Bristol-Myers Squibb Canada Co. v. Mylan Pharmaceuticals ULC

Bristol-Myers Squibb Canada Co. v. Mylan Pharmaceuticals ULC
Court (s) Database
Federal Court Decisions
Date
2012-09-27
Neutral citation
2012 FC 1142
File numbers
T-2072-10
Decision Content
Date: 20120927
Docket: T-2072-10
Citation: 2012 FC 1142
Ottawa, Ontario, September 27, 2012
PRESENT: The Honourable Mr. Justice Barnes
BETWEEN:
BRISTOL-MYERS SQUIBB CANADA CO. AND MERCK SHARP & DOHME CORP.
Applicants
and
MYLAN PHARMACEUTICALS ULC AND THE MINISTER OF HEALTH
Respondents
PUBLIC REASONS FOR JUDGMENT AND JUDGMENT
I. Introduction
[1] This is an application under the Patented Medicines (Notice of Compliance) Regulations, SOR/93-133 as amended (NOC Regulations) for an order prohibiting the Minister of Health from issuing a Notice of Compliance to Mylan Pharmaceuticals ULC (Mylan) for a generic version of the Applicants’ efavirenz compound marketed as “Sustiva”. Efavirenz is an anti-retroviral drug used to treat HIV infection typically in combination with other antiretroviral agents.
[2] The Applicants seek protection until the expiry of Canadian Letters Patent 2,101,572 (the 572 Patent) and Canadian Letters Patent 2,279,198 (the 198 Patent). The 572 Patent will expire on July 29, 2013 and the 198 Patent will expire on February 2, 2018.
[3] Merck Sharp & Dohme Corp. is the owner of the patents in issue and Bristol-Myers Squibb Canada Co. (BMS) is its Canadian licensee.
II. Background
A. Summary of the Science
(1) History of HIV and AIDS
[4] A biological virus works by inserting its own information into a host cell causing the infected cell to misdirect its efforts to making more viruses, which can then pass the information on to other cells. Side effects of this replication process can lead to the death of the infected cells. The loss of important cells in the body of the host can lead to disease.
[5] AIDS or acquired human immunodeficiency syndrome was first recognized as a disease following a 1981 outbreak of very rare infections by a variety of bacteria, protozoa and/or viruses combined with cases of otherwise rare cancers among gay men and transfusion recipients in California and New York. It was rapidly recognized that the underlying cause of AIDS was a transmissible agent that attacked the immune system causing the loss of critical helper T cells. This loss left the body unable to protect itself against infection with many types of bacteria, parasites, and viruses normally present in the environment. It takes about ten years from the time of infection to die from AIDS if left untreated.
[6] HIV or human immunodeficiency virus was finally identified in 1983. By 1993, it was understood in the scientific community that HIV infection was the cause of AIDS. Soon thereafter, a second virus named HIV-2 was discovered that is associated with a much slower and less uniformly fatal course of AIDS. In consequence, the original HIV discovery was renamed HIV-1. HIV-1 and HIV-2 respond differently to antiviral drugs. References to HIV in the prior art, and even now, are interpreted to mean HIV-1 and not HIV-2 unless stated otherwise.
[7] At the time of the 572 Patent, ARC or AIDS-related complex was thought to be distinct from and a precursor to AIDS. ARC was used to describe the condition that resulted from HIV infection. While this term appears in the 572 Patent, it has subsequently been realized that there is no separate clinical entity and the term is no longer used.
(2) Infection by the HIV Virus
[8] The virus particle is called a virion and it carries genetic information in the form of a genome from one cell to another. Retroviruses, like HIV, have an RNA genome which is a single strand of genetic material. Each HIV virion contains two RNA strands with an enzyme called reverse transcriptase (HIV RT) and protein structures.
[9] The proteins on the outer layer of the virion (the envelope) use the receptors located on the surface of the helper T cell to bind to the envelope’s protein. The envelope protein then pierces the host cell’s membrane and draws the viral membrane and the host cell membrane together. This results in fusion of the two membranes. The contents of the virion are then released into the host cell, which include the virion’s proteins, enzymes and two strands of RNA. The proteins are digested by the host cell while the enzymes and RNA remain to infect the cell.
[10] HIV RT builds a complimentary strand of RNA using the host cell’s nucleotides to convert the viral RNA into a single strand of DNA. These nucleotides are the building blocks that make up the virion’s and the host cell’s genetic material. In doing this, HIV RT will make some random errors due to its poor “proof-reading” activity. HIV RT then converts the viral DNA strand into a double strand of DNA; this is the form of DNA found inside the nucleus of the host cell.
[11] Integrase, one of the enzymes brought into the host cell with the virus, carries the double strand of DNA into the nucleus of the cell. Within the nucleus, integrase finds the host cell’s DNA and makes a nick in the host DNA to allow the viral DNA to insert itself into the host DNA. This is the event that establishes lifelong infection.
[12] Another enzyme called RNA polymerase transcribes the host cell’s DNA where the viral DNA has been inserted and creates several different messenger RNAs (mRNAs). The mRNAs leave the host cell’s nucleus to begin the process of translation. In translation, organelles of the host cell read the mRNA and produce a specific amino acid chain which folds into the active proteins that are needed to form a new virion. These viral proteins are shuttled to the cell surface where they join with the other proteins initially left on the cellular membrane when the virion fused with the now infected host cell. Two strands of RNA are also brought up to this part of the surface.
[13] The virus buds off at the cell surface taking the RNA, enzymes, envelope proteins and other viral proteins with it. Within the virion, an enzyme called protease breaks up any protein chains made in the host cell into smaller functional molecules in order to allow the proteins to form the mature structure of a complete virion. This virion can now go on to infect other cells. Each host cell will continue to produce hundreds of virions.
(3) Treatment of HIV and AIDS
[14] While no vaccine has yet been discovered to completely prevent HIV, drugs have been discovered which have potent activity against it. An anti-HIV drug called AZT was discovered and reported to have potent activity against HIV in cell culture. AZT is a nucleoside reverse transcriptase inhibitor (NRTI). In 1993, the FDA licensed two other NRTIs in addition to AZT that alone or in combination could somewhat ameliorate HIV infection, but they did not have a significant impact on patient survival.
[15] While it was initially thought that genetic information could only be transferred from DNA to RNA, it was discovered in 1970 that RNA could transfer genetic information to DNA through HIV RT. As discussed above, this is how retroviruses such as HIV transfer genetic information to a host cell’s DNA.
[16] In order to become part of RNA or DNA, a nucleotide must be bound to the neighbouring nucleotide’s hydroxyl group by an enzyme called polymerase. An enzyme called kinase adds a triphosphate group to the nucleoside creating a nucleotide. Polymerase then binds the nucleotide to a neighbouring nucleotide on the RNA/DNA chain by creating a bond using the nucleotide’s hydroxyl group.
[17] For NRTIs to work, kinase must recognize them as a nucleoside and add to them a trisphosphate group so that they look enough like nucleotides to be recognized by HIV RT. However, they must lack the hydroxyl group necessary to bind them to the next nucleotide. Therefore, when polymerase attaches the NRTI triphosphate to its neighbouring nucleotide on the RNA chain, there is no hydroxyl group on the NRTI to bind it to the next nucleotide. This prevents HIV RT from continuing the RNA chain. In other words, HIV RT is halted from continuing its synthesis.
[18] The rules for recognition of nucleosides or nucleotides by cellular uptake systems, kinases, polymerases and HIV RTs are not well understood. Therefore, finding NRTIs with the correct properties involves considerable trial and error. NRTIs also have to be sufficiently foreign to the cell that they are not used by normal cell DNA polymerases. This would result in them being highly toxic to the cell.
[19] It soon became apparent that while NRTIs initially reduced the amount of virus in the blood, viral loads quickly rebounded resulting in a limited survival rate. It was discovered that HIV’s genes would mutate in HIV RT’s synthesis rendering it resistant to the NRTI triphosphates. Specifically, HIV RT would sometimes mutate at the region of HIV RT where NRTIs bind.
[20] In the late 1980s and early 1990s, it became clear that truly effective control of HIV infection would require drugs of different classes used in combination, specifically NRTIs, protease inhibitors and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Protease inhibitors stop viral protease from breaking down the protein chains in a new virion thereby preventing the proteins from forming a mature virion.
[21] NNRTIs are a set of compounds that inhibit HIV RT by blocking its ability to synthesize DNA in infected cells. Specifically, NNRTIs inhibit HIV RT and interfere with polymerase’s transcription of the host cell’s DNA by binding to the allosteric site. An effector molecule such as NNRTI is a molecule that binds to a protein and thereby alters the activity of that protein. When an effector molecule binds to the allosteric site, it creates a conformational change that can result in enzyme inhibition. The allosteric site of HIV RT where NNRTIs bind is described as a pocket that contains amino acids at approximately amino acid positions 100 to 236. While all NNRTIs inhibit HIV RT by binding the enzyme in the allosteric site, each NNRTI has a unique interaction with the amino acids in the allosteric site pocket.
[22] Soon after their development, it was discovered that HIV could evolve to become resistant to NNRTIs through mutations in HIV RT. Specifically, an inappropriate nucleotide is incorporated into a DNA strand which may cause a change in the amino acid pattern such that the sequence codes for a different protein or results in the protein adopting a slightly different shape. Some of these mutations can cause changes in HIV RT’s amino acid sequence, that affect the parts of HIV RT where the various drugs act.
[23] In normal circumstances, these mutant varieties of HIV do not replicate as efficiently as the non-mutated virus called the wild-type virus (the WT virus). If untreated, the WT virus is able to replicate faster than the mutants and infect a greater number of the host cells. WT virus is predominant in HIV infected persons who are not taking any antivirals. If an infected person is taking antivirals such as an NRTI or an NNRTI, the antivirals will typically block replication of the WT virus. However, mutated viruses can still proliferate because antivirals effective against the WT virus may not effectively operate where the mutations have caused alterations in the antivirals’ allosteric sites. These mutants are drug resistant mutants because they have changed in such a way that they are no longer susceptible to the antivirals that target the WT virus.
[24] As of 1993, a number of such mutations had been identified. HIV RT mutant strains are named by reference to the numbered amino acid position on the enzyme where the mutations occurred, the WT amino acid and the new amino acid due to the mutation. For example, K103N indicates that lysine (K) has changed to asparagine (N) at HIV RT amino acid position 103.
(4) The 572 Patent
[25] The 572 Patent is entitled “Benzoxazinones as Inhibitors of HIV Reverse Transcriptase” and was filed in Canada on July 29, 1993, published on February 8, 1994 and issued on August 28, 2001. It claims a family of NNRTI compounds including efavirenz (referred to as Compound 37.2). The 572 Patent specifically demonstrates efavirenz’s ability to inhibit the K103N mutation, the Y181C mutation and the double mutant which has both the K103N and Y181C mutations.
The 572 Patent also describes how efavirenz’s potency against these HIV RT mutations may therefore be useful in the treatment of infection by HIV and thus in the treatment of AIDS and/or ARC.
[26] The potency of efavirenz is demonstrated by the results of two assays published in the 572 Patent: the reverse transcriptase assay, which measures efavirenz’s ability to inhibit HIV RT in vitro and the cell culture assay, which measures efavirenz’s ability to inhibit the spread of HIV in cell culture in vitro. The assay results in the 572 Patent reveal that efavirenz is an extremely potent inhibitor of HIV RT in the K103N, the Y181C and the double mutant. It also reveals inhibitory activity against the WT virus. The 572 Patent goes on to demonstrate that efavirenz is bioavailable in humans based on bioavailability studies performed on rhesus monkeys.
(5) Crystalline Forms and Polymorphism
[27] Crystals are solids in which the atoms or molecules are arranged in a periodic repeating pattern that extends in three dimensions. When crystals are grown slowly and carefully they normally have flat surfaces extending in different directions called plane faces that can be seen with the naked eye (eg. salt, minerals) However, some materials do not display these obvious plane faces and instead are made up of small crystals that can be seen under a light or electron microscope (eg. steel, concrete, bone, teeth). Some materials are only partially crystalline or have crystalline regions (eg. wood, silk, hair, plastics). Solids that are not crystalline and have no long range order are said to be amorphous (eg. glass).
[28] The internal structure of molecular crystals is called the crystal structure and is determined by the position of the molecules relative to each other and the symmetry of the structure. The dimensions of the crystal structure are unique and can be used to distinguish one crystalline form of a molecule from another.
[29] Crystal morphology refers to the external shape of the crystals. The shape of a crystal can be influenced by both its internal structure and the conditions of its crystallization, including growth rate, heat, solvents used in the crystallization process and/or the presence of any impurities. Two crystals made from the same material with the same crystal structure can have very different morphologies.
[30] Polymorphism is the ability of a solid material to exist in more than one form or crystal structure. Properties that vary in different polymorphs include hardness, density, electrical conductivity, shape, solubility, dissolution rate and vapour pressure. In different thermodynamic conditions, one polymorph will be more stable than the others. In a monotropic system, one polymorph is the most stable at all temperatures. If the stability of a polymorph is a function of temperature, the system is said to be enantiotropic. Consequently, the stability of enantiotropic polymorphs will vary according to temperature.
[31] In order to convert one crystal form into another, one must apply energy (often in the form of heat) to the initial form. Direct solid conversion is another way to create a polymorph. It is the slowest form of transformation because it is literally the transition of one solid crystal to another. The molecules within these crystals have lower molecular mobility than in a liquid, which is what makes the transformation so much slower.
[32] The most common type of crystallization is crystallization from solution where a material that is solid is dissolved in a solvent. Crystallization is induced by changing the state of the system in some way that reduces the solubility of a crystallizing species. The change of state from solution to crystal can be done by temperature change, evaporating the solvent, changing the solvent composition or changing the pH. When this change of state occurs, the solution is said to be supersaturated. At this point, the solution is unable to hold all of the solute resulting in its emergence from the solution as a crystalline solid.
(6) Identifying Crystalline Structures
[33] X-ray powder diffraction (XRPD) is the most commonly used method of x-ray analysis to identify crystal forms. The XRPD pattern measures peaks and d-spacings, both of which are used to characterize a crystal form.
[34] The differential scanning calorimetry (DSC) is a technique that measures the amount of heat required to increase the temperature of a sample where the heat increases linearly over time. The DSC is often used to measure the melting point of a crystal.
(7) Granulation
[35] Polymorphs of pharmaceuticals have become an increasingly important part of drug development as the differences in the chemical and physical characteristics of polymorphs can affect the manufacturability, performance and/or quality of the drug product. It is for this reason that pharmaceutical companies generally seek out the most stable crystal form of a substance when developing a new drug.
[36] In the pharmaceutical industry, granulation refers to the act or process in which primary powder particles of the active pharmaceutical ingredient (API) are made to bind to one another to form larger, multi-particle entities called granules. The API is usually mixed with excipients that are pharmacologically inactive substances used as a carrier for the API. Bonds are formed between the powder particles by compression or by using a binding agent.
[37] Granulation is extensively used in the manufacturing of tablets. The pharmaceutical industry employs two types of granulation techniques: wet granulation and dry granulation. However, only wet granulation is relevant to this litigation. Wet granulation is the process of adding a liquid solution to the powder particles. The fluid contains a solvent which must have characteristics that allow it to be removed by drying. It is common ground in this case that the solvent used by Mylan in its wet granulation process is purified water.
[38] The solution mixed into the powders can form bonds between powder particles that are strong enough to lock them together. Water is not always strong enough to create and hold a bond once the solution dries resulting in the powders falling apart. In such instances, a liquid solution that includes a binder (pharmaceutical glue) is required. The binder is dissolved in the solvent and is added to the process. The binder forms a bond with the powders during the process and then the solvent is evaporated. Once the solvent has been dried and the powders have formed a more densely held mass, the granulation is milled. This process results in the formation of granules. The process can be very simple or very complex depending on the characteristics of the powders, the final objective of tablet making, and the equipment that is available.
(8) The 198 Patent
[39] The 198 Patent is entitled “Process of the crystallization of a reverse transcriptase inhibitor using an anti-solvent” and was filed on February 2, 1998, published on August 6, 1998 and issued on April 14, 2009. It claims Form I efavirenz, which is one of many crystal forms of efavirenz. The 198 Patent describes the processes for the crystallization of efavirenz and describes methods to convert Form II and Form III efavirenz into Form I. The 198 Patent also claims and characterizes efavirenz Form I by its XRPD pattern.
B. Expert Witnesses
(1) BMS’s Expert Witnesses
(a) Dr. Barry M. Trost
[40] Dr. Barry M. Trost is a Professor in the Department of Chemistry, School for Humanities & Sciences at Stanford University. He has a 45 year career as an organic chemist and has experience in synthesis and design of biologically active molecules, including molecules that have activity as pharmaceuticals. Dr. Trost has been elected to the National Academy of Sciences, which is considered to be one of the highest honours possible for scientists in the United States. Among the many awards and honours he has received, he has received the Arthur C. Cope Award for outstanding achievement in the field of organic chemistry, which is considered the most prestigious award given by the American Chemical Society in the field of organic chemistry and the Roger Adams Award for his outstanding contributions to research in organic chemistry. Dr. Trost has been recognized as one of the world’s 50 most cited chemists and one of the 1000 most cited contemporary scientists: Affidavit of Dr. Barry M. Trost (27 July 2011) at paras 1-12 [Affidavit of Dr. Trost].
(b) Dr. John M. Coffin
[41] Dr. John M. Coffin is the American Cancer Society Professor and Distinguished Professor in the Department of Molecular Biology and Microbiology at Tufts University in Boston, Massachusetts. Like Dr. Trost, he has also been elected to the National Academy of Sciences. He has been involved in RT research for more than 40 years and has been actively involved in HIV research since 1997. Dr. Coffin was a student in the laboratory that initially discovered retroviruses and his ongoing research in this field culminated in his participation of the national committee that named HIV. He then became the Director of the HIV Drug Resistance Program within the nationally renowned U.S. National Cancer Institute. Dr. Coffin is now or has previously been on the editorial boards of the top journals in his field and edited and coauthored the definitive text on retroviruses, which is referred to as the “bible of retrovirology”. Dr. Coffin’s research has led to some of the key new insights on how antiviral therapy works and how HIV evolves resistance to it: Affidavit of Dr. John M. Coffin (27 July 2011) at paras 1-13 [Affidavit of Dr. Coffin].
(c) Dr. Mark A. Wainberg
[42] Dr, Mark A. Wainberg is a Professor of Medicine and Microbiology at McGill University and the Director of the McGill AIDS Centre at the Montreal Jewish General Hospital. He is an internationally recognized scientist specializing in the area of HIV/AIDS. His research particularly focuses on the study of HIV reverse transcriptase and HIV drug resistance and has played a lead role in the development of anti-HIV drugs. Some of the many honours he has received include being made an Officer of the Order of Canada and an Officer in the Ordre National du Québec in recognition of his contributions to the study and treatment of HIV. He has also received the Prix Galien for Research, one of the most prestigious awards in the field of Canadian pharmaceutical research and development. He has been a member of various government committees such as the Expert Advisory Committee to Evaluate Drugs and Vaccines for HIV-1-Associated Disease. He is currently the Editor-in-Chief of the Journal of the International AIDS Society and has coauthored over 450 research papers and over 200 book chapters, commentaries and reviews, which have been published in various peer-reviewed journals: Affidavit of Dr. Mark A. Wainberg (28 July 2011) at paras 1-16 [Affidavit of Dr. Wainberg].
(d) Dr. Allan S. Myerson
[43] Dr. Allan S. Myerson is a Professor of the Practice of Chemical Engineering in the Department of Chemical Engineering at the Massachusetts Institute of Technology (MIT). He is a chemical engineer by training and has been active in researching pharmaceutical development and manufacturing and has conducted research in the area of industrial crystallization for over 34 years. He also consults with pharmaceutical companies, which has helped him understand industrial needs and practices. Included in the several awards he has received are the American Chemical Society Division of Industrial and Engineering Fellow Award and the American Chemistry Society Award in Separation Sciences and Technology. Dr. Myerson has edited five books on crystallization and is the Associate Editor of a journal published by the American Chemical Society entitled “Crystal Growth and Design”. Dr. Myerson is also a named author on over 150 publications: Affidavit of Dr. Allan S. Myerson (22 August 2011) at paras 1-18 [Affidavit of Dr. Myerson].
(2) Mylan’s Expert Witnesses
(a) Dr. Donna L. Romero
[44] Dr. Donna L. Romero is the current President of Pharma-Vation Consulting, LLC where the focus of her expertise and work relates to the design and optimization of compounds for clinical development in a variety of therapeutic areas including the treatment of HIV and AIDS. She has a Ph.D. in synthetic organic chemistry and has held the positions of Director and Senior Director of Medicinal Chemistry at Pharmacia Corp. and Pfizer Inc. respectively. As a Research Scientist, she was a leader on teams that discovered drugs and drug candidates for HIV RT and protease targets and developed structure activity relationships for inhibitors of HIV RT and protease. She is a named author on over 40 publications in her field and has received numerous awards from the Universities and Companies with which she has been employed: Affidavit of Donna L. Romero, Ph.D. (28 October 2011) at paras 1-17 [Affidavit of Dr. Romero].
(b) Dr. Michael J. Cima
[45] Dr. Michael J. Cima is a Professor of Material Science and Engineering at MIT and was recently appointed as one of a selected group of engineering faculty to the Koch Institute for Integrative Cancer Research at MIT. He has been elected to the National Academy of Engineering and is a named author on over 200 peer-reviewed scientific publications and 45 patents. He is actively involved in materials and engineered systems for improving human health such as treatments for cancer, metabolic diseases, trauma and urological disorders. He has co-founded a specialty pharmaceutical company and a company that develops drug products for urology. He has won the International Award of Materials Engineering for Resources and occupies the endowed chair at MIT under the titled of the David H. Koch Professor of Engineering: Affidavit of Michael J. Cima, Ph.D. (28 October 2011) at paras 1-12 [Affidavit of Dr. Cima].
[46] All of these experts are eminently qualified in their respective fields and to give opinion evidence on the matters in issue in this proceeding.
D. The Person of Ordinary Skill in the Art
[47] The person of ordinary skill in the art is the person to whom the patent is addressed. A person of skill must possess certain qualifications or experiences in the field to which the patent relates. The person of skill is further defined by Justice Roger Hughes in Janssen-Ortho Inc v Novopharm Ltd, 2006 FC 1234 at para 90, 301 FTR 166:
90 Care must be taken in describing a person skilled in the art as there could be danger in defining such a person so narrowly that few, if any, would qualify. Conversely, if the net is cast too broadly, a danger exists in bringing in those unfamiliar with the field. The Court must take a fair and generous view as to what sort of person comprises a person skilled in the art. That person is the ordinary person skilled in the art, not the least qualified or slowest witted. It must not be too astute or technical in its inclusion or exclusion of any group of persons. Further, with respect to evidence as to the understanding of such person, the Federal Court of Appeal has said that a witness on the subject need not be that very person, so long as they are in a position to provide appropriate evidence as to what such a person would have known and understood at the relevant time (Halford v. Seed Hawk Inc., [2006] F.C.J. No. 1205, 2006 FCA 275 at para. 17).
As between the parties, this is not an issue of particular controversy. Nevertheless, the person of skill for each patent will be addressed separately below.
(1) The 572 Patent
[48] The 572 Patent has a biological component and an organic chemistry component, which means that the Patent addresses two groups of people of skill: Cross-Examination of Dr. Barry M. Trost, Ph.D. (6 January 2012) at pp 33-34, 37. With regard to the biological component, Drs. Trost, Coffin and Wainberg opine that the person of skill would be a scientist with a Ph.D. in virology, microbiology or pharmacology who has experience with HIV and/or retroviruses because the 572 Patent describes the potential therapeutic value of the disclosed compounds: see Affidavit of Dr. Trost at para 46; Affidavit of Dr. Coffin at para 20; and Affidavit of Dr. Wainberg at para 22. In addition, Dr. Wainberg believes that a person of skill is also a person with a Masters in the above specializations or a M.D. who has spent considerable time working in the field of HIV therapeutics and/or retrovirology and/or molecular studies pertaining to retrovirology or HIV therapeutics: see Affidavit of Dr. Wainberg.
[49] Though Dr. Romero does not include persons with the above qualifications and experiences in her description of a person of skill, I am willing to accept all of the above descriptions (including the addition made by Dr. Wainberg). The 572 Patent describes the potential therapeutic value of its disclosed compounds and the person of skill described above would have the qualifications and experience necessary to understand and implement its teachings.
[50] With regard to the organic chemistry component, Drs. Trost, Coffin, Wainberg and Romero agree that the person of skill to whom the 572 Patent is addressed is a person with a Ph.D. in organic chemistry or medicinal chemistry who has several years of experience synthesizing compounds or a Masters in organic chemistry or medicinal chemistry with many years of experience synthesizing compounds. This person would be knowledgeable about the structure and synthesis of organic compounds: see Affidavit of Dr. Trost at para 45; Affidavit of Dr. Coffin at para 20; Affidavit of Dr. Wainberg at para 23; and Affidavit of Dr. Romero at para 63.
[51] Dr. Romero further asserts that this person of skill will also have experience “evaluating the results of experiments which assess HIV-RT inhibition activity” or will have a “familiarity with organic synthesis and . . . compounds intended for uses in the area of HIV and AIDS” as well as “particular knowledge of the in vitro testing of NNRTIs during the 1990s”: see Affidavit of Dr. Romero at paras 63-64. While these experiences are helpful in understanding the 572 Patent, I disagree that they are experiences necessarily possessed by a person of skill in this context. The person of skill is “the notional person to whom the patent is addressed, and who takes his or her place in the spectrum of other fictional legal persons, such as the “reasonable person” in tort law”: Allergan Inc v Canada (MOH), 2012 FC 767 at para 101 . The person of skill is not required to have specific experience with the exact or similar tests performed in the 572 Patent, however, they must have the qualifications and experience to understand and implement them. Additionally, Dr. Romero acknowledged in her cross-examination that a separate biology team would conduct the above experiments using the compound prepared by chemists: Cross-Examination of Dr. Donna L. Romero (20 January 2012) at pp 17-18. I believe the of the organic chemist or medicinal chemist described above by Drs. Trost, Coffin, Wainberg and Romero is a person of skill capable of understanding and implementing the teachings of the 572 Patent.
(2) The 198 Patent
[52] Drs. Myerson and Cima generally agree that the person of skill in the context of the 198 Patent has a bachelor’s degree in chemistry, chemical engineering or other related fields with at least three years experience in the pharmaceutical industry or with a Masters or Ph.D. in these fields with less experience: see Affidavit of Dr. Myerson at para 53; and Affidavit of Dr. Cima at paras 47, 49. However, Dr. Cima further asserts that the person of skill must have some practical experience with crystalline forms because the 198 Patent discloses processes for crystallizing and characterization results for efavirenz: Affidavit of Dr. Cima at para 48. I agree that the person of skill will be familiar with crystallography in addition to the above qualifications and experience for the reasons provided by Dr. Cima.
III. Analysis
A. Burden of Proof
[53] The issue of burden of proof in NOC proceedings is not in dispute and I adopt the following analysis provided by Justice Roger Hughes in the Eli Lilly Canada Inc v Apotex Inc, 2009 FC 320 at paras 37-40, 346 FTR 78:
37 The issue as to who bears the burden of proof in NOC proceedings, as to validity of a patent or infringement of a patent is an issue that I had thought had been put to rest. Nonetheless the parties in such proceedings continue to argue the point. It seems that my recent decision in Brystol-Myers Squibb Canada Co. v. Apotex Inc., 2009 FC 137 has given fresh ammunition to those continually wishing to stir the pot in this regard. Let me state emphatically that I did not intend in Brystol-Myers to say or apply any burden different than I had stated in previous decisions.
38 To be perfectly clear, when it comes to the burden as to invalidity I canvassed the law, in particular recent Federal Court of Appeal decisions, in Pfizer Canada Inc. v. Canada (Minister of Health), (2008), 69 C.P.R. (4th) 191, 2008 FC 11 and concluded at paragraph 32:
32 I do not view the reasoning of the two panels of the Federal Court of Appeal to be in substantial disagreement. Justice Mosley of this Court reconciled these decisions in his Reasons in Pfizer Canada Inc. v. Apotex Inc., [2007] F.C.J. No. 1271, 2007 FC 971 at paragraphs 44 to 51. What is required, when issues of validity of a patent are raised:
1. The second person, in its Notice of Allegation may raise one or more grounds for alleging invalidity;
2. The first person may in its Notice of Application filed with the Court join issue on any one or more of those grounds;
3. The second person may lead evidence in the Court proceeding to support the grounds upon which issue has been joined;
4. The first person may, at its peril, rely simply upon the presumption of validity afforded by the Patent Act or, more prudently, adduce its own evidence as to the grounds of invalidity put in issue.
5. The Court will weigh the evidence; if the first person relies only on the presumption, the Court will nonetheless weigh the strength of the evidence led by the second person. If that evidence is weak or irrelevant the presumption will prevail. If both parties lead evidence, the Court will weigh all the evidence and determine the matter on the usual civil balance.
6. If the evidence weighed in step 5 is evenly balanced (a rare event), the Applicant (first person) will have failed to prove that the allegation of invalidity is not justified and will not be entitled to the Order of prohibition that it seeks.
39 I stated the matter more succinctly in Pfizer Canada Inc. v. Canada (Minister of Health), 2008 FC 500 at paragraph 12:
12 Here the only issue is validity. Pharmascience has raised three arguments in that respect. Each of Pfizer and Pharmascience have led evidence and made submissions as to those matters. At the end of the day, I must decide the matter on the balance of probabilities on the evidence that I have and the law as it presently stands. If, on the evidence, I find that the matter is evenly balanced, I must conclude that Pfizer has not demonstrated that Pharmascience's allegation is not justified.
40 The above cases state correctly in my view, the law as to the burden in NOC proceedings as to invalidity.
[Emphasis in original]
B. The 572 Patent
(1) The Sufficiency of Mylan’s Notice of Allegation
[54] BMS argues that Mylan has failed to put its allegation of inutility into play because Dr. Romero’s evidence on point is substantially different from the Notice of Allegation (NOA). In short, BMS says that the NOA assertion is not justified by the evidence Mylan produced and falls short of the requirement set out in section 5 of the NOC Regulations that an NOA shall include “a detailed statement of the legal and factual basis for [an] allegation”. BMS relies on several authorities that state that a second person cannot build its Notice of Compliance (NOC) case on the strength of evidence that fails to conform to its NOA allegation or by prosecuting a case in a piecemeal fashion.
[55] Although Mylan does not attempt to defend its literal and broad NOA allegations, it contends that the issues were appropriately framed, that BMS knew enough to effectively meet Mylan’s allegations and that any potential prejudice was mitigated by Prothonotary Aalto’s decision to allow BMS a right of reply.
[56] There is, of course, considerable jurisprudence dealing with the issue of the sufficiency of NOAs. A useful general statement can be found in the following passage from AB Hassle v Apotex Inc, 2006 FCA 51 at para 4, [2006] 4 FCR 513:
4 It has been recognized by this Court that a notice of allegation, together with the detailed statement of the factual and legal basis of the allegations stated in the notice, plays a critical role in defining the issues to be determined in proceedings under the NOC Regulations. The notice of allegation and detailed statement must address all relevant patent claims, and must contain enough information to allow the "first person" (as defined in [section 2 of] the NOC Regulations) to make an informed decision as to whether to respond to the notice of allegation by commencing an application for a prohibition order. A notice of allegation that meets these tests is said to be "sufficient". The corollary is that a "second person" (as defined in [section 2 of] the NOC Regulations) cannot, in response to a first person's application for prohibition, present evidence and argument relating to an issue that is outside the scope of the notice of allegation and detailed statement. The jurisprudence on sufficiency arises from a line of cases that includes Bayer AG v. Canada (Minister of National Health and Welfare) (1993), 163 N.R. 183, 51 C.P.R. (3d) 329 (F.C.A.) at paragraph 15; AB Hassle v. Canada (Minister of National Health and Welfare) (2000), 7 C.P.R. (4th) 272, 256 N.R. 101 (F.C.A.) at paragraph 21; SmithKline Beecham Inc. v. Apotex Inc. (2001) 10 C.P.R. (4th) 338, 267 N.R. 101 (F.C.A.) at paragraph 27, and AstraZeneca AB v. Apotex Inc. (2005), 335 N.R. 1 (F.C.A.) at paragraph 12.
[57] Other authority establishes that it is impermissible for a second person to improve its case in a piecemeal fashion by relying on a new factual basis for an invalidity allegation or to resile from a position of fact or law taken in an NOA: see Mayne Pharma (Canada) v Aventis Pharma Inc, 2005 FCA 50 at para 25, 38 CPR (4th) 1; Merck & Co v Pharmascience Inc, 2010 FC 510 at para 96; 85 CPR (4th) 179; and Pfizer Canada Inc v Novopharm Ltd, 2005 FCA 270 at para 4, 42 CPR (4th) 97.
[58] There is no question that the Mylan NOA left much to be desired at least insofar as it concerned the inutility allegation that was later advanced by Dr. Romero. Mylan’s NOA asserted that the promise of the 572 Patent is fundamental to the utility analysis. It then went on to characterize the promise of the 572 Patent in the following way:
The skilled person would understand the promise of “potent inhibition” in the 572 Patent to mean the compounds of the invention, including efavirenz, are more effective against all known resistant mutants of HIV RT than previously known compounds including, but not limited to the three compounds specifically discussed (the “Comparison Compounds”).
[59] I do not agree with Mylan that the BMS witnesses understood the nature of the case that later emerged as a result of Dr. Romero’s evidence. In my view, the nature of the case that BMS was required to meet was significantly changed by that evid