IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`v.
`
`
`AMGEN INC.,
`
`Defendant and Counterclaim Plaintiff.
`
`
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`
`v.
`
`SAMSUNG BIOEPIS CO., LTD,
`
`Defendant and Counterclaim Plaintiff.
`
`
`
`C.A. No. 18-924-CFC
`
`C.A. No. 18-1363-CFC
`
`
`
`DECLARATION OF DR. HOLLY PRENTICE IN SUPPORT OF
`PLAINTIFFS’ OPENING CLAIM CONSTRUCTION BRIEF
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 1 of 37 PageID #: 9644
`
`
`FOR THE DISTRICT OF DELAWARE
`
`v.
`
`
`AMGEN INC.,
`
`Defendant and Counterclaim Plaintiff.
`
`
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`
`v.
`
`SAMSUNG BIOEPIS CO., LTD,
`
`Defendant and Counterclaim Plaintiff.
`
`
`
`C.A. No. 18-924-CFC
`
`C.A. No. 18-1363-CFC
`
`
`
`DECLARATION OF DR. HOLLY PRENTICE IN SUPPORT OF
`PLAINTIFFS’ OPENING CLAIM CONSTRUCTION BRIEF
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 1 of 37 PageID #: 9644
`
`
`
`
`
`I, Dr. Holly Prentice, declare as follows:
`
`I.
`
`Professional Experience and Qualifications
`
`1.
`
`I am an expert in cell culture technology, which is the science of
`
`growing living cells under controlled conditions. I have particularly deep technical
`
`expertise in the development of Chinese Hamster Ovary (“CHO”) cell lines, as well
`
`as cell culture media and supplements. I have over twenty years of experience in the
`
`biopharmaceutical industry and have participated in the development of over twenty
`
`clinical and commercial therapeutic products.
`
`2.
`
`I obtained a Bachelor of Science Degree in biology from Rensselaer
`
`Polytechnic Institute in 1981, a Master’s Degree in geophysical sciences from the
`
`University of Chicago in 1983, and a Ph.D. in molecular biology from Harvard
`
`University in 1993.
`
`3.
`
`I have extensive experience in the field of cell culture technology. I
`
`began my work in the field in 1994 with Serono Laboratories, where I developed a
`
`novel expression technology in mammalian cells. From 1996 to 2006, I worked at
`
`Biogen where I either led or participated in the development of cell lines and
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 2 of 37 PageID #: 9645
`culturing processes for seven clinical products, including antibodies. Over the next
`
`seven years, I continued to work in the field of cell culture technology in positions
`
`at Momenta Pharmaceuticals and Millipore.
`
`4.
`
`In 2013, I began consulting for other biotechnology companies,
`
`2
`
`
`
`
`
`focusing in part on recombinant protein production and the development of cell
`
`culture processes. As a consultant, I often provide support to companies in the areas
`
`of cell line and process development, typically for early stage clinical development
`
`of programs for therapeutic recombinant proteins. To date, I have provided services
`
`for more than fifteen companies of various sizes with programs in various stages of
`
`clinical development.
`
`5.
`
`I am a named inventor on eleven different patents, many of which are
`
`related specifically to cell culture technology. I have also published twenty works
`
`and given numerous presentations on cell culture technology.
`
`6. My curriculum vitae, which describes in greater detail my professional
`
`experience and qualifications, is attached as Exhibit 11.1
`
`7.
`
`During the preceding five years, I have testified once at deposition, on
`
`behalf of Genentech in Pfizer, Inc. v. Genentech, Inc., Case No. IPR2017-02019
`
`and IPR2017-02020 before the United States Patent Trial and Appeal Board.
`
`II. Legal Standards and Instructions
`
`8.
`
`I have been asked by counsel for Genentech to provide my opinion as
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 3 of 37 PageID #: 9646
`to the construction of claim language in U.S. Patent No. 8,512,983 (the “’983
`
`Patent”) and U.S. Patent No. 9,714,293 (the “’293 Patent”) (collectively, the
`
`
`1 All exhibits cited herein are Exhibits to the Declaration of Nancy Lynn
`Schroeder, as described in the Exhibit List at the end of this declaration.
`
`3
`
`
`
`
`
`“Gawlitzek Patents”), and U.S. Patent No. 7,390,660 (the “Behrendt Patent”). The
`
`purpose of this section of my declaration is to summarize the instructions I received
`
`from counsel in connection with preparing this opinion.
`
`A.
`
`Instructions Regarding Legal Concepts
`
`1.
`
`The Person of Ordinary Skill
`
`9.
`
`I have been asked to provide an opinion as to the qualifications of the
`
`person of ordinary skill in the art (or “POSA”) to whom the inventions disclosed and
`
`claimed in the Gawlitzek and Behrendt Patents were directed. I understand that the
`
`POSA is a hypothetical person and can possess the skills and experience of multiple
`
`individuals working together as a team. I have been informed that factors that may
`
`be considered in determining the level of ordinary skill in the art may include: (1)
`
`the educational level of the inventors; (2) the types of problems encountered in the
`
`art; (3) prior art solutions to those problems; (4) rapidity with which innovations are
`
`made; (5) sophistication of the technology; and (6) the educational level of active
`
`workers in the field.
`
`10.
`
`I have been instructed that this assessment is performed as of the time
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 4 of 37 PageID #: 9647
`of the invention. I have been asked to assume that the time of the invention for the
`
`Gawlitzek Patents is August 11, 2009, the filing date of the provisional application
`
`No. 61/232,889, from which both Gawlitzek Patents claim priority. For the Behrendt
`
`Patent, I have been asked to assume that the time of the invention is March 5, 2002,
`
`4
`
`
`
`
`
`the filing date of the foreign priority Application No. EP02004366. My opinion
`
`concerning the ordinary level of skill in the field of either the Gawlitzek or Behrendt
`
`Patents would not change if a date a few years earlier or later were used instead.
`
`When I refer to the person of ordinary skill in this declaration, I am referring to that
`
`hypothetical person as of these operative dates.
`
`11. Based upon my experience working in the field and my interactions
`
`with others, the person of ordinary skill in the art for the Gawlitzek Patents and the
`
`Behrendt Patent would have had a Ph.D. in chemical engineering, molecular
`
`biology, or a related discipline and experience in the process development and
`
`manufacture of recombinant proteins in mammalian cell lines for therapeutic use.
`
`Alternatively, the person of ordinary skill could have less formal education (i.e., a
`
`B.S. or M.S.) but at least five more years of direct experience.
`
`2.
`
`Claim Construction
`
`12.
`
`I have been instructed that claim language should generally be given its
`
`“ordinary and customary” meaning to the person of ordinary skill in the art in the
`
`context of the patent.
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 5 of 37 PageID #: 9648
`13.
`In ascertaining that meaning, I have been instructed that the words of
`
`the patent’s claims and the context in which the term is used in the claims can be
`
`highly instructive. I further understand that the terms of a claim are to be interpreted
`
`in the context of the entire patent, including the patent’s claims, its “written
`
`5
`
`
`
`
`
`description,” and its figures (which together I have been told are called the
`
`“specification”).
`
`14. Further, I have been instructed that a patent’s “prosecution history” may
`
`provide helpful evidence about how the Patent Office and the inventor understood
`
`the patent and its claims. Consequently, I have been instructed that claim terms
`
`should, in addition to the claims themselves and the patent specification, also be
`
`interpreted in light of the patent’s prosecution history.
`
`15.
`
`I have been instructed that these sources—the claims, the written
`
`description, the figures, and the prosecution history—are referred to as “intrinsic
`
`evidence.”
`
`16.
`
`In addition to the “intrinsic evidence,” I have been instructed that
`
`certain “extrinsic evidence” such as the testimony of individuals working in the field
`
`and scientific or technical references may also shed useful light on the way in which
`
`the person of ordinary skill in the art might understand the claim term. I have been
`
`instructed that such extrinsic evidence must always be considered in the view of the
`
`intrinsic evidence.
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 6 of 37 PageID #: 9649
`17.
`I have been retained on behalf of Plaintiff Genentech, Inc. to perform
`
`this analysis, but the opinions set forth in this declaration are my own. I am being
`
`paid my normal, hourly rate of $275 for my time. My compensation does not depend
`
`in any way on the outcome of this matter.
`
`6
`
`
`
`
`
`B. Materials Considered
`
`18.
`
`I have reviewed the Gawlitzek and Behrendt Patents and their
`
`respective prosecution histories. I also have reviewed the parties’ “Joint Claim
`
`Construction Chart,” and in particular, the proposals concerning the disputed terms
`
`for the Gawlitzek and Behrendt Patents. I understand that both Plaintiffs and
`
`Defendants have cited in this Chart the “Intrinsic Evidence” that they contend to be
`
`relevant and I have paid particular attention to those portions of the Gawlitzek and
`
`Behrendt Patents and their prosecution histories and their meanings to the person of
`
`ordinary skill in the art.
`
`19.
`
`I also have considered the various articles and books cited throughout
`
`this declaration in forming my opinion, as well as my many years of experience in
`
`the cell culture field.
`
`III. Technical Background
`
`20. Antibodies are proteins that recognize and bind specifically to other
`
`molecules. They are naturally produced by the body to target “foreign” molecules,
`
`like viruses, bacteria, or other toxins. They are essential components of any well-
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 7 of 37 PageID #: 9650
`functioning immune system.
`
`21. Over the past few decades, scientists have identified particular
`
`antibodies that bind specifically to targets of therapeutic interest. For example,
`
`bevacizumab is an engineered antibody capable of binding to the protein VEGF and
`
`7
`
`
`
`
`
`neutralizing it, thereby helping treat various forms of cancer.
`
`22. Therapeutic antibodies are typically made in so-called “recombinant”
`
`cell lines that have been genetically engineered to produce the antibody. Ex. 7 (Birch
`
`2006) at 672.2 These recombinant cell lines are typically mammalian. Ex. 7 (Birch
`
`2006) at 672. Frequently, the mammalian cell line is a Chinese hamster ovary (or
`
`“CHO”) cell line. Ex. 7 (Birch 2006) at 672. It is necessary to cultivate large
`
`quantities of such cells to manufacture commercial quantities of a therapeutic
`
`antibody. The cell culture field is concerned with the processes and technologies for
`
`doing so.
`
`A. Cell Culture and the Cell Culture Medium
`
`23. Cell culture in its most general sense refers to growing cells in an
`
`artificial environment. Ex. 12 (Cell Culture Basics) at 2.3 “[T]he artificial
`
`environment in which the cells are cultured invariably consists of a suitable vessel
`
`containing a substrate or medium that supplies the essential nutrients (amino acids,
`
`carbohydrates, vitamins, minerals), growth factors, hormones, and gases (O2, CO2),
`
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 8 of 37 PageID #: 9651
`2 The Birch 2006 review is a general overview of antibody production which I cite
`multiple times in this section. Its authors were affiliated with Lonza, an industry
`leader in the manufacture of antibodies.
`
`3 This handbook is distributed by Invitrogen and Gibco, two vendors of reagents and
`supplies for culturing cells. The handbook is intended to assist their customers with
`using their products to culture cells successfully, and it provides a useful
`introduction to cell culture.
`
`8
`
`
`
`
`
`and
`
`regulates
`
`the physico-chemical environment
`
`(pH, osmotic pressure,
`
`temperature).” Ex. 12 (Cell Culture Basics) at 2.
`
`24. While many cells must be anchored to a solid support to grow in
`
`culture, the cells typically used in the industrial manufacture of antibodies have been
`
`adapted to be “grown floating in the culture medium.” Ex. 12 (Cell Culture Basics)
`
`at 2. Such cultures are known as “suspension cultures.” Because suspension
`
`cultures can be grown at larger scales, they are the preferred type of culture used for
`
`the industrial manufacture of antibodies. Ex. 7 (Birch 2006) at 675 (“The preferred
`
`culture format for large-scale (substantially greater than 10 L) is single cell
`
`suspension.”).
`
`25. The liquid in which a cultured cell floats is referred to as the “culture
`
`medium” or “cell culture medium.” Ex. 12 (Cell Culture Basics) at 2. As the
`
`Handbook explains, “[t]he culture medium is the most important component of the
`
`culture environment, because it provides the necessary nutrients, growth factors, and
`
`hormones for cell growth, as well as regulating the pH and the osmotic pressure of
`
`the culture.” Ex. 12 (Cell Culture Basics) at 20. Consistent with this industry usage
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 9 of 37 PageID #: 9652
`of the term, the Gawlitzek Patents specifically define “cell culture medium” as a
`
`“nutrient solution used for growing mammalian cells that typically provides at least
`
`one component from one or more of the following categories . . .” JA00000338
`
`(’983 Patent at 5:60-6:7). The Behrendt Patent uses the terms “cell culture medium,”
`
`9
`
`
`
`
`
`and “culture medium” consistently with the ordinary understanding of a POSA and
`
`the definition of “cell culture medium” in the Gawlitzek Patents, but does not
`
`specifically define these terms. See, e.g., JA00000445-446 (Behrendt at 2:38-40;
`
`2:58-65; 4:42-45).
`
`26. A cell in a suspension culture interacts with the culture medium. It
`
`takes up nutrients from the culture medium, like amino acids, thus reducing the
`
`concentration of amino acids in the culture medium. Under some conditions, a cell
`
`can synthesize various compounds (including many amino acids) and may excrete
`
`them into the culture medium. A cell in suspension culture also excretes metabolic
`
`waste products into the culture medium. When cells die, the integrity of the cell
`
`membrane becomes compromised, resulting in the compounds inside the cell being
`
`released into the culture medium. As a result, the culture medium’s composition is
`
`not static. Its composition will change based on the influence of the cells.
`
`27. The culture medium’s composition also depends upon the composition
`
`of its component parts. The solution introduced to the bioreactor at the beginning of
`
`the cell culture process is typically referred to as the “basal cell culture medium” or
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 10 of 37 PageID #: 9653
`“base cell culture medium.” The “inoculum” typically refers to the cells (and any
`
`culture medium in which the cells were grown that is carried over in the transfer)
`
`that is used to “seed” or initiate the cell culture. In many cell culture processes,
`
`nutrients continue to be added to the culture medium over the course of production.
`
`10
`
`
`
`
`
`The solutions added to the culture medium are referred to as “feeds.” All of these
`
`components, as well as those discussed in the previous paragraph, affect the culture
`
`medium’s composition at a given point in time.
`
`28. To survive in cell culture, mammalian cells require the presence of iron
`
`and other transition metal ions (e.g., Cu, Mn, and Zn), which are essential to cell
`
`respiration and metabolism. Iron is an essential co-factor for a number of cellular
`
`proteins and plays an important role in oxidation-reduction catalysis. Iron can be
`
`provided to the cells by the addition of serum. However, where the cell culture
`
`medium is serum free, an iron-containing supplement appropriate for cell culture
`
`should be added to the culture medium. The cells only need iron in trace amounts,
`
`but if the cells are deprived of iron, they will slow their growth and die. Conversely,
`
`too much iron can be toxic to cells.
`
`29. Certain compounds in solution can bind iron in solution in a process
`
`called “chelation.” Citrate and citric acid can bind very quickly and strongly to iron
`
`in solution. If there is a significant molar excess of citrate or citric acid relative to
`
`iron, an iron chelate complex (or “chelated”) may form however, there will be a
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 11 of 37 PageID #: 9654
`remaining fraction of excess citrate or citric acid that will not be part of the iron
`
`chelate-complex.
`
`B.
`
`Large-Scale Cell Culture Operations
`
`30. The industrial manufacture of antibodies happens on a massive scale.
`
`11
`
`
`
`
`
`Typical cell culture processes culminate in culturing the cells in massive vessels (or
`
`“bioreactors”) that can be as large as 20,000 liters.4 Ex. 7 (Birch 2006) at 678, 680.
`
`A typical antibody manufacturing process is summarized in Figure 3 of Birch 2006.
`
`I have excerpted a portion of the figure below to emphasize typical steps in the cell
`
`culture operations:
`
`
`
`31. The box in the upper left labeled “inoculum” refers to cells used to
`
`initiate the cell culture process. The inoculum typically originates from a single vial
`
`of frozen cells taken from a “working cell bank.” After the thawed cells from that
`
`vial have divided enough times to generate a sufficient number of cells, the
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 12 of 37 PageID #: 9655
`
`“inoculum” can be transferred to a small bioreactor.
`
`
`4 A bioreactor typically allows a manufacturer to manage specific characteristics of
`the cell culture like temperature, pH, gas (e.g. oxygen, carbon dioxide), and agitation
`controls to support cell growth and production.
`
`12
`
`
`
`
`
`32. The bioreactors are represented in the figure above as the series of three
`
`increasingly larger tanks. In each tank, the cells are grown in medium that contacts
`
`the cells and supplies nutrients. Once the cells have expanded to the desired density,
`
`they are transferred to a larger bioreactor (as indicated by the red arrow). The cells
`
`continue to expand and, upon reaching the desired cell density, the cells and the
`
`culture medium containing them are transferred to a yet-larger bioreactor. The
`
`above description is an example of how a large scale process may be implemented.
`
`In practice the number of expansion steps from vial thaw to the final bioreactor will
`
`vary depending on process requirements.
`
`33. The box in the lower left labeled “media prep” refers to the solution
`
`preparation for the base cell culture medium. As shown in the figure, such media is
`
`combined with the inoculum/contents of the prior bioreactor (that is, the cells and
`
`the medium in which they were grown).
`
`34. The final yellow box, labeled “feeds,” refers to nutrient solutions added
`
`to the cell culture medium to replenish the supply of nutrients in the cell culture
`
`medium during production.
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 13 of 37 PageID #: 9656
`35. The process exemplified in Figure 3 of Birch 2006 is known as a “fed-
`
`batch” process because the culture medium is supplemented with nutrients over the
`
`course of production. Ex. 7 (Birch 2006) at 678. Notably, in a fed-batch process,
`
`“no spent culture medium is removed.” Ex. 7 (Birch 2006) at 678. That means that
`
`13
`
`
`
`
`
`in a fed-batch process, the concentration of toxic byproducts like ammonia (which
`
`is produced by the cells during the metabolism of glutamine and other amino acids,
`
`as discussed further below) or lactate (produced by cells during the metabolism of
`
`glucose, as discussed further below) can build up in the culture medium. Reducing
`
`or eliminating the production or build-up of these waste byproducts is addressed by
`
`the Gawlitzek and Behrendt Patents. See, e.g., JA00000331-335 (’983 Patent at
`
`Figs. 12, 13); JA00000445 (Behrendt at 1:20-25) (“Lactate is a major waste product
`
`formed during the cultivation of mammalian cells. Under typical culture conditions,
`
`the cells consume glucose in great excess and metabolize it mainly to lactate. The
`
`accumulation of lactate affects cell growth, CTI and protein production adversely as
`
`a result of pH and/or pH adjustment by alkali….”).
`
`36.
`
`In the typical antibody manufacturing process using CHO cells, the
`
`antibody is secreted by the cells into the culture medium as well. In sum, the
`
`components of the culture medium are affected by all of the processes discussed
`
`above, including consumption of nutrients, secretion of compounds by the cells, cells
`
`breaking apart and releasing compounds, and the compositions of the inoculum
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 14 of 37 PageID #: 9657
`introduced into the bioreactor, the basal media, and any feeds added to the
`
`bioreactor.
`
`C. The Cell Culture Timeline
`
`37. The cell culture process in the largest-scale or “production” bioreactor
`
`14
`
`
`
`
`
`typically lasts around two weeks. It is frequently described as having “phases.” In
`
`the Gawlitzek Patents, these phases are defined as follows:
`
`
`
`the “growth phase,” meaning “the period of exponential cell growth . . .
`
`where cells are generally rapidly dividing,” which typically lasts
`
`“between about two and three days,” JA00000339 (’983 Patent at 7:46-
`
`59);
`
`
`
`
`
`the “transition phase,” during which “environmental factors such as
`
`temperature are shifted from growth conditions to production conditions,”
`
`JA00000339 (’983 Patent at 7:60-64); and
`
`the “production phase,” when “logarithmic cell growth has ended and
`
`protein production is primary,” JA00000339 (’983 Patent at 7:65-8:3).
`
`38.
`
`In sum, the growth phase refers to the initial period in the process where
`
`the cells are directing their energy to cell division, resulting in a higher cell density
`
`in the bioreactor and providing the necessary biomass to maximize production. The
`
`production phase refers to the latter period in the process where the large number of
`
`cells are producing correspondingly large amounts of antibody.
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 15 of 37 PageID #: 9658
`IV. Gawlitzek Patents: U.S. Pat. Nos. 8,512,983 and 9,714,293
`
`A. Overview
`
`39.
`
`I have reviewed the Gawlitzek Patents and the file histories of
`
`Application Nos. 12/852,377 (JA00003124-3271) and 14/670,079 (JA00003298-
`
`15
`
`
`
`
`
`3482), the applications from which the ’983 and ’293 patents issued, respectively.5
`
`40. The Gawlitzek Patents are directed to methods of producing antibodies.
`
`At the time of the invention, it was “conventional to have glutamine in cell culture
`
`media” because it was known that cells in culture could use glutamine as an
`
`alternative to glucose as a source of energy as well as a nitrogen source.
`
`JA00000336 (’983 patent at 1:22–26). On the other hand, it also was known that a
`
`byproduct of glutamine metabolism was ammonia, a toxic chemical whose
`
`accumulation resulted in lower cell viability and reduced culture longevity.
`
`JA00000336 (’983 patent at 1:50-57).
`
`41. The Gawlitzek Patents describe a solution for this dilemma. Genentech
`
`scientists researched cell culture methods using various amounts of glutamic acid,
`
`aspartic acid, glutamine, and asparagine. JA00000336, JA00000357 (’983 patent at
`
`2:17-31, 44:59-64). They developed methods that resulted in lower ammonia
`
`accumulation and cell death and substantially increased productivity in terms of the
`
`titer, or yield, of the antibody generated. JA00000359 (’983 patent at 47:47-62;
`
`48:25-36).
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 16 of 37 PageID #: 9659
`42. For reference, I have reproduced below the language of claim 1 and
`
`
`5 The ’983 and ’293 patents share the same specification, and as such, I only include
`citations to the ’983 patent here. In each case, the same disclosure is contained in
`the ’293 specification but can be found at different column and/or line cites.
`
`16
`
`
`
`
`
`highlighted the language whose meaning I understand to be in dispute:
`
`1. A process for producing a polypeptide in a mammalian
`host cell expressing said polypeptide, comprising
`culturing the mammalian host cell in a production phase
`of the culture in a glutamine-free production culture
`medium containing asparagine, where the asparagine is
`added at a concentration in the range of 7.5 to 15 mM.
`
`B.
`
`“glutamine-free production culture medium”
`
`43.
`
`I understand the parties have proposed competing constructions for the
`
`phrase “glutamine-free production culture medium.” I understand from the Joint
`
`Claim Chart that Plaintiffs contend that it means a “production culture medium that
`
`is essentially free of glutamine.” I further understand that Defendants contend that
`
`it means a “culture medium used in the production phase that does not contain
`
`glutamine when formulated.”
`
`44. A POSA would agree with Plaintiffs’ proposed construction and would
`
`reject Defendants’ proposed construction. I understand there to be two important
`
`distinctions between these constructions.
`
`45. First, Defendants’ construction suggests that the “glutamine-free
`
`production culture medium” is something “formulated.” It is not. As explained
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 17 of 37 PageID #: 9660
`
`above and below, it refers to the cell culture medium within the bioreactor during
`
`the production phase. As discussed above, this medium is necessarily a mixture of
`
`inoculum and base media, has been affected by cellular processes, and has been
`
`potentially supplemented by feeds. The POSA would reject the notion that it is
`
`17
`
`
`
`
`
`something that is “formulated.”
`
`46. Second, Plaintiffs’ construction explains what it means for the
`
`“production culture medium” to be “glutamine-free.” The POSA would understand
`
`for a variety of reasons that “glutamine-free” does not mean “containing zero
`
`molecules of glutamine,” but rather that the “production culture medium” is
`
`“essentially free” of glutamine.
`
`47.
`
`I discuss each of these points in more detail below.
`
`1.
`
`POSA’s Understanding of “production culture medium”
`
`a. Ordinary Meaning and the Written Description
`
`48. As I discussed above, the cell culture process has multiple phases, and
`
`the’983 patent distinguishes between the growth phase, transition phase, and
`
`production phase. JA00000339 (’983 patent at 7:44-8:3). The production phase is
`
`defined in the ’983 patent as follows:
`
`“Production phase” of the cell culture refers to the period
`of time during which cell growth has plateaued. During the
`production phase, logarithmic cell growth has ended and
`protein production is primary. During this period of time
`the medium
`is generally supplemented
`to support
`continued protein production and to achieve the desired
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 18 of 37 PageID #: 9661
`protein product.
`
`JA00000339 (’983 patent at 7:65-8:3). This definition of “production phase” is
`
`consistent with the POSA’s ordinary understanding.
`
`49. The Gawlitzek Patents further make clear that the “production culture
`
`medium” is the culture medium “in the production phase”:
`
`18
`
`
`
`
`
`The present invention is based, at least in part, on the
`unexpected finding that not only can recombinant proteins
`be produced in a mammalian host cell using a glutamine-
`free production medium without any significant adverse
`effect, in fact the use of a glutamine-free medium in the
`production phase significantly increases cell viability,
`culture longevity, specific productivity and/or the final
`recombinant protein titer.
`
`JA00000336 (’983 patent at 2:17-24) (emphasis added).
`
`50. This conclusion is further reinforced by the language of claim 1 of the
`
`’983 Patent, which reads:
`
`A process for producing a polypeptide in a mammalian
`host cell expressing said polypeptide, comprising
`culturing the mammalian host cell in a production phase
`of the culture in a glutamine-free production culture
`medium containing asparagine, wherein the asparagine is
`added at a concentration in the range of 7.5 mM to 15 mM.
`
`JA00000360 (’983 patent at 49:12-17) (emphasis added); see also JA00000415
`
`(’293 patent at 49:65-66 (claim 1)). The claim language explicitly requires that the
`
`“production culture medium” is being used to culture a cell “in a production phase
`
`of the culture.” JA00000360 (’983 patent at 49:12-17).
`
`51.
`
`In light of the claim language, the POSA would understand “production
`
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 19 of 37 PageID #: 9662
`culture medium” to refer to the cell culture medium as it exists in the production
`
`phase.
`
`52. As I have discussed above, cell culture is a dynamic process, and the
`
`culture medium is not static. The culture medium in a bioreactor is constantly
`
`19
`
`
`
`
`
`changing as the various components of the nutrient mix and cells interact with each
`
`other, take up molecules (including amino acids), secrete molecules (including
`
`amino acids), and die and release their contents (including amino acids).
`
`Concentrations of various components will differ over time.
`
`53. By the time the process reaches the production phase, the cells have
`
`been growing in the bioreactor for multiple days and interacting with the cell culture
`
`medium. The written description of the Gawlitzek Patents recognize that, because
`
`nutrients in the cell culture medium may have been depleted over the preceding days,
`
`during the production phase “the medium is generally supplemented to support
`
`continued protein production and to achieve the desired protein product.”
`
`JA00000339 (’983 patent at 8:1-3). The POSA would understand that the “medium”
`
`referred to here that needs to be “supplemented” is the cell culture medium as it
`
`exists in the bioreactor during the production phase, rather than some formulated
`
`composition that was introduced days earlier and whose contents differ significantly
`
`from the medium with which the cells are in contact. That original formulated
`
`composition no longer exists; the notion of supplementing it would make no sense
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 20 of 37 PageID #: 9663
`to the POSA in this context.
`
`54. The written description’s discussion of the inventors’ experiments also
`
`supports this understanding. In these experiments, the inventors compared batch
`
`processes—that is, processes in which no supplemental nutrients were added during
`
`20
`
`
`
`
`
`the culturing process—using a starting cell culture medium with various
`
`concentrations of glutamine and asparagine, as well as the amino acids glutamate
`
`and aspartate. JA00000357 (’983 patent at 44:59-64). To analyze the effects of
`
`these concentrations on the “production culture medium,” the inventors used a
`
`“Nova 400 Biomedical Bioprofile®.” JA00000359 (’983 patent at 47:6-7).
`
`55. A Nova 400 is a widely used device for analyzing samples, such as
`
`those taken from a bioreactor, to determine the concentrations of various
`
`components, including nutrients like glutamine and byproducts like ammonium (the
`
`ionized form of ammonia), at the time that the samples are drawn. The POSA would
`
`understand that Nova 400 nutrient analysis would be useful for taking a snapshot of
`
`the changing composition of the cell culture medium inside a bioreactor. The written
`
`description of the ’983 patent includes graphs depicting changing ammonia
`
`concentrations in the culture medium, based on data apparently obtained through the
`
`Nova 400, reaffirming the well-understood proposition that the changes in
`
`concentrations of components over time, rather than just the concentrations at the
`
`beginning of a process, are critical to the POSA. JA00000359, JA0000331-335
`Case 1:18-cv-01363-CFC Document 80 Filed 03/22/19 Page 21 of 37 PageID #: 9664
`(’983 patent at 48:25-36, Figs. 12, 13).
`
`b.
`
`Analysis of Defendants’ Position
`
`56. Defendants’ proposed construction
`
`requires
`
`that
`
`the claimed
`
`“production culture medium” “not contain glutamine when formulated.” This
`
`21
`
`
`
`
`
`statement would not make sense to the POSA because the “production culture
`
`medium” is not “formulated,” it is the complex mixture generated during the cell
`
`c
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