AMGEN INC. v. AMGEN CANADA INC., 2020 FC 522

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. IN SUFFICIENCY 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: A . Abuse of Process / Judicial Comity: i . 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? ii . 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? iii . Skilled Person: Who is the person skilled in the art to whom the 537 Patent is addressed [the Skilled Person]? iv .

Claim Construction: How should the Asserted Claims be construed? v . 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? B . Validity: C . Material Misrepresentation: Is the 537 Patent void pursuant to

section 53 of the Old Act? D . Insufficiency: Is the disclosure of the 537 Patent insufficient pursuant to

section 34 of the Old Act? E . 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: A . obtaining an adequately purified sample of the naturally occurring G-CSF protein; B . identifying a partial amino acid sequence of the protein; C . 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; D . 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; E . 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: A . 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; B .

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; C . She helped to express a different version of the recombinant protein in mammalian cells (as opposed to E. coli cells); and D . 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 Science degrees in Math and Biology from the Massachusetts Institute of Technology [MIT] in 1978 and a combined MD/PhD degree from Stanford University in 1984. He did his PhD research at Stanford from 1979 to June 1984 in the laboratory of Dr. David Clayton, who he describes as one of the world leaders in recombinant DNA technology. Dr. Van Etten then completed his internship and residency in Internal Medicine at Brigham & Women’s Hospital in Boston from 1984 to 1988 and a subsequent fellowship in hematology at the same hospital.

Then, from 1988 to 1991, he conducted post-doctoral research at the Whitehead Institute for Biomedical Research at MIT. Dr. Van Etten’s research focused on the molecular structure and function of a particular protein involved in cell signalling that can cause chronic myeloid leukemia when it becomes dysregulated. [ 59 ] Throughout his professional career, Dr. Van Etten has been a professor and researcher at several American universities, as well as practising medicine as a hematologist. For the past 27 years, he has operated a research laboratory dedicated to the study of leukemias. Dr.

Van Etten has authored many peer-reviewed publications, frequently presents at conferences, universities, and hospitals on the subject of his laboratory’s research, and has won many awards for that research. He was qualified at trial as an expert in hematology, protein biochemistry, and molecular biology, including recombinant DNA technology. [ 60 ] Dr. Van Etten provided two reports. In his first and principal report, he explains that Pfizer’s counsel assigned him several mandates. The following summarizes the mandates related to the issues in this action and Dr.

Van Etten’s opinion in relation to each of them. 1. Mandate 1 – Welte 1985 [ 61 ] First, Dr. Van Etten was asked to review and then summarize Welte 1985. [ 62 ] He describes Welte 1985 as reporting on the discovery and isolation of a human protein—which Dr. Welte named " “pluripotent CSF” " —that was reported to act as a pluripotent hematopoietic growth factor in the laboratory. Dr.

Van Etten opines that this was a significant discovery in the area of hematology and of considerable interest to scientists in biotechnology companies, particularly those interested in developing drugs to treat disorders of the hematopoietic system. 2. Mandate 2 - Research following from Welte 1985

[ 63 ] After he summarized Welte 1985, Pfizer’s counsel asked Dr. Van Etten if scientists at the time would have thought there was any research that naturally followed from Welte 1985. When he answered in the affirmative, counsel asked him what the next research project would be. [ 64 ] Dr.

Van Etten responded that the last paragraph of Welte 1985 set out the next research project: to test the potential of " “purified human pluripotent CSF […] in the management of clinical diseases involving hematopoietic derangement or failure.” " To do so, Welte 1985 suggests using recombinant DNA technology to allow for large-scale production of pluripotent CSF needed for clinical testing. Making recombinant pluripotent CSF for clinical testing would require two steps: (

a) cloning the gene for pluripotent CSF; and (

b) transforming the gene into host cells to cause them to produce biologically active pluripotent CSF. 3. Mandate 3 - Literature related to steps after Welte 1985 [ 65 ] After discharging Mandate 2, counsel asked Dr. Van Etten to identify sources of information scientists would have relied upon as of August 23, 1985 to carry out the recombinant expression of pluripotent CSF that he described in Mandate 2. Counsel asked him to focus on hematopoietic growth factors. [ 66 ] Dr.

Van Etten responded that a flurry of activity between 1982 and 1986 led to the isolation of genes for several hematopoietic growth factors, including the protein described in Welte 1985. He opines that, by August 23, 1985, there were laboratory manuals that explained in detail the techniques necessary to carry out the recombinant expression of pluripotent CSF. A laboratory manual entitled Molecular Cloning: A Laboratory Manual , authored by T. Maniatis and others in 1982 [Maniatis 1982], was the leading and comprehensive guide to recombinant DNA technology.

Maniatis 1982 would have taught scientists how to use this technology to make proteins such as pluripotent CSF in large scale. 4. Mandate 4 – The 537 Patent [ 67 ] After completing the previous mandates, counsel provided Dr. Van Etten with a copy of the 537 Patent and asked him to: (

a) summarize what the 537 Patent discloses; (

b) identify the Skilled Person to whom the 537 Patent is addressed; (

c) explain the Skilled Person’s CGK as of the July 31, 2007 publication date of the patent; and (

d) opine how the Asserted Claims would have been understood by the Skilled Person as of July 31, 2007. [ 68 ] Dr. Van Etten opines that the 537 Patent begins where Welte 1985 left off—it describes how Amgen made a recombinant form of the protein that Welte 1985 isolated. The patent renames this protein " “hpG-CSF” " . Dr. Van Etten states that the technical path described in the 537 Patent for achieving recombinant expression of this protein is the path that he stated earlier in his report would naturally follow from Welte 1985: (

a) cloning the gene for hpG-CSF; and (

b) transforming the gene into host cells to produce recombinant hpG-CSF. [ 69 ] Dr. Van Etten concludes the Skilled Person to whom the 537 patent is addressed would have expertise in the fields of molecular biology, hematology, and protein biochemistry.

Therefore, the Skilled Person would be a team, possessing the qualifications and experience to understand and implement the teachings of the patent, consisting of one or more people with the following skills: A . a molecular biologist with a PhD and several years of work experience in academia or industry; B . a hematologist with an MD and board certification or, alternatively, a PhD in hematology and several years of work experience in academia or industry; and C . a protein biochemist with a PhD and several years of work experience in academia or industry. [ 70 ] Dr.

Van Etten also provides scientific background information that he considers would have been included in the CGK of the Skilled Person as of the July 31, 2007 publication date of the 537 Patent. He explains this information was also CGK as of August 23, 1985, as the essence of protein biochemistry, molecular biology, and hematology had been largely worked out by 1985, including the basic tools of recombinant DNA technology.

However, he also explains that, between 1985 and 2007, there were significant advances in the CGK concerning hematopoietic lineages and growth factors, including hpG-CSF (which had become known as G-CSF). It was CGK by 2007 that the naturally occurring and recombinant versions of this protein did not in fact have pluripotent hematopoietic biological activity. [ 71 ] Dr. Van Etten then opines that the Asserted Claims claim the following: A .

Claim 43 - a recombinant hpG-CSF polypeptide with the 174 amino acid sequence of naturally occurring hpG-CSF and an additional N-terminal methionine (Met) [the Claim 43 Polypeptide]; B . Claims 44 to 46: recombinant DNA tools to express the Claim 43 Polypeptide; and C . Claim 47: a process to make the Claim 43 Polypeptide. [ 72 ] As discussed in more detail below, Dr. Van Etten finds the Skilled Person would not understand the polypeptide or tools in Claims 43-46 to possess any particular biological activity.

However, the Skilled Person would understand the polypeptide resulting from the process of Claim 47 to possess granulocyte colony-stimulating activity. 5. Mandate 5 - Obviousness [ 73 ] Pfizer’s counsel then asked Dr. Van Etten whether any of the Asserted Claims were obvious. While he was asked to consider that question as of August 23, 1985 (the filing date of the 959 Application) and a subsequent date in 1986 (the filing date of the 548 Application), Amgen confirmed at trial that it is now relying only on the 1985 date.

[ 74 ] Dr. Van Etten opines that all of the Asserted Claims were obvious as of August 23, 1985. He concludes that, after Welte 1985 was published, a Skilled Person would inevitably make a recombinant form of hpG-CSF so that its clinical potential could be explored. In Dr. Van Etten’s view, Welte 1985 clearly signalled the path forward, and the potential medical and commercial value of the protein was too great for this project not to have been pursued. He also concludes there was no inventiveness required to make this recombinant protein. [ 75 ] Dr.

Van Etten opines that Amgen’s success in producing the recombinant protein was not surprising, as there were only a limited number of ways to use recombinant DNA technology to express the protein. After reading Welte 1985, the Skilled Person would have understood that achieving the goal of large-scale production of this protein would require the usual tools and standard techniques of recombinant DNA technology well known in the art.

By August 23, 1985, the Skilled Person would also have expected that recombinant hpG-CSF that was directly expressed in E. coli would likely have some or all of the biological activities of naturally occurring hpG-CSF. 6. Mandate 6 - Priority Application [ 76 ] Counsel asked Dr. Van Etten whether the subject matter of the Asserted Claims is disclosed in the 959 Application. In Dr. Van Etten’s opinion, it is not, for two reasons: A.

Each of the Asserted Claims relies on the amino acid sequence set out in Claim 43, which is different from the amino acid sequence in the 959 Application. (This opinion relates to what it appears the parties agree are typographical errors in the sequence in the 959 Application.); and B. The 959 Application does not disclose that the recombinant protein has granulocyte colony-stimulating activity as set out in Claim 47 of the 537 Patent. 7. Mandate 7 - The Patent Specification [ 77 ] Counsel asked Dr.

Van Etten to describe the invention of the 537 Patent and then asked whether the 537 Patent specification (being the description and claims) contains the information necessary to make use of the invention as of July 31, 2007 (the issue date). [ 78 ] Dr. Van Etten describes the invention of the 537 Patent as the production of recombinant pluripotent granulocyte colony- stimulating factor, referring to the patent as being replete with references to pluripotency.

He states that, by 2007, it had been clearly shown that naturally occurring and recombinant hpG-CSF did not have pluripotent hematopoietic biological activity. As such, the 537 Patent did not contain the information necessary to allow the Skilled Person to produce a granulocyte colony-stimulating factor with pluripotent activity. [ 79 ] Dr. Van Etten’s second report responds to the claim construction opinion of one of Amgen’s experts, Dr. Maloy. However, it became apparent at trial there are no material differences between the parties’ respective constructions of the Asserted Claims. 8.

General Observations on Reliability [ 80 ] I found Dr. Van Etten to be a forthright witness. Amgen does not contend that he (or indeed any of Pfizer’s experts) were dishonest or materially influenced by bias in any aspect of their opinions. Amgen acknowledges Dr. Van Etten was fair in responding to the propositions put to him by Amgen's counsel on cross-examination. Rather, Amgen submits that the differences between his opinion and its experts’ opinions predominantly reflect differences in their respective approaches to answering the same questions.

Amgen argues its experts' evidence, and evidence elicited from Pfizer's experts on cross-examination, is the more germane to the legal tests relevant to the issues in this action. I will consider the specifics of the evidence of the parties’ respective experts later in these Reasons in relation to the individual issues to which it relates. B. Dr. Mark Hermodson (Pfizer Expert) [ 81 ] Pfizer’s next expert, Dr. Mark Hermodson, is a protein biochemist with experience in protein structure and amino acid sequence analysis, having worked in these disciplines since the 1960s. Dr.

Hermodson received a Bachelor of Arts degree in chemistry and mathematics in 1964 and a PhD in biochemistry in 1968. He then conducted post-doctoral research at the University of Washington from 1969 to 1972, working with professors who ran one of the world’s largest amino acid sequencing laboratories. He spent most of his subsequent career at Purdue University, ultimately holding the position of Head of Biochemistry until 2001. He is the author of numerous peer-reviewed publications and estimates that, since 1977, he has personally conducted several hundred amino acid sequencings. [ 82 ] Dr.

Hermodson explains that during the early-to-mid 1980s, when the work leading to the 537 Patent was being performed, he was a Professor at Purdue University and actively engaged in protein biochemistry research and amino acid sequencing work. In particular, he managed a facility (often called a core facility) that conducted amino acid sequencing for other scientists.

This work included, in particular, Edman degradation (a chemical reaction employed to remove each amino acid, one by one, from the protein chain to sequence that amino acid) and HPLC (which produces chromatograms that can be read to determine which amino acid has been removed). [ 83 ] Dr. Hermodson was qualified at trial as a protein biochemist with experience in amino acid sequencing. Pfizer’s counsel asked Dr. Hermodson to discharge two mandates. The following summarizes these mandates and Dr. Hermodson’s opinion in relation to each of them. 1. Mandate 1 – Review of Welte 1985 [ 84 ] Counsel provided Dr.

Hermodson with a copy of Welte 1985 and asked him to comment on the work done in that publication and what researchers working with proteins in 1985 would have done with the information in Welte 1985.

[ 85 ] Dr. Hermodson concludes that Welte 1985 describes the successful isolation, purification, and characterization of a human pluripotent hematopoietic colony-stimulating factor (referred to as “pluripotent CSF”) from the human bladder carcinoma cell line 5637. He opines that researchers reading Welte 1985 would have recognized they could produce pluripotent CSF recombinantly using well- documented approaches that involved: (

a) obtaining a partial amino acid sequence; (

b) making oligonucleotide probes; (

c) cloning the gene for pluripotent CSF; and (

d) expressing pluripotent CSF in a host cell. 2. Mandate 2 – Review of the 537 Patent [ 86 ] After Dr. Hermodson reviewed Welte 1985 and commented on it, counsel provided him with the 537 Patent and asked him to comment on the amino sequencing work described therein, in light of the state of the art in 1985. Counsel specifically asked Dr.

Hermodson whether any of that work would have been outside the normal level of technical skill expected of the Skilled Person as of August 23, 1985. [ 87 ] After receiving instructions as to the nature of the Skilled Person, he opines the patent is addressed to a protein biochemist with a PhD and several years of work experience in a discipline related to protein biochemistry. He explains that the skilled protein biochemist may oversee the work of a technician operating the sequencer (a machine that, by 1985, was widely used to perform Edman degradation) and HPLC column. Dr.

Hermodson also provides scientific background information that he considers would have been included in the CGK of the skilled protein biochemist. [ 88 ] The 537 Patent sets out in several Examples the steps undertaken by Amgen in producing the recombinant protein. As Dr. Hermodson’s expertise relates to the amino acid sequencing step, he reviews Example 1, which sets out the process used for amino acid sequencing of the target protein.

He reviews the information disclosed in the patent related to each of the five sequencing runs and concludes the 537 Patent does not describe any amino acid sequencing work that was outside the abilities of an ordinary skilled protein biochemist as of August 23, 1985. He opines that, through successive runs, Amgen used the same iterative process for amino acid sequencing that was used by skilled biochemists at the time. 3. General Observations on Reliability [ 89 ] As with Dr. Van Etten, Amgen does not contend Dr.

Hermodson was materially influenced by any bias in any aspect of his opinions, and it acknowledges he was fair in responding to the propositions put to him by Amgen's counsel on cross-examination. Consistent therewith, I found him to be a straightforward and knowledgeable witness. C. Dr. Steven Boxer (Pfizer Expert) [ 90 ] Dr. Steven Boxer is currently the Camille Dreyfus Professor of Chemistry at Stanford University. Since he started his laboratory at Stanford in 1976, the focus of his research has been investigating and researching the structure of biological systems, particularly proteins. Dr.

Boxer’s education includes a Bachelor of Science degree in Chemistry, earned in 1969, and a PhD in Physical and Physical- Organic Chemistry, earned in 1976. He has spent his academic career at Stanford University, where he became an Associate Professor in 1982 and a Full Professor in 1986. He has held his current position since 2000. Dr. Boxer has received many awards and has served as a member or elected fellow of several scientific organizations.

He has authored over 325 publications, mostly in peer-reviewed journals, and has been invited to present his research at universities and scientific conferences around the world. [ 91 ] Dr. Boxer was qualified at trial as an expert in protein biochemistry and molecular biology including recombinant DNA technology. Like Dr. Van Etten, he provided two reports, the second of which responds to the claim construction opinion of Amgen’s expert Dr. Maloy, However, as previously noted, there are no material differences between the parties’ positons on claim construction. In Dr.

Boxer’s first and principal report, he addresses the following four mandates: 1. Mandate 1 - Welte 1985 [ 92 ] Pfizer’s counsel provided Dr. Boxer with a copy of Welte 1985. They asked him to review and summarize the

article and provide his opinion on what, if any, research a Skilled Person would have wanted to pursue following the publication of this article. [ 93 ] Dr. Boxer explained that Welte 1985 describes the isolation of a human protein called human pluripotent hematopoietic colony- stimulating factor (or pluripotent CSF) that is said to be involved in hematopoiesis. Welte 1985 also describes some aspects of the purified protein’s structure and function. [ 94 ] Dr.

Boxer’s opinion is that, following the publication of Welte 1985, the Skilled Person would have wanted to determine if pluripotent CSF had clinical promise. The Skilled Person would recognize that clinical testing would require large amounts of the protein and that the fastest and cheapest way to make large amounts was recombinant DNA technology. Therefore, the next logical steps would be for the Skilled Person to: (

i) clone the gene for pluripotent CSF; and (ii) use the cloned gene to express recombinant pluripotent CSF in E. coli . 2. Mandate 2 – The 537 Patent [ 95 ] After providing his opinion on Mandate 1, Dr. Boxer was provided with a copy of the 537 Patent. He was asked to summarize it and opine on how the Asserted Claims would have been understood by the Skilled Person as of July 31, 2007. [ 96 ] Dr. Boxer describes the 537 Patent as presenting the work that he expected would follow from Welte 1985, that is: (

i) the cloning of the gene for pluripotent CSF (which the inventor renames “hpG-CSF”); and (ii) the recombinant expression of this protein in E. coli . He construes the Asserted Claims as follows:

A . Claim 43: a recombinant polypeptide; B . Claims 44 to 46 : tools to express that polypeptide in a host cell such as E. coli ; C . Claim 47: a general process for making a biologically active form of the polypeptide. Dr. Boxer notes that the polypeptide has the amino acid sequence of naturally occurring hpG-CSF, but with an additional N-terminal methionine (i.e., a particular amino acid at one end of the amino acid chain), which is required for expression in E. coli . 3. Mandate 3 – Obviousness of Claim 43 [ 97 ] Pfizer’s counsel asked Dr.

Boxer to opine whether Claim 43 was obvious as of August 23, 1985, focusing in particular on the portion of the process following isolation of the gene encoding naturally occurring hpG-CSF. He was also asked to provide this opinion with an additional assumption that the claimed polypeptide had to have one or more of the biological activities of naturally occurring hpG-CSF. [ 98 ] In conducting this analysis, Dr.

Boxer opines that the relevant CGK of the Skilled Person would include an understanding of the fundamentals of molecular biology and protein biochemistry, which would include the available tools and techniques of recombinant DNA technology and protein biochemistry as of August 23, 1985. Earlier in his report, Dr.

Boxer also states that the CGK included the following standard laboratory processes: A . determining a partial amino acid sequence for a target protein; B . using that partial amino acid sequence to make a probe that targeted the gene for the protein; and C . using the probe to isolate the gene for the protein from a cDNA library. [ 99 ] Dr. Boxer concludes Claim 43 was obvious as of August 23, 1995. Starting with the cloned gene, it would have been obvious to make recombinant hpG-CSF using direct expression in E. coli .

It was standard practice to express mammalian proteins in E. coli by direct expression, and the Skilled Person would have anticipated that approach would work. Dr. Boxer also opines that the work described in the 537 Patent uses standard tools and procedures that were well known. [ 100 ] His conclusion remains the same if the polypeptide had to have one or more of the biological activities of naturally occurring hpG- CSF, as the Skilled Person would have expected the polypeptide to have such biological activity. As discussed in more detail below, Dr.

Boxer is confident the Skilled Person would be able to purify and properly fold the polypeptide after direct expression in E. coli , so that it had biological activity. Welte 1985 provided information about the secondary and tertiary structure of the naturally occurring protein, which would encourage the Skilled Person about the recombinant protein’s potential biological activity. 4. Mandate 4 - Obviousness of Claims 44 to 47 [ 101 ] Finally, Dr. Boxer was asked whether Claims 44 to 47 were obvious as of August 23, 1985, again focusing on the portion of the process following isolation of the cloned gene.

He concludes these claims were obvious for the same reasons as Claim 43. The tools claimed in Claims 44 to 46 and the process claimed in Claim 47 were commonplace and therefore added nothing inventive to the Claim 43 polypeptide. 5. General Observations on Reliability [ 102 ] As with Pfizer’s other experts, Amgen does not contend that Dr. Boxer was materially influenced by any bias in any aspect of his opinion. I found him to be a credible and knowledgeable witness. D. Dr. Stanley Maloy (Amgen Expert) [ 103 ] Dr.

Stanley Maloy is currently a Professor of Biology and the Associate Vice President for Research and Innovation at San Diego State University. He completed a Bachelor of Science degree in biological sciences in 1975, a Masters degree in microbiology in 1977, and a PhD in molecular biology and biochemistry in 1981. He conducted post-doctoral research until 1984, and then joined the faculty of the University of Illinois Urbana-Champaign as an Assistant Professor, leaving that institution as a full professor in 2002.

His teaching focused on molecular genetics, and his research focused on genetics and biochemistry of membrane proteins. In the 1985-1986 timeframe, Dr. Maloy was actively researching in the fields of molecular biology and biochemistry and had been doing so for a decade. He was also knowledgeable about developments in hematology and protein chemistry. [ 104 ] Dr.

Maloy has held leadership positions with the American Society for Microbiology, the Center for Microbial Sciences, the Center for Applied and Experimental Genomics, and the American Academy for Microbiology, and has authored numerous scientific publications and books. He was qualified at trial as an expert in microbiology, biochemistry, molecular biology and genetics, including recombinant DNA technology. Dr.

Maloy notes that he does not consider himself an expert in protein sequencing, although he explains he is generally knowledgeable in that area, as he has experience accessing protein sequencing services in connection with his research projects. [ 105 ] Dr. Maloy authored two reports on this matter. The first involves claim construction, providing his opinion on the characteristics of the person to whom the 537 Patent is addressed, as of July 31, 2007, and how that person would have understood the Asserted Claims. His second report responds to the reports of Drs.

Van Etten, Boxer, and Hermodson, addressing particular tasks assigned to him by Amgen’s counsel. His opinions in relation to the tasks relevant to the issues in this action are summarized below.

1. Report 1 – Construction Report (

a) Skilled Person [ 106 ] In Dr. Maloy’s opinion, in 2007, the 537 Patent is addressed to a research scientist with a PhD in the field of molecular biology, biochemistry, hematology, or protein chemistry; graduate students with at least three years of research experience in the fields of molecular biology, biochemistry, hematology, and protein chemistry; or an MD with a focus on research and at least two years of relevant, post-doctoral research that includes molecular biology, biochemistry, hematology, or protein chemistry. (

b) Claim Construction [ 107 ] Dr. Maloy opines the Asserted Claims relate to a process for preparing a functional, synthetic version of human granulocyte colony-stimulating factor, the DNA sequence, expression vector and transformed host cell used in that process, and the polypeptide resulting from that process. He provides more detailed constructions for each of the individual Asserted Claims. However, as explained later in these Reasons, there is no material disagreement between the parties surrounding construction of the Asserted Claims. It is therefore not necessary to review this aspect of Dr. Maloy’s opinion in any detail. 2. Report 2 –Validity Report (

a) Identity of the Skilled Person [ 108 ] In his second report, Dr. Maloy was first asked to identify the Skilled Person as of August 23, 1985 (as well as dates in 1986 that are no longer relevant to this action). He disagrees with Dr. Van Etten’s description of the Skilled Person, as he considers the Skilled Person described by Dr. Van Etten to have the same experimental skill as an expert in the field, lacking only their inventiveness. Dr. Maloy describes the person of ordinary skill as having less education or experience than Dr. Van Etten’s Skilled Person. (

b) Knowledge of the Skilled Person [ 109 ] Asked about the Skilled Person’s CGK, in particular what the Skilled Person would have understood from Welte 1985 and Maniatis 1982, Dr. Maloy substantially agrees with Dr. Van Etten’s and Dr. Boxer’s identification of the various laboratory tools and techniques that would have been available to the Skilled Person. He also agrees that, by August 1985, there were published examples in which various combinations of these tools and techniques had been used to genetically engineer a recombinant version of a naturally occurring protein. [ 110 ] However, Dr.

Maloy states that in August 1985 recombinant protein expression was a long and complex process that was fraught with difficulty. H e agrees that many of the tools and techniques involved in the gene cloning process could individually be characterized as standard or routine (noting as an exception the use of inosine probes, a technique that is explained later in these Reasons).

Nevertheless, he opines that devising and successfully executing a strategy for how to combine those tools and techniques to clone a gene for a protein and express a functional recombinant version of the protein for the first time was not routine in August 1985. (

c) Information Disclosed by the 537 Patent [ 111 ] Dr. Maloy was asked to summarize the information disclosed by the 537 Patent that is relevant to Claims 43 to 47, and that would not have been known to the Skilled Person. He opines that the patent discloses the 174 amino acid sequence of the naturally occurring colony-stimulating factor G-CSF and discloses a process for making biologically active recombinant G-CSF. (

d) Obviousness [ 112 ] Next, Dr. Maloy was asked to consider whether the invention claimed in each of the Asserted Claims would have been obvious to the Skilled Person on August 23, 1985. He concludes the c laims were not obvious. Specifically, Dr. Maloy opines that the amino acid sequence of G-CSF, and the process for making biologically active recombinant G-CSF, had not yet been discovered and were determined by Dr. Souza through a series of experiments that were not obvious to try.

While he agrees there would have been a strong motive to clone and recombinantly express the gene of the protein identified by Welte 1985, there was no roadmap available to the Skilled Person that would have led them directly and without difficulty to achieving that objective. [ 113 ] Dr. Maloy acknowledges published examples in which other genes were successfully cloned and other proteins expressed recombinantly. These would have provided the Skilled Person with ideas for what could be tried. However, Dr.

Maloy opines that the Skilled Person would not have expected that what worked for a different protein ought to work for G-CSF. He states that, even within the narrow realm of hematopoietic growth factors (like G-CSF), there was no single cloning strategy that had consistently worked. Further, most of the strategies that had worked were significantly different from the strategy that the Souza team successfully executed for cloning and recombinantly expressing the gene for G-CSF. (

e) Response to Pfizer’s Experts’ Claim Construction [ 114 ] Dr. Maloy responds to Dr. Van Etten’s and Dr. Boxer’s opinions as to how the Asserted Claims would have been understood (by what he refers to as the " “skilled reader” " ) as of July 31, 2007. He generally agrees with their opinions. However, he disagrees with a statement (related to Claim 44) by Dr. Van Etten that there is no limit to what the DNA sequence can be in the recombinant DNA as long as it includes sequences encoding the Claim 43 polypeptide. Dr.

Maloy responds that, while the Skilled Person would appreciate the degeneracy of the genetic code (i.e. that different DNA sequences could code for the same polypeptide sequence), this reading would not have allowed for an unlimited DNA sequence in Claim 44 or the subsequent claims. However, this difference between those experts’

opinions does not appear to be material to any of the arguments the parties are advancing. (f) 959 Application [ 115 ] Asked to consider whether the 959 Application disclosed the same invention as Claim 47, including the granulocyte colony- stimulating activity that is part of the invention of Claim 47, Dr. Maloy concludes that it did. He opines that t he Skilled Person would have understood the amino acid sequence in the 959 Application, realizing that it contained typographical errors and logically overcoming those errors.

Also, while Claim 47 of the 537 Patent claims a process that allows production of a functional polypeptide having granulocyte-stimulating activity, the 959 Application showed that the functional polypeptide had granulocyte-stimulating activity when properly folded. (

g) Sufficiency [ 116 ] Asked to consider whether the 537 Patent Specification contains the information necessary to produce " “pluripotent granulocyte colony-stimulating factor” " as of July 31, 2007, Dr. Maloy concludes that it does. He opines that, by July 31, 2007, the Skilled Person would have understood that the " “pluripotent granulocyte colony-stimulating factor” " described in 1985 referred to " “granulocyte colony-stimulating factor” " , which the 537 Patent specification contains the information necessary to produce. 3.

General Observations on Reliability [ 117 ] In addition to several criticisms of the depth of Dr. Maloy’s expertise and the methodology he employed in arriving at his opinions, Pfizer submits Dr. Maloy acted more as an advocate for Amgen than as an independent and impartial expert. While not all the points raised by Pfizer in support of this submission resonate with me, some do raise concerns that Dr. Maloy strayed into the role of an advocate.

The following are the most compelling examples of this concern. [ 118 ] One of the cloning techniques upon which both parties focus significantly is the use of inosine probes, because this technique had been developed only shortly before Amgen’s work on the G-CSF project. This tool will be explained in greater detail later in these Reasons. For present purposes, the point is that Dr. Maloy asserts the use of inosine probes was not routine in 1985.

In support of this assertion, he observes how long it took for the technique to appear in the handbook by Maniatis : " “… it is telling that inosine probes were not included in the handbook until the 1989 edition.” " However, on cross-examination, Dr. Maloy acknowledged there were no editions of Maniatis between 1982 and 1989. [ 119 ] I agree with Pfizer’s argument that Dr. Maloy’s language suggests there were editions of Maniatis between 1985 and 1988 that did not include any reference to inosine probes, supporting his assertion the technique was not routine.

In fact, the length of time that elapsed before these probes appeared in Maniatis was a function of the fact that 1989 was the next edition published after such probes were first developed and reported on in 1985. This aspect of his evidence supports Pfizer’s assertion that Dr. Maloy demonstrated a tendency towards advocacy. [ 120 ] I have a similar concern about the manner in which Dr. Maloy describes Amgen’s purification procedure when it created its in- house samples of the target protein. He describes Amgen’s protocol as a " “complete rework” " of the purification procedure described in Welte 1985.

Following his statement of that opinion, Dr. Maloy provides in table form a

summary of the differences between the Welte and Souza procedures. However, in cross-examination, Dr. Maloy acknowledged some of the items in the table used different terms to describe the same substance or technique. [ 121 ] Amgen responds to this argument by pointing out that, in his " “warm-up” " direct examination, Dr. Maloy identified some of the items in the table represented similarities and others represented differences. Pfizer, in turn, asserts Dr. Maloy’s oral evidence was an effort to improve his written evidence, because Pfizer had telegraphed in opening submissions that they would be challenging Dr.

Maloy’s opinion that Amgen’s purification process was a complete rework. [ 122 ] I find Pfizer’s argument the more compelling. Dr. Maloy’s report clearly describes the table as a

summary of the differences between the procedures of Drs. Welte and Souza. Moreover, the next paragraph of Dr. Maloy’s report refers to this " “particular combination of changes” " as not being obvious to the Skilled Person. It is at best severely lacking in precision for Dr. Maloy to have supported an important element of his opinion in this manner and raises concern that, consciously or not, Dr. Maloy’s work has strayed into advocacy. My concern does not rise to the level that I will necessarily prefer the evidence of other witnesses over Dr.

Maloy, particularly if his evidence on a particular point is compelling for other reasons. However, I will treat his evidence with caution. E. Dr. David Speicher (Amgen Expert) [ 123 ] Dr. David Speicher is a protein biochemist, currently the Caspar Wistar Professor of Computational and Systems Biology at The Wistar Institute [Wistar] in Philadelphia, PA. Since 1986, he has also been the Scientific Director of the Proteomics and Metabolomics Core Facility at Wistar. He is the Co-chair of the Molecular & Cellular Oncogenesis Program and the Director of the Center for Systems and Computational Biology. Dr.

Speicher is also an adjunct professor in the Department of Biochemistry and Biophysics at the University of Pennsylvania and an adjunct professor of Biochemistry and Molecular Medicine at Drexel University. [ 124 ] Dr. Speicher received his undergraduate degree in biochemistry in 1972 and his PhD in biochemistry in 1977. He then received post-doctoral training at the Yale University School of Medicine and was promoted to Research Scientist in 1984.

From 1980 to 1986, he was also Director of the Protein Chemistry Laboratory at the Yale School of Medicine, a core facility that provided protein sequencing, amino acid analysis, and HPLC technologies to Yale University faculty. Dr. Speicher has published numerous peer-reviewed papers, has acted in an editorial capacity for many scientific publications, and has authored numerous book chapters and reviews. He is also a member of several relevant professional organizations. He was qualified at trial to give expert opinion evidence in the fields of protein chemistry and amino acid sequencing.

[ 125 ] Having been asked by Amgen’s counsel to discharge three mandates, Dr. Speicher’s opinions can be summarized as follows: 1. Mandate 1 – Skilled Person and Common General Knowledge [ 126 ] Focusing in particular on Example 1 of the 537 Patent, which relates to his area of expertise, Dr. Speicher opines this Example is addressed to a biochemist with an advanced degree related to protein biochemistry. Such a person would have a PhD with two years of experience or a Masters degree with substantially more years of relevant experience. [ 127 ] Dr.

Speicher identifies the CGK possessed by that Skilled Person as comprising the general approaches to protein purification and partial amino acid sequencing in 1985; the operation of automated Edman degradation amino acid sequencers; and some ability to make " “calls” " of partial amino acid sequences when provided a sufficient amount of a sufficiently pure experimental protein that produced strong and straightforward signals. [ 128 ] Dr.

Speicher further opines that, armed with that CGK, the number of contiguous residues (i.e. amino acids) a Skilled Person would be able to correctly assign in an experimental protein sequence would vary substantially depending upon the protein’s properties, but the length of sequence determined would typically not be extensive and may or may not be sufficient to allow the construc

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