Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 1 of 30 PageID #: 13786
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`C.A. No. 18-924-CFC
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`C.A. No. 18-1363-CFC
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`DECLARATION OF SUSAN SHARFSTEIN, PH.D.
`IN SUPPORT OF DEFENDANTS’
`CLAIM CONSTRUCTION BRIEF
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`GENENTECH, INC. and CITY OF HOPE, )
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`Plaintiffs and Counterclaim Defendants,
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`AMGEN INC.,
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`Defendant and Counterclaim Plaintiff.
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`GENENTECH, INC. and CITY OF HOPE, )
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`Plaintiffs and Counterclaim Defendants,
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`SAMSUNG BIOEPIS CO., LTD,
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`Defendant and Counterclaim Plaintiff.
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`C.A. No. 18-924-CFC
`
`C.A. No. 18-1363-CFC
`
`
`DECLARATION OF SUSAN SHARFSTEIN, PH.D.
`IN SUPPORT OF DEFENDANTS’
`CLAIM CONSTRUCTION BRIEF
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`
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`GENENTECH, INC. and CITY OF HOPE, )
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`)
`Plaintiffs and Counterclaim Defendants,
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`v.
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`AMGEN INC.,
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`Defendant and Counterclaim Plaintiff.
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`GENENTECH, INC. and CITY OF HOPE, )
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`Plaintiffs and Counterclaim Defendants,
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`v.
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`SAMSUNG BIOEPIS CO., LTD,
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`Defendant and Counterclaim Plaintiff.
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 2 of 30 PageID #: 13787
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`I, Dr. Susan Sharfstein, declare as follows:
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`I.
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`Background and Qualifications
`1.
`I am an expert in cell culture technology. In general, cell culture refers
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`to growing cells under controlled conditions, and it is the process by which
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`biopharmaceutical companies produce therapeutic proteins. I have extensive
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`experience with cell culture technology, including the formulation of cell culture
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`media, and the use of Chinese hamster ovary (“CHO”) cells in cell culture and
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`protein production.
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`2.
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`I received my B.S. with honors in Chemical Engineering from the
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`California Institute of Technology in 1987. I received my Ph.D. in Chemical
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`Engineering from the University of California, Berkeley in 1993.
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`3.
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`I am currently on the faculty of the State University of New York
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`Polytechnic Institute, where I am currently Professor of Nanobioscience.
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`Previously, I held faculty positions at other institutions including Rensselaer
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`Polytechnic Institute, and I performed postdoctoral research at the University of
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`California, Los Angeles, and the University of California, Berkeley.
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`4.
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`Over the course of my academic career, I have conducted extensive
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`research on a variety of cell culture-related topics. My research efforts are currently
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`aimed at understanding the role of culture conditions and cell physiology on use of
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`living systems for industrially relevant processes. My current projects include the
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`2
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 3 of 30 PageID #: 13788
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`production of heparin (a critically important anticoagulant drug) in CHO cells, and
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`studying and characterizing CHO cell clones producing recombinant monoclonal
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`antibodies to identify factors that affect productivity.
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`5. My publications include over 50 articles and nine book chapters, many
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`of which concern cell culture technology.
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`6.
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`Further details regarding my background, experience, research, and
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`publications are contained in my curriculum vitae, attached as Exhibit 1.
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`7.
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`In the past four years, I have not testified as an expert witness at trial
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`and have testified once by deposition in C.A. No. 17–1407-CFC.
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`8.
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`I am being compensated for my time at my normal rate of $350 per
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`hour. My compensation does not depend on the outcome of this litigation.
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`II. Nature of Assignment and Materials Considered
`9.
`I have been asked by counsel for Amgen to opine regarding the
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`construction of the claim term “glutamine-free production culture medium” in U.S.
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`Patent Nos. 8,512,983 (the “’983 patent”) and 9,714,294 (the “’293 patent”).
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`10.
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`In forming my opinions, I have relied on my knowledge, education,
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`skills, experience, and training, in addition to the documents and materials cited in
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`this declaration.
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`11.
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`I have reviewed the ’983 patent, the ’293 patent, excerpts from their
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`respective prosecution histories, as well as the references and materials cited in the
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`3
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 4 of 30 PageID #: 13789
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`text of my declaration. In addition, I have reviewed the Declarations of Dr. Holly
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`Prentice in Support of Plaintiffs’ Opening Claim Construction Brief and exhibits,
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`and the transcript of Dr. Prentice’s January 17, 2019 and February 1, 2019
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`depositions, as well as the portions of Genentech Inc.’s Opening Claim Construction
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`Briefs in C.A. No. 18-924-CFC and C.A. No. 17–1407-CFC regarding the ’983 and
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`’293 patents.
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`III. Person of Ordinary Skill in the Art
`12.
`I understand that claim terms are interpreted from the perspective of a
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`person of ordinary skill in the art (“POSA”). I understand that a POSA is a
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`hypothetical person who is presumed to have known the relevant art at the time of
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`the invention.
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`13. For the ’983 and ’293 patents, I have been asked to assume that the
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`relevant time of invention is August 11, 2009, which is the filing date of the earliest
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`application listed on the first page of the ’983 and ’293 patents (provisional
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`application No. 61/232,889).
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`14.
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`I have been informed that the following factors may be considered in
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`determining the level of ordinary skill: (A) type of problems encountered in the art;
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`(B) prior art solutions to those problems; (C) rapidity with which innovations are
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`made; (D) sophistication of the technology; and (E) educational level of active
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`workers in the field.
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`4
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 5 of 30 PageID #: 13790
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`15.
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`In my opinion, a POSA would have had a Ph.D. in chemical
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`engineering, molecular biology, or a closely related field, and at least 2-3 years of
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`experience related to cell culture media and protein and/or antibody production in
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`cell culture.
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`IV. Legal Standards for Claim Construction
`16. The purpose of this section is to summarize the instructions I have been
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`provided by counsel regarding legal standards for claim construction to apply in
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`connection with preparing my opinion.
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`17.
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`I am informed that patent claims define the scope of the patented
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`invention, and they must be definite in that they must particularly point out and
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`distinctly claim the invention.
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`18.
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`I am informed that words in a claim are generally given their ordinary
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`and customary meaning to a POSA, in view of the context of the claim language in
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`which the term appears, other claims, the specification and figures of the patent, and
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`the prosecution history. I understand that these sources are collectively called the
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`“intrinsic evidence,” and that claim terms must be interpreted in light of the intrinsic
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`evidence because a POSA would read the term in the context of the intrinsic
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`evidence.
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`19.
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`I am informed by counsel that the claim language, specification, and
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`figures are deemed highly relevant to understanding the meaning of a claim term.
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`5
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 6 of 30 PageID #: 13791
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`20.
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`I am informed by counsel that the prosecution history can be
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`informative for understanding the meaning of a claim term. I am informed that if
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`the patentee makes clear and unambiguous disavowals of claim scope during
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`prosecution, that a claim term should be interpreted to exclude the disclaimed scope.
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`21.
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`I am informed that a patentee may define a term and act as a
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`lexicographer.
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`22.
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`I am informed by counsel that “extrinsic evidence” refers to evidence
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`outside of the intrinsic evidence, such as expert testimony, scientific articles and
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`dictionary definitions. I am informed that extrinsic evidence can also be useful in
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`understanding the scope of the claim terms, but is generally considered less
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`significant than intrinsic evidence.
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`V. Technical Background
`23. Proteins are complex biomolecules that serve diverse roles in living
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`organisms. See JA00000340(9:4-6).1 The building blocks of proteins are substances
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`known as amino acids, of which there are twenty varieties, including glutamine and
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`asparagine, that link together in a chain-like fashion to form protein chains. See
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`JA00000338(5:66-67), JA00000340(9:4-6).
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`1 Because the ʼ983 and ʼ293 patents share a common specification, for ease of
`reference, I only include citations to the ’983 patent here. In each case, the same
`disclosure is contained in the ’293 patent specification but can be found at different
`column and/or line cites.
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`6
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 7 of 30 PageID #: 13792
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`24. Antibodies are a type of protein that has gained therapeutic
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`significance. See JA00000340(9:10-13, 10:53-54). Antibodies specifically bind to
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`other molecules. See JA00000340(10:56-58).
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`25. Pharmaceutical companies have developed ways of manufacturing
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`large quantities of proteins, including antibodies, for therapeutic use. Almost
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`invariably, these methods involve cell culture. See JA00000340(9:19-29). CHO
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`cells, for example, may be grown in large quantities in suitable vessels. See Ex. 4
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`(Butler 2005) at 284 (“Chinese hamster ovary (CHO) cells have become the standard
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`mammalian host cells used in the production of recombinant proteins . . . [a]ll these
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`cell lines have been adapted to grow in suspension culture and are well suited for
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`scale-up in stirred tank bioreactors”). When antibody manufacturers wish to produce
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`a particular antibody that CHO cells do not produce naturally, they will manipulate
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`the cells genetically such that the cells produce the antibody and either retain it
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`internally or secrete it into their surroundings. See JA00000340(9:32-39),
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`JA00000349(28:26-29), JA00000351(31:4-7). Trastuzumab is an example of a
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`recombinant protein produced by genetically engineered cells grown in bioreactors.
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`26. Antibody manufacturers culture large numbers of cells to produce
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`therapeutic antibodies at commercial manufacturing scale. See JA00000340(9:19-
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`29). Antibody manufacturers prefer to use CHO cells to produce large amounts of
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`antibodies. Unlike certain other cell types, CHO cells can be adapted not to require
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 8 of 30 PageID #: 13793
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`a solid surface on which to grow, and instead may be cultured while suspended in a
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`liquid known as culture medium (or culture media) inside a tank known as a
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`bioreactor. See Ex. 5 (Chu 2001) at 181. Culture medium refers to “a nutrient source
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`used for growing or maintaining cells.” JA00000338(5:60-62).
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`27. A typical commercial manufacturing scale cell culture process involves
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`the use of numerous vessels of increasing volume. See JA00000350(30:52-57). To
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`start a so-called “fed-batch” culture for commercial-scale manufacturing, antibody
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`manufacturers typically formulate the culture medium in which they plan to grow
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`the cells, thaw a frozen vial of the cells, and add the thawed cells to the culture
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`medium, allowing them to grow and multiply at relatively low volume for several
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`days. See JA00000349(28:11-13). Before the culture becomes too dense to support
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`further growth, the culture is moved (“inoculated”) into a larger volume vessel. See
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`JA00000349(28:13-16). This process is repeated multiple times, with the culture
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`volume continually increasing until the manufacturer deems the culture to have
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`sufficient cells to complete the production process. See JA00000349-50(28:23-25,
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`30:52-57). Throughout, the cells produce the antibody-of-interest. See, e.g.,
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`JA00000317(Fig.
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`6B),
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`JA00000320(Fig.
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`7B),
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`JA00000338(5:4-16),
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`JA00000349(28:26-29), JA00000351(31:4-7); see also Ex. 6 (Sandadi 2005) at
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`1541.
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`8
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`28. When antibody manufacturers wish to produce an antibody at
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`commercial scale, they develop and thoroughly vet the production process, including
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`the conditions inside the bioreactor, before using the process to produce antibodies
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`to be sold. See JA00000350(29:2-5, 29:27-33, 30:59-64); Ex. 7 (Wurm 2004) at
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`1393 (“The development of a manufacturing process for a recombinant protein in
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`mammalian cells usually follows a well-established scheme”), 1397 (“Most high-
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`yielding processes today are extended batch cultures . . . [t]he development of these
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`extended batch processes requires a good understanding of the cell line and the
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`product, and is usually only applied to processes that supply material for phase 3
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`clinical trials and for the market”). The content of the culture medium in which the
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`antibody-producing cells are suspended is an important aspect of process
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`development for commercial antibody production as one cell type may have nutrient
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`requirements and other needs that other cell types may not have (see
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`JA00000350(29:27-33, 30:59-64)).
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`29. Commercial antibody manufacturers experimentally determine
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`whether existing culture medium recipes will achieve their goals for a particular
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`culture, or if those existing recipes need to be modified in some way (e.g., adding a
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`new ingredient not listed in the existing recipe or increasing / decreasing the amounts
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`of ingredients listed in the existing recipe). See, e.g., JA00000349-50(28:51-29:2,
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`29:5-12, 29:27-33).
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`9
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`13795
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`30. Example 1 of the ’983 and ’293 patents provide an example of how an
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`antibody manufacturer might develop a media recipe for use in formulating media
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`prior
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`to or during
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`future cultures.
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` See, e.g., JA00000357(44:56-65),
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`JA00000359(47:26-34) (demonstrating that the inventors evaluated the effect of
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`different concentrations and combinations of substances of interest, including
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`glutamine, glutamate, asparagine, and aspartate, on the productivity of a cell
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`culture). Indeed, “[t]he necessary nutrients and growth factors for the medium,
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`including their concentrations, for a particular cell line, are determined empirically
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`without undue experimentation,” and once
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`this determination
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`is made,
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`manufacturers may document the recipe and use it in future production runs.
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`JA00000350(29:27-33); see also JA00000349-50(27:44-49, 28:51-29:12, and
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`29:33-50).
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`31. Culture media recipes may include any number of ingredients, and
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`while antibody manufacturers use culture media to nourish and maintain cell
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`cultures, cells are not a necessary component of culture media. What makes a fluid
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`mixture a culture medium is its suitability for growing or maintaining cells, not the
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`existence of cells in that mixture. See JA00000338(5:60-6:15). Indeed, the ’983
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`and ’293 patents show exemplary culture media recipes and none of them list cells
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`as a necessary ingredient. See JA00000358(45:12-46:4, 46:10-61).
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`10
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 11 of 30 PageID #:
`13796
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`32. Once an antibody manufacturer settles on a culture medium recipe for
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`use in a particular stage of cell culture, the manufacturer will use that recipe to
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`formulate the culture medium prior to initiating that cell culture stage in the future.
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`If the medium is to be used in a bioreactor, the medium can be formulated prior to
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`being introduced to the bioreactor. See JA00000336(1:27-29); see also Ex. 7 (Wurm
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`2004) at 1397 (“In a ‘simple’ batch or extended batch production process, the scale-
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`up to very large volumes can occur by the dilution of the content of a bioreactor into
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`5-20 volumes of fresh medium held prewarmed in a larger reactor”). Formulating a
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`culture medium at this stage is relatively simple—a predetermined culture medium
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`recipe lists numerous ingredients to be included in the final formulation and the
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`manufacturer simply adds those ingredients in an amount dictated by the recipe. See,
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`e.g., Ex. 8 (Freshney 2005) at 158-62.
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`33. Culture media recipes often include an ingredient list, as well as
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`corresponding concentration terms that dictate what amount of a given ingredient to
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`add per unit volume or weight of the intended culture. See, e.g., JA00000358(46:5-
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`61) (showing that commercially-available DMEM/F-12 culture medium contains,
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`for example, 365 mg of L-glutamine per liter of culture medium).
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`34. Cell culture media recipes include an ingredient list for a simple,
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`obvious reason—those ingredients, not other functionally similar or dissimilar
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`ingredients, are to be used in formulating the culture medium in accordance with the
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`11
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 12 of 30 PageID #:
`13797
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`recipe. In other words, if, as in the ’983 and ’293 patents, a recipe calls for, e.g., L-
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`cysteine HCl monohydrate at 17.56 mg/L and L-cystine 2HCl at 31.29 mg/L, the
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`manufacturer would use those ingredients in the prescribed amounts, not the same
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`ingredients in different amounts or different ingredients in the same or different
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`amounts. See JA00000358(46:27-28).
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`35. Because antibody manufacturers thoroughly vet their production
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`processes well in advance of producing commercial-scale amounts of antibody for
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`sale, and understand their commercial needs for a particular cell culture,
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`manufacturers know what volume of culture medium needs to be formulated prior
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`to initiating a particular stage of cell culture. See JA00000340(9:19-29). A POSA
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`need only multiply that volume by the concentration listed for a particular ingredient
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`to know the amount of that ingredient to be added to the volume to formulate the
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`culture medium in accordance with its recipe. See Ex. 9 (Masterson 1977) at 287
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`(demonstrating, in Example 12.4, a simple calculation for determining the amount
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`of a particular ingredient to add to a known volume to generate a desired
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`formulation).
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`36. Culture media formulated at the outset of a given stage of culture will
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`need to be supplemented as cells consume nutrients. For example, cells use glucose
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`as an energy source, and if cells consume the amount of glucose called for in a
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`culture medium recipe, the cells may die if glucose is not supplemented into the
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`12
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 13 of 30 PageID #:
`13798
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`medium. These supplements, often referred to as “feeds,” are a routine aspect of
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`maintaining antibody-producing cell cultures. See JA00000350(29:62-30:3).
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`37. Antibody manufacturers formulate culture media for use during culture
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`in the same manner as they formulate culture media at the initiation of culture—
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`antibody manufacturers simply would follow a predetermined recipe listing
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`ingredients and concentrations at which the ingredients are to be added to the
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`existing culture medium in the bioreactor at a predetermined time. See, e.g.,
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`JA00000339(8:4-10); JA00000349-50(27:44-49, 28:51-29:12, 29:27-50). For
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`example, if, through process development experiments, an antibody manufacturer
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`knew that a particular culture should be supplemented with various ingredients at a
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`time point after culture initiation, the manufacturer would, at that time point, add
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`those ingredients in amounts corresponding to the concentrations of the ingredients
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`called for in the recipe. The manufacturer would know the culture volume at the
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`time of supplementation, so it would only be a matter of multiplying the culture
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`volume at the time of supplementation by the concentration called for in the recipe
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`to understand what amount of an ingredient needs to be added to the culture at that
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`time. See Ex. 9 (Masterson 1977) at 287.
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`38.
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`It is not the case that an antibody manufacturer would need to know the
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`exact concentration of a particular ingredient in the bioreactor at a time point after
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`culture initiation in order to properly formulate the culture medium at that time. It
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`13
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 14 of 30 PageID #:
`13799
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`is precisely because a culture medium’s composition changes during the culture that
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`a POSA would rely on its process development knowledge, a predetermined recipe,
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`and the current culture volume to formulate the culture medium at time points after
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`cells have been added. See Ex. 7 (Wurm 2004) at 1397 (“[An] important factor is
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`the quality of the derived product. The continuously changing composition of the
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`culture medium during the production phase can affect the quality of earlier
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`synthesized products . . .
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`[r]eproducible processes will, however, produce
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`populations of protein molecules within a definable range of molecular variation”).
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`39. As discussed above, commercial antibody manufacturers understand,
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`prior to using a particular cell culture process, how the culture likely will behave at
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`all times during the culturing period. If, during process development, the
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`manufacturer determined that the culture would perform better if a given substance
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`was supplemented into the culture medium at a certain concentration at a particular
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`time, the manufacturer would simply follow the predetermined recipe for
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`formulating the supplemented culture medium and would not be paralyzed by a lack
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`of actual knowledge regarding the culture medium’s current composition. See Ex.
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`7 (Wurm 2004) at 1397 (“Reproducible processes will, however, produce
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`populations of protein molecules within a definable range of molecular variation”).
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`40. Culture medium generally is defined by its composition. See
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`JA00000338(5:60-6:15). If a recipe for a culture medium calls for certain
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`14
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 15 of 30 PageID #:
`13800
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`ingredients, it is understood that culture media formulated according to that recipe
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`will contain those ingredients upon formulation. See, e.g., Ex. 8 (Freshney 2005) at
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`158-162. However, culture medium may also be defined by what it lacks,
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`particularly if the ingredient(s) it lacks normally is included in culture medium. See
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`Ex. 10 (Kuwae 2005) at 502-503.
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`41. Glutamine is a common ingredient in culture medium.
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` See
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`JA00000336(1:22-24). Glutamine is an amino acid that functions both as a building
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`block of proteins as well as an energy source for cells. See JA00000336(1:25-26).
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`However, when cells consume glutamine, they release a toxic byproduct—
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`ammonium—into the surrounding media that, if allowed to accumulate, can cause
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`cell death. See JA00000336(1:50-55). In addition, glutamine spontaneously
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`degrades, releasing additional ammonia.
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`42. Antibody manufacturers and others began formulating culture media
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`without glutamine as an ingredient and used these so-called “glutamine-free” culture
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`media recipes when they were concerned about ammonium accumulation in culture
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`or, occasionally, for other biological applications requiring culture medium devoid
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`of glutamine. See Ex. 11 (Jun 2006) at 771 (generally describing experiments
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`requiring glutamine-free medium and noting that “[a]fter transfection, the cells were
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`maintained in glutamine-free medium (G-IMDM). The G-IMDM consists of IMDM
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`prepared without glutamine . . . .”).
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`15
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`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 16 of 30 PageID #:
`13801
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`43. As a general matter, if a culture medium is described as “free” of a given
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`substance, then the culture medium did not contain that substance at formulation.
`
`See, e.g., Ex. 11 (Jun 2006) at 771. When formulated, the composition of culture
`
`medium vis-à-vis a particular substance is binary—either it “contains” the substance
`
`or is “free” of the substance.
`
`44. Using glutamine as an example, if a recipe noted that a culture medium
`
`was “glutamine-free,” antibody manufacturers would understand that no glutamine
`
`was used in the formulation of that medium. See Ex. 11 (Jun 2006) at 771 (“After
`
`transfection, the cells were maintained in glutamine-free medium (G-IMDM). The
`
`G-IMDM consists of IMDM prepared without glutamine . . . .”); see also Ex. 21
`
`(Prentice Tr.) 204:4-11 (“Q. Now, are you aware of the commercial availability of
`
`glutamine-free culture media? A. Yes. Q. And that culture media that is
`
`characterized as glutamine-free would have 0 millimolar of glutamine in it, right?
`
`A. I believe that’s how the vendors would describe it.”). Likewise, if a culture
`
`medium was described as “glutamine-containing,” they would know that the
`
`medium was formulated with glutamine as an ingredient. See, e.g., JA000003336-
`
`37(2:66-3:3), JA00000357-58(44:66-45:6).
`
`45. Once an antibody manufacturer thoroughly understands its culture
`
`process for producing an antibody, it may know that certain culture parameters are
`
`critical to the culture surviving and/or meeting the manufacturer’s goals. See Ex. 12
`
`16
`
`
`
`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 17 of 30 PageID #:
`13802
`
`(Gawlitzek 2009) at 1165 (“In the present study, several cell culture factors that
`
`affect [quality] of two different recombinant glycoproteins expressed in CHO cells
`
`were identified . . . [t]he studies reported here underline the importance of proper
`
`process understanding
`
`to ensure production of recombinant glycoprotein
`
`therapeutics with consistent product quality”). Manufacturers typically outfit their
`
`bioreactors with various means for monitoring these so-called critical process
`
`attributes in real-time. Examples include oxygen probes for measuring the dissolved
`
`oxygen content of the culture medium in the bioreactor or pH probes for determining
`
`the pH of the culture medium at a given time. See Ex. 13 (Harms 2002) at 124.
`
`46. However, as of the earliest possible filing date of the ’983 and ’293
`
`patents, then-current technology did not allow for real-time monitoring of certain
`
`culture parameters within a bioreactor—instead, manufacturers resorted to devices
`
`separate from the bioreactor, such as the Nova 400, which had the ability to measure
`
`glutamine, but not asparagine or aspartic acid, concentration in a sample taken from
`
`the bioreactor and separately run through the device. See Ex. 14 (Nova Biomedical
`
`Manual 2004) at 2, 4, 10. The ’983 and ’293 patents disclose that the inventors had
`
`a Nova 400 device at their disposal, but does not disclose any glutamine
`
`concentration data measured from that device at any time point after media
`
`formulation. See JA00000359(47:3-7).
`
`17
`
`
`
`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 18 of 30 PageID #:
`13803
`
`47. Having vetted its culturing process and with means to measure critical
`
`process parameters, an antibody manufacturer may wish to begin producing a
`
`particular antibody for commercial sale. As described above, a typical commercial
`
`culture process for antibody production begins with the manufacturer thawing a
`
`small vial of cells and culturing them in a relatively small culture vessel, usually a
`
`flask. See Ex. 7 (Wurm 2004) at 1397 (“The entire process from the thawing of
`
`banked cells to the production vessel consists of three separate phases—seed train,
`
`inoculum train and production phase. The seed train is usually performed at a small
`
`scale to provide fresh cells for scale-up during the period chosen for production”).
`
`As the cells grow and multiply, the manufacturer will expand the culture into larger
`
`culture vessels until the manufacturer is satisfied that it has sufficient cells to initiate
`
`the final stage of its culture process—the production phase. See Ex. 7 (Wurm 2004)
`
`at 1397 (“The inoculum train starts with a small volume of cell suspension from the
`
`seed train and its volume is expanded so that a sufficient cell number will be
`
`generated for the final production phase”).
`
`48. The ’983 and ’293 patents disclose that the production phase is signified
`
`by culturing cells in a large-scale bioreactor. See JA00000349(28:23-25) (“When
`
`the cells grow to sufficient numbers, they are transferred to large-scale production
`
`tanks to begin the production phase, and grown for a longer period of time”). These
`
`so-called “production bioreactors” are on the order of 10,000 liters. A “production
`
`18
`
`
`
`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 19 of 30 PageID #:
`13804
`
`phase” of culture merely is the last culture stage before the culture is subjected to
`
`subsequent antibody purification protocols and is not defined in terms of the
`
`biological activity of the cells. See Ex. 7 (Wurm 2004) at 1397 (“The inoculum train
`
`starts with a small volume of cell suspension from the seed train and its volume is
`
`expanded so that a sufficient cell number will be generated for the final production
`
`phase”). This has to be the case because, even in the earliest stages of a culture,
`
`when the culture is grown in a relatively small culture vessel, the cells produce the
`
`antibody-of-interest. Instead, a “production phase” is a term of art used to describe
`
`the situation when a culture is growing and producing antibody in the final, large-
`
`volume bioreactor.
`
`49. Prior
`
`to adding cells
`
`to
`
`the production bioreactor, antibody
`
`manufacturers formulate medium to be used in the production bioreactor according
`
`to a pre-determined recipe and desired culture volume. See, e.g., JA00000349-
`
`50(27:44-49, 28:51-29:12, 29:27-50); see also Ex. 7 (Wurm 2004) at 1397 (“In a
`
`‘simple’ batch or extended batch production process, the scale-up to very large
`
`volumes can occur by the dilution of the content of a bioreactor into 5-20 volumes
`
`of fresh medium held prewarmed in a larger reactor”). At this point, prior to the
`
`addition of cells, a POSA would understand whether the medium was “glutamine-
`
`free” or “glutamine-containing”: if the production culture medium was formulated
`
`19
`
`
`
`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 20 of 30 PageID #:
`13805
`
`with glutamine as an ingredient, then it is “glutamine-containing.” If not, it is
`
`“glutamine-free.” See Ex. 11 (Jun 2006) at 771.
`
`50. Moreover, a POSA would understand that a “glutamine-containing”
`
`culture medium does not become a “glutamine-free” medium by the addition of
`
`cells, or any time thereafter. Nowhere in the ’983 and ’293 patents do the inventors
`
`describe a “glutamine-containing” culture medium as becoming a “glutamine-free”
`
`culture medium after the addition of cells. “Glutamine-free” and “glutamine-
`
`containing” are descriptive terms used to describe the glutamine content of the
`
`culture medium when it was formulated. See, e.g., JA00000314(Fig. 4),
`
`JA00000337(4:59-65) (confirming that “[g]lutamine-free” culture medium was
`
`“formulated with 0 mM [g]lutamine”).
`
`VI.
`
`’983 and ’293 Patent Claim Construction
`A. Background
`51. The ’983 and ’293 patents are entitled, and are generally directed to,
`
`“Production of Proteins in Glutamine-Free Cell Culture Media.” Glutamine-
`
`containing media were known at the time. The patents explain that “most
`
`commercially available media [were] formulated with free L-glutamine” because
`
`cells were known to use glutamine as an energy and nitrogen source.
`
`JA00000336(1:25-29). Glutamine-free media were also known at the time, for
`
`20
`
`
`
`Case 1:18-cv-01363-CFC Document 97 Filed 04/10/19 Page 21 of 30 PageID #:
`13806
`
`example for use with particular cell lines (i.e., glutamine synthetase transfected cell
`
`lines) that could produce their own glutamine. JA00000336(1:29-33).
`
`52. The ’983 and ’293 patents describe experiments with cell culture media
`
`to ascertain the effects of various media formulations on protein production levels.
`
`In particular, the ’983 and ’293 patents describe experiments with glutamine-free
`
`media and glutamine-containing media, with supplements of asparagine, aspartic
`
`acid, and glutamic acid. JA00000311-35(Figs. 1-13); JA00000337-38(4:38-5:54).
`
`53. Claim 1 of the ’983 and ’293 patent contain the language whose
`
`meaning I understand to be in dispute.2 Claim 1 of the ’983 patent reads as follows,
`
`with the disputed language underlined:
`
`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, wherein the asparagine is added
`at a concentration in the range of 7.5 mM to 15 mM.
`
`JA00000360.
`B.
`54.
`
`“glutamine-free production culture medium”
`I understand that Amgen has proposed that “glutamine-free production
`
`culture medium” means “culture medium used in the produc
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