35 years ago. It also emphasizes a portion of Dr. Lu’s cross-examination, which Pfizer characterizes as follows: “Dr. Lu made up evidence that was wholly untrue, and was forced to recant when confronted with his fabrication.”
[42] This argument relates to Dr. Lu’s responses to questions by Pfizer’s counsel as to whether an affidavit he swore in the Apotex Application attached all the same exhibits as his affidavit in the present proceeding. After reviewing the documents during a break, Dr. Lu testified that certain chromatograms attached to his Apotex affidavit were not attached to his current affidavit. When asked if these omissions were an unintentional oversight, Dr. Lu responded that probably an intentional decision was made to remove the chromatograms to reduce complexity.
[43] However, a short time later in the cross-examination, Dr. Lu located the missing chromatograms in the current affidavit, concluding they had all been included, just in a different order than in the Apotex affidavit. Under further questioning, Dr. Lu acknowledged that his previous evidence, stating a decision had been made not to include certain chromatograms, was not true.
[44] Amgen argues that Pfizer has unfairly accused Dr. Lu of being untruthful. Amgen submits this allegation of dishonesty does not relate to any statement material to the issues in this litigation. Nor did it represent an effort to distort evidence in Amgen’s favour. Amgen also asserts that Dr. Lu was initially speculating that a decision had been made to remove certain chromatograms from his present affidavit, and he described an actual recollection of such a decision only after being pressed by Pfizer’s counsel.
[45] I agree with Pfizer that this portion of Dr. Lu’s testimony raises concerns about his reliability as a witness. The point is not that this evidence was material to the issues. Rather, the concern is whether the Court can rely on Dr. Lu’s professed recollections of events. While Pfizer’s counsel pressed Dr. Lu to confirm whether the decision to leave out certain documents was speculation or an actual recollection, I consider the pursuit of this questioning to have been entirely fair, given the ambiguity in the manner he described this decision.
[46] I am not left with the impression of a deliberately dishonest witness, but rather of a witness who is prone to speculation and influence, and who cannot necessarily be relied upon to testify with precision as to what he actually remembers. Regardless, little actually turns on this impression. Amgen’s closing submissions actually rely very little on the evidence of Dr. Lu. As will be noted later in these Reasons, Amgen does emphasize in its obviousness submissions his evidence that one of the amino acids within the stretch selected by Dr. Souza and Mr. Boone (residues 23-30) to design oligonucleotide probes had been mis-called in the fourth run. However, this fact does not itself appear to be controversial.
D. Ms. Anita Hammer (Amgen Witness)
[47] Ms. Anita Hammer is the Director of Regulatory Affairs at Amgen Canada, which she explains is an indirectly wholly-owned subsidiary of Amgen Inc. Like the other fact witnesses, she provided direct evidence through an affidavit. However, as agreed between the parties, she was not called as a viva voce witness at trial and was not cross-examined. Pfizer raises no concerns with the veracity of her evidence.
[48] Ms. Hammer is responsible for completing regulatory requirements to list Amgen’s patents on Health Canada’s Patent Register, including the 537 Patent. She explains that process, including the means by which Amgen Canada obtained the consent of Amgen Inc. as patent owner.
[49] Ms. Hammer also explains that Dr. Souza, the named inventor of the 537 patent, left Amgen’s employ in 2000. She describes her unsuccessful efforts to contact Dr. Souza, through his legal counsel, to discuss his possible participation as a witness in the trial of this action.
[50] Finally, Ms. Hammer describes contacting Joan Fare, a former Amgen employee who worked on the G-CSF project. [REDACTED].
E. Ms. Sheila Ahmed (Pfizer Witness)
[51] Ms. Sheila Ahmed is a Manager, Regulatory Affairs at Pfizer, a subsidiary of Pfizer Inc., and has worked in a regulatory role since 2015. Her responsibilities include managing Pfizer’s Canadian regulatory portfolio for biosimilars. She prepares and files regulatory submissions to Health Canada, including Pfizer Canada’s NDS concerning its filgrastim product NIVESTYM, which was filed on February 28, 2018.
[52] Ms. Ahmed’s affidavit attaches excerpts from the NDS for NIVESTYM, copies of the product monographs for both NIVESTYM and Amgen’s drug NEUPOGEN, and Health Canada’s letter to Pfizer Canada dated February 8, 2019, advising that the review of its NIVESTYM submission was complete, but that an NOC would not be issued until the requirements of the Regulations are met. By agreement of the parties, Ms. Ahmed did not provide oral evidence at trial and was not cross-examined. Amgen raises no concerns about her evidence.
F. Dr. Goran Valinger (Pfizer Witness)
[53] Dr. Goran Valinger is the Director of Manufacturing Science and Technology at Hospira Zagreb d.o.o [Hospira Zagreb], which is a subsidiary of Pfizer. He holds both an undergraduate degree and a PhD in biotechnology. Dr. Valinger worked at PLIVA, a pharmaceutical company in Croatia, in various positions between 2001 and 2009. In 2006, he became the Director of Biotechnology Development, assuming responsibility for drug substance process development, including for filgrastim. In 2009, PLIVA was acquired by Hospira Inc. [Hospira], and Dr. Valinger became the Director of Technical Support of Hospira Zagreb. In 2015, Pfizer acquired Hospira, and Dr. Valinger received his current title of Director of Manufacturing Science and Technology with Hospira Zagreb.
[54] Dr. Valinger explains Hospira Zagreb will manufacture the filgrastim to be sold by Pfizer Canada. He also explains the manufacturing process, employing a system with two cell banks (called a two-tiered cell banking system). The first tier is a Master Cell Bank [MCB], comprising E. coli host cells that were transformed by expression vectors containing the DNA sequence coding for filgrastim. The second tier is a Working Cell Bank [WCB], created by replicating cells from the MCB. The cells of the WCB are in turn grown to make additional cells, called production cells, which are used to make filgrastim. The MCB, WCB, and production cells are all identical.
[55] Dr. Valinger states that the MCB was created on or about April 6, 2004, the first WCB was created on or about April 19, 2005, and the first filgrastim protein was produced by December 23, 2005. Amgen does not challenge the reliability of Dr. Valinger’s evidence.
VI EXPERT WITNESSES
[56] Each of the parties introduced expert evidence in support of its respective positions on construction of the Asserted Claims and the various grounds of invalidity that are at issue, including opining on the credentials and characteristics of the Skilled Person, the state of the art as of August 23, 1985, and the common general knowledge [CGK] of the Skilled Person as of August 23, 1985 and July 31, 2007. The following is a summary of each expert’s qualifications and the areas to which his evidence relates. As with the above fact witnesses, I will include in these summaries some level of detail, intended to support analysis of the issues later in these Reasons. The following also identifies my general observations as to the reliability of the individual experts.
A. Dr. Richard Van Etten (Pfizer Expert)
[57] The first expert to testify on Pfizer’s behalf, Dr. Richard Van Etten, is presently the Director of the Chao Family Comprehensive Cancer Center and a Professor of Medicine and Biological Chemistry at the University of California Irvine. He also practices medicine as a physician in the Division of Hematology/Oncology at the University of California Irvine Medical Centre. Dr. Van Etten’s academic research and clinical practice is focused on cancers of the human blood system.
[58] Dr. Van Etten earned Bachelor of Sci