Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 1 of 26 PageID #: 13760
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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 JEFFREY CHALMERS, 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 JEFFREY CHALMERS, PH.D.
`IN SUPPORT OF DEFENDANTS’
`CLAIM CONSTRUCTION BRIEF
`
`
`
`GENENTECH, INC. and CITY OF HOPE, )
`
`
`
`
`
`
`
`)
`Plaintiffs and Counterclaim Defendants,
`)
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`)
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`
`
`v.
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`AMGEN INC.,
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`)
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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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`)
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`Defendant and Counterclaim Plaintiff.
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 2 of 26 PageID #: 13761
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`I, Dr. Jeffrey Chalmers, declare as follows:
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`I.
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`Background and Qualifications
`1.
`I am an expert in cell culture technology. Cell culture refers generally
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`to the science and engineering of growing cells under controlled conditions. I have
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`experience and expertise in cell culture processes for the production of recombinant
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`proteins such as antibodies, including deep expertise in the science and engineering
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`related to sparging in bioreactors during cell culturing. I have over thirty-five years
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`of experience in bioengineering and molecular biology and have conducted and
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`published significant research regarding cell culture technology including the use
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`and effects of sparging in bioreactor cell culturing.
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`2.
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`I received a Bachelor of Science in Natural Science from Westmont
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`College in 1983 and a Bachelor of Science in Chemical Engineering with High
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`Honors in 1983. I also received my Ph.D. in Chemical Engineering from Cornell
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`University in 1988.
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`3.
`
`After earning my Ph.D., I joined the Department of Chemical
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`Engineering at the Ohio State University as an Assistant Professor. In 1993, I was
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`promoted to Associate Professor. In 1999, I was promoted to Professor, and I am
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`currently Professor and Associate Chair of the department. In these positions, in
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`addition to my research and extensive publication activity with respect to cell culture
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`technology, I taught undergraduate and graduate courses including a class in
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`2
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`
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 3 of 26 PageID #: 13762
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`Experimental Cell Culture. I have also supervised many graduate student research
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`projects and dissertations, as well as undergraduate thesis projects, many of which
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`related specifically to cell culture technology.
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`4.
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`I have received numerous honors and awards for my work in the field,
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`including the Cell Culture Engineering Award in 2014, which is awarded by
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`Engineering Conference International to recognize an outstanding contributor to the
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`field of cell culture technology and engineering. I was also selected to give the Cell
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`Culture Engineering Award Lecture in 2016. I have been awarded the Ohio State
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`University College of Engineering Lumley Research Award on five separate
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`occasions for exceptional research activity and success. I am also a Fellow of the
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`American Association for the Advancement of Science.
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`5.
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`I am a named inventor on thirteen patents, many of which relate to cell
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`culture technology. I have published extensively over the course of my career,
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`including over 140 published or submitted articles and proceedings submissions, and
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`eighteen book chapters, which also include many on cell culture technology.
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`6.
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`Further details
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`regarding my education, employment history,
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`experience, and publications are contained in my curriculum vitae, attached as
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`Exhibit 1.
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`7.
`
`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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`3
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 4 of 26 PageID #: 13763
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`8.
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`I am being compensated for my time at my normal rate of $500 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 “following fermentation” in U.S. Patent No.
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`8,574,869 (the “’869 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 ’869 patent and excerpts from its prosecution
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`history, as well as the references and materials cited in the text of my declaration. In
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`addition, I have reviewed the Declarations of Dr. Hansjorg Hauser in Support of
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`Plaintiffs’ Opening Claim Construction Brief and exhibits, and the transcript of Dr.
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`Hauser’s January 23, 2019 and January 24, 2019 depositions, as well the portion of
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`Genentech Inc.’s Opening Claim Construction Briefs in C.A. No. 18-924-CFC and
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`C.A. No. 17–1407-CFC regarding the ’869 patent.
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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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`4
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 5 of 26 PageID #: 13764
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`the invention. I have been asked to assume that the relevant time of invention is July
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`9, 2007, which is the filing date of the earliest application listed on the first page of
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`the ’869 patent (provisional application No. 60/948,677).
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`13.
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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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`14.
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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 protein and/or antibody production.
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`IV. Legal Standards for Claim Construction
`15. 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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`16.
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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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`17.
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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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`5
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 6 of 26 PageID #: 13765
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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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`18.
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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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`19.
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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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`20.
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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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`21.
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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 not cited
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`in the patent or prosecution history, and dictionary definitions. I am informed that
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`extrinsic evidence can also be useful in understanding the scope of the claim terms,
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`but is generally considered less significant than intrinsic evidence.
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`6
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 7 of 26 PageID #: 13766
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`V. Background
`22. Proteins are biological molecules composed of amino acids. See
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`JA00000196(8:61-63). A protein functions, in part, through its structure – a protein
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`that acts by binding to another molecule does so because it has a particular three-
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`dimensional shape. See JA00000193(1:33-37). Protein structure classically
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`involves four hierarchical levels: primary structure, secondary structure, tertiary
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`structure, and quaternary structure. All structural levels contribute to a protein’s
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`overall shape. See Ex. 5 (Alberts 2002) at 140.
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`23. A protein’s primary structure is the most important contributor to its
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`three-dimensional shape. See Ex. 5 (Alberts 2002) at 129, 140. Primary structure
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`refers to a protein’s amino acid sequence, with individual amino acids referred to as
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`residues. See Ex. 5 (Alberts 2002) at 140. In proteins, amino acids chemically bind,
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`one to another, to form amino acid chains of variable length. See JA00000196(8:61-
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`63); see also Ex. 5 (Alberts 2002) at 129, 148. There are twenty amino acids, each
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`with distinct chemical properties that can influence the other hierarchical levels of
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`structure. See Ex. 5 (Alberts 2002) at 129.
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`24. Secondary structure refers to distinct, local substructures that exist
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`throughout a protein’s three-dimensional shape. The form of a substructure depends
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`on the amino acid content (i.e., the primary structure) of a particular portion of an
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`amino acid chain. For example, some amino acids are more stable when they interact
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`with water whereas other amino acids benefit from being shielded from water.
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`Amino acid chains containing both of these types of amino acids may form local
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`substructures, such as helical or sheet-like substructures, that optimize the amino
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`acids’ interactions with water. Amino acid chains often comprise a combination of
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`both local substructures and relatively unstructured regions. See Ex. 5 (Alberts
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`2002) at 140, 158.
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`25. Tertiary structure refers to the three-dimensional shape of a protein.
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`The local substructures and other unstructured regions of an amino acid chain
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`interact with each other to form distinct three-dimensional conformations. See Ex.
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`5 (Alberts 2002) at 140. Again, the amino acid content of the protein dictates how
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`it will fold – for example, positively-charged amino acids may interact with
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`negatively-charged amino acids, thus bringing two portions of the amino acid chain
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`into close proximity. See Ex. 5 (Alberts 2002) at 158. The tertiary structure is the
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`highest-order structure for proteins with only a single amino acid chain. See Ex. 5
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`(Alberts 2002) at 140.
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`26. For proteins composed of multiple amino acid chains, the highest-order
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`structural level is the quaternary structure, which refers to how multiple amino acid
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`chains interact with each other. See Ex. 5 (Alberts 2002) at 140. The same principles
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`apply here as for secondary and tertiary structures: water-repelling amino acids may
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`be shielded from water in the interior of the protein whereas amino acids that
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 9 of 26 PageID #: 13768
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`favorably interact with water may be moved to the exterior of the three-dimensional
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`structure, and positively-charged and negatively-charged amino acids may interact,
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`thus strongly linking two or more amino acid chains together. See Ex. 5 (Alberts
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`2002) at 140, 158.
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`27. One additional aspect of protein structure is disulfide bonds. Some
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`proteins contain the amino acid cysteine interspersed throughout their primary
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`structure. Cysteine residues contain chemical groups known as sulfhydryl groups,
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`which are comprised of a sulfur atom and a hydrogen atom and often are referred to
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`by the following designation: “—SH.” See Ex. 5 (Alberts 2002) at 133, 151-152. In
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`what are known as “reducing” environments, sulfhydryl groups can maintain their
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`sulfur and hydrogen components. In “oxidizing” environments, sulfhydryl groups
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`can lose their hydrogen atom, and the remaining sulfur atoms on two different
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`cysteine residues can bind together, thereby linking the cysteine residues and
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`forming a disulfide bond, often denoted as “—S—S—.” See Ex. 5 (Alberts 2002)
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`at 133, 151-152. Disulfide bonds have been “reduced” if they have been broken due
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`to exposure to a reducing environment. See JA00000196(8:47-60). Notably,
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`“[d]isulfide bonds do not change the conformation of a protein but instead act as
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`atomic staples to reinforce its most favored conformation.” Ex. 5 (Alberts 2002) at
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`151-152.
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 10 of 26 PageID #:
`13769
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`28. Antibodies are a type of protein that specifically binds to other
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`molecules. JA00000197(10:4-6). They are composed of four amino acid chains,
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`and thus four primary structures: two “heavy chains” and two “light chains,”
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`described as such due to differences in their relative lengths. See Ex. 5 (Alberts
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`2002) at 161. Antibodies are held together by all four levels of hierarchical structure,
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`with the primary structure linking amino acids together in the heavy and light chains,
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`secondary structure creating localized substructures that further stabilize the chains,
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`tertiary structure establishing the three-dimensional structure of each chain, and the
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`quaternary structure linking the chains together to form the antibody’s three-
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`dimensional shape. See Ex. 5 (Alberts 2002) at 140, 142, 161.
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`29. Disulfide bonds in antibodies vary in their susceptibility to reducing
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`environments. See JA00000204(23:36-42). These outcomes rely both on the overall
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`structure of the antibody, including all levels of its hierarchical structure, as well as
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`the chemical strength of the reducing environment. See Ex. 5 (Alberts 2002) at 140,
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`151-152.
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`30. Higher organisms produce antibodies as a component of their immune
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`system. See, e.g., Ex. 5 (Alberts 2002) at 1364. Because antibodies can bind
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`specifically to other molecules, they have both therapeutic and non-therapeutic uses
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`(e.g., as a research reagent). See JA00000197(9:21-25, 9:44-51).
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`31. Antibody manufacturers produce an antibody-of-interest by cultivating
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`cells that have been genetically programmed to produce the antibody in a process
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`known as cell culture. See JA00000193(1:52-54). Commercial cell culture
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`operations are massive, with antibody manufacturers utilizing large tanks known as
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`bioreactors to cultivate culture volumes on the order of thousands of liters. See
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`JA00000197(9:9-20).
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` When producing an antibody-of-interest, commercial
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`manufacturers include in the bioreactor, among other things, the cells programmed
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`to generate the antibody, as well as culture medium. See JA00000205(25:43-49).
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`32. Antibody manufacturers have options
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`to choose from when
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`determining what cell type to use as antibody-producing cells, including bacterial
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`cells and mammalian cells. See, e.g., JA00000193(1:28-33), JA00000195(5:4-9).
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`Antibody-producing bacterial cells generally do not secrete the antibodies into the
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`surrounding culture medium. Instead, the bacteria retain the antibodies inside their
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`cells. See JA00000206(28:38-51). To access the antibodies, antibody manufacturers
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`typically need to disrupt the integrity of the cells in some way such that they break
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`open and release their contents into the culture medium before harvesting the
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`antibody. See JA00000205(26:43-53), JA00000206(28:38-51).
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`33. To access antibodies retained inside cells, the integrity of the cells must
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`be disrupted in a way such that cells break open and release the antibodies into the
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`culture medium. This step of breaking the cells open is unnecessary when antibodies
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`are secreted. See JA00000205(26:41-56). This step involving breaking open the
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`cells to release the antibody is commonly referred to as cell lysis and is required
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`prior
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`to harvesting
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`the
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`antibody.
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` See
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`JA00000205(26:43-53)
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`and
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`JA00000206(28:38-51).
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`34. Culture medium is a nutrient-rich liquid in which antibody-producing
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`cells are suspended during the culturing process. Culture medium provides, among
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`other things, the nutrients that cells need to survive and produce the antibody-of-
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`interest. See Ex. 7 (Butler 2005) at 286. Antibody manufacturers understand the
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`needs of a particular antibody-producing cell prior to using that cell for producing
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`commercial amounts of the antibody-of-interest. See JA00000205(25:36-39, 26:12-
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`24), JA00000216(48:39-41); see also Ex. 8 (Wurm 2004) at 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”).
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`35. Oxygen can be consumed during the manufacturing process and as a
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`result, antibody manufacturers supplement the culture medium by “sparging,” or
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`bubbling, oxygen-containing gas directly
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`into
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`the culture medium.
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` See
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`JA00000204(23:22-26), JA00000218(51:18-21).
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` A “sparger”
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`is a device
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`incorporated in a bioreactor that is submerged in culture medium and serves to
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 13 of 26 PageID #:
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`bubble a desired gas into the culture medium. See, e.g., Ex. 9 (Bailey 1986) at 475.
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`When a sparger introduces, for example, pure oxygen into a bioreactor’s culture
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`medium, a portion of that oxygen dissolves into the culture medium. See, e.g., Ex.
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`9 (Bailey 1986) at 459-60. The culture medium thus has a dissolved oxygen (“DO”)
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`content, and if that value drops below a certain level (again, determined through
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`process development), the productivity of the culture could be impacted due to
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`inhibitory conditions and potentially increased cell death. See, e.g., Ex. 9 (Bailey
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`1986) at 639.
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`36. However, a bioreactor can be outfitted with means for monitoring and
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`controlling its internal environment, including probes for measuring the dissolved
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`oxygen (“DO”) content of the culture medium contained within. Therefore, if the
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`culture medium’s DO content dips below a predetermined threshold, the DO probe
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`will send a signal to a monitoring system (usually computer software) that will then
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`cause oxygen, or an oxygen-containing gaseous mixture, to be supplemented into
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`the culture medium via the sparger. See JA00000216(48:37-39); see also Ex. 9
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`(Bailey 1986) at 661-64 and 700-01.
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`37.
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`It is worth noting that antibody manufacturers introduce numerous
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`gases into bioreactor-contained culture medium. For example, while antibody
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`manufacturers may introduce pure oxygen into the culture medium to boost the
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`culture medium’s DO content, they also may introduce carbon dioxide to modify the
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`13
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`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 14 of 26 PageID #:
`13773
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`culture medium’s pH in response to a signal from a pH probe.
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` See
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`JA00000218(51:15-18). Antibody manufacturers may also sparge air into
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`bioreactor-contained culture medium.
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` See JA00000204-205(23:22-26-42),
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`JA00000218(51:10-26).
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`38. The DO content of a culture medium may also determine whether the
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`culture medium
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`is an “oxidizing” or a “reducing” environment.
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` See
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`JA00000204(23:22-42). During process development, antibody manufacturers
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`determine not only what DO level the cultured cells need to survive, but also the DO
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`level necessary to prevent commercially significant amounts of the secreted antibody
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`from being exposed to a reducing environment. As discussed above, this latter DO
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`level will vary from antibody to antibody, but through process development,
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`antibody manufacturers understand prior to making commercial-scale amounts of
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`antibody what DO level is required to achieve these goals. See JA00000204(23:36-
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`42).
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`39. The ’869 patent presents a typical antibody production process using
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`cells genetically engineered to produce an antibody-of-interest. The patent provides
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`that “[o]nce the cells have undergone several rounds of replication, they are
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`transferred to a larger container where they are prepared to undergo fermentation.”
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`JA00000193(1:54-57). Therefore, the ’869 patent indicates that “fermentation”
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`14
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`13774
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`begins when cells are transferred to a larger container, after several rounds of
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`replication. However, the ’869 patent does not state when “fermentation” ends.
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`40. Nonetheless, the ’869 patent is explicit that “[f]ollowing fermentation
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`proteins are purified.” JA00000205(26:41). The patent recognizes that different
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`purification protocols are necessary depending on whether the antibody-producing
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`cells retain the produced antibody or secrete it into the culture medium. See
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`JA00000205(26:43-56).
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`41. The ’869 patent explains that, for cells “engineered to secrete the
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`polypeptide into the cell culture media . . . the first step in the purification process is
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`to separate the cells from the media.” JA00000193(1:67-2:3). The very next
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`sentence invokes the term “harvest,” and discloses that “harvesting includes
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`centrifugation and filtration to produce a Harvested Cell Culture Fluid (HCCF).”
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`JA00000193(2:3-4). Later, the patent describes the HCCF, explaining that “[t]he
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`HCCF lacks intact host cells but typically contains host cell proteins and other
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`contaminants, including DNA, which are removed in subsequent purification steps.”
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`JA00000203(22:5-8). Thus, “harvest” produces an HCCF which “lacks intact host
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`cells.” For cells engineered to secrete antibody, because “the first step in the
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`purification process is to separate the cells from the media,” I understand “harvest”
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`to be the first step in the purification process, with “centrifugation” and “filtration”
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`being components of this step.
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`13775
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`42. For cells that retain, rather than secrete, the antibody-of-interest, the
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`’869 patent discloses that another step precedes the “harvest” components of
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`“centrifugation” and “filtration.” The patent states: “For [cells that retain the
`
`antibody-of-interest], the first step of a purification process involves lysis of the cell,
`
`which can be done by a variety of methods, including mechanical shear, osmotic
`
`shock, or enzymatic treatments.” JA00000205(26:45-49). Lysis generally refers to
`
`breaking open the cells such that they release their contents, including the antibody-
`
`of-interest, into the culture medium, producing unwanted cellular debris as a result.
`
`After lysis, this debris is “removed by differential centrifugation or by filtration.”
`
`JA00000205(26:52-53).
`
`43. To summarize the teaching of the ’869 patent, for manufacturers that
`
`use antibody-producing cells that secrete the antibody-of-interest, the first step
`
`following fermentation is “harvest,” a purification step that includes “centrifugation”
`
`and/or “filtration.” For antibody manufacturers that use antibody-producing cells
`
`that retain the antibody-of-interest, the first step following fermentation is “lysis”
`
`(necessary to release the antibody into the culture medium), which is then followed
`
`by “harvest” – again, involving “centrifugation” and/or “filtration.” In both
`
`scenarios, “harvest” produces a HCCF, which “is then subjected to several additional
`
`purification steps that remove any cellular debris, unwanted proteins, salts, minerals
`
`or other undesirable elements.” JA00000193(2:5-7).
`
`16
`
`
`
`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 17 of 26 PageID #:
`13776
`
`VI.
`
` “Following Fermentation”
`44. The claim term “following fermentation” occurs in claim 1 of the ’869
`
`patent. Claim 1 reads as follows, with the claim language at issue underlined:
`
`1. A method for the prevention of the reduction of a disulfide bond in
`an antibody expressed in a recombinant host cell, comprising,
`following fermentation, sparging the pre-harvest or harvested culture
`fluid of said recombinant host cell with air, wherein the amount of
`dissolved oxygen (dO2) in the pre-harvest or harvested culture fluid is
`at least 10%.
`45.
`I understand that Amgen has proposed that, if “following fermentation”
`
`is construed by the Court, it means “steps starting with the initiation of purification.”
`
`46.
`
`I understand
`
`that Genentech has proposed
`
`that “following
`
`fermentation” means “after the end of cell growth and antibody production phases
`
`(which is indicated by a change in the cell culture environment that substantially
`
`ends growth and antibody production).”
`
`47.
`
`I also understand
`
`that Amgen has proposed
`
`that “following
`
`fermentation” is indefinite, which I am informed means that the scope of the claim
`
`would not be reasonably certain to a POSA, such that it would not be reasonably
`
`certain to a POSA when fermentation ends and steps following fermentation begin.
`
`I agree that “following fermentation” is indefinite. However, if a POSA were to seek
`
`to interpret this term despite its indefiniteness, a POSA would find Amgen’s
`
`construction to best reflect the limited guidance given in the patent.
`
`A. Ordinary Meaning
`
`17
`
`
`
`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 18 of 26 PageID #:
`13777
`
`48.
`
`In my experience, the ordinary meaning of “fermentation” relates to
`
`activities such as making beer or wine, in which there is a chemical breakdown of a
`
`substance, e.g. sugar, usually under anaerobic conditions by bacteria or yeast. See
`
`Ex. 10 (The New Oxford American Dictionary 2001) at 623; see also Ex. 11
`
`(McGraw-Hill Dictionary of Scientific and Technical Terms 2003) at 786.
`
`“Fermentation” is not typically used to refer to culturing mammalian cells. As a
`
`result, a POSA would find the use of “fermentation” in the patent to refer to culturing
`
`of mammalian host cells to be misplaced and inconsistent with the word’s ordinary
`
`meaning.
`
`B.
`Specification
`49. The specification of the ’869 patent is unclear as to when
`
`“fermentation” ends and “following fermentation” begins. The specification states
`
`that “[f]ollowing fermentation proteins are purified.” JA00000205(26:41). If a
`
`POSA had to assign some meaning to this term, Amgen’s construction, i.e., that
`
`“steps starting with the initiation of purification” come after fermentation, is
`
`consistent with this statement.
`
`50.
`
`I understand that Genentech contends that Amgen’s construction
`
`conflicts with the claim language and specification. I disagree with Genentech for
`
`the following reasons.
`
`18
`
`
`
`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 19 of 26 PageID #:
`13778
`
`51. First, I understand that Genentech contends that Amgen’s construction
`
`does not account for the language in the claim regarding “sparging the pre-
`
`harvest . . . culture fluid . . . with air.” JA00000246(claim 1). As I understand it,
`
`Genentech’s contention is premised on the view that harvest always precedes the
`
`initiation of purification, but that is not the case. In fact, the ’869 patent explicitly
`
`teaches that purification “depend[s] on the site of expression of the protein.”
`
`JA00000205(26:42-43). The ’869 patent teaches that when the protein is “made
`
`intracellularly . . . the first step of a purification process involves lysis of the
`
`cell . . . .” Id.(26:45-47). Cell fragments from lysis “are generally removed by
`
`differential centrifugation or by filtration.”
`
` JA00000205(26:52-53).
`
` The
`
`centrifugation and filtration steps the patent is referring to are harvesting.
`
`JA00000193(2:3-4) (“Typically, harvesting includes centrifugation and filtration”),
`
`JA00000203(22:3-5) (“harvested cell culture fluid (HCCF), which is obtained after
`
`harvesting by centrifugation,
`
`filtration, or similar separation methods”),
`
`JA00000216(48:54-67) (lysis product is centrifuged to produce HCCF). After
`
`harvesting,
`
`there are usually “several additional purification steps . . . .”
`
`JA00000193(2:5-6); see also JA00000205-206(26:57-27:25) (purification steps
`
`after harvest).
`
`19
`
`
`
`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 20 of 26 PageID #:
`13779
`
`52.
`
`I understand that Dr. Hauser testified that Claim 1 of the ’869 patent
`
`includes both mammalian recombinant host cells and non-mammalian recombinant
`
`host cells, such as bacterial cells:
`
`Q. And Claim 1 talks about a recombinant host cell.· Do you see that?
`A. I see that.
`Q. Now, the reference to that recombinant host cell, that includes
`both mammalian cells as well as non-mammalian cells, correct?
`A. Correct.
`Q. And, in fact, the reference to a recombinant host cell includes
`bacteria, right?
`A. Correct.
`
`Ex. 12 (Hauser Tr.) 123:8-17.
`
`53.
`
`I agree with Dr. Hauser that Claim 1 of the ’869 patent includes both
`
`mammalian recombinant host cells and non-mammalian recombinant host cells,
`
`such as bacterial cells.
`
`54.
`
`I understand that Dr. Hauser testified that he would not expect proteins
`
`expressed in recombinant bacterial cells to be secreted, and instead expects the
`
`protein to be expressed intracellularly:
`
`Q. And if the protein that is recombinantly expressed in the bacteria
`cell is an antibody, you would not expect that antibody to be secreted
`into the culture medium, correct?
`A. Yes, all correct.
`Q. And so if we took E. coli as an example, you would agree that for
`E. coli the expression of the antibody is intracellular, correct?
`
`20
`
`
`
`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 21 of 26 PageID #:
`13780
`
`A. I'm not aware of any exceptions on that.
`
`Ex. 15 (Hauser Tr. 2) 76:14-22.
`
`55.
`
`I agree with Dr. Hauser and would also generally not expect proteins
`
`expressed in recombinant bacterial cells to be secreted, and instead expect the
`
`protein to be expressed intracellularly.
`
`56.
`
`I understand that Dr. Hauser testified that when he was preparing his
`
`declaration and opinions he did not consider the non-secreted or intracellular
`
`embodiment included within the scope of Claim 1 of the ’869 patent:
`
`Q. And so it's true that in construing the term "following
`fermentation," you didn't consider how your construction might be
`used in a situation that addresses a non-secreted protein of interest,
`correct?
`…
`A. It was not the task to do so.
`Q. And when you say it wasn't the task, what's your understanding of
`the task that you were provided?· Was it to only construe “following
`fermentation” as it related to secreted proteins?
`A. This is how I understood the task.
`
`Ex. 12 (Hauser Tr.) 125:8-21. I believe that Dr. Hauser’s misunderstanding of the
`
`construction of the term “following fermentation” is based in part on his oversight
`
`of the non-secreted or intracellular embodiment.
`
`57. To summarize, when protein is made intracellularly and the cell is
`
`lysed, after fermentation, the patent identifies lysis as “the first step of the
`
`21
`
`
`
`Case 1:18-cv-01363-CFC Document 96 Filed 04/10/19 Page 22 of 26 PageID #:
`13781
`
`purification process.” Harvest follows lysis/first step of purification. In the
`
`language of the claim, the “pre-harvest” lysis step can also include air sparging. A
`
`POSA would understand that purification starting with lysis, as described in the
`
`patent, is consistent with Amgen’s construction.
`
`58.
`
`I understand that Dr. Hauser testified that it is his opinion that for non-
`
`secreted proteins (i.e., proteins made intracellularly), lysis occurs before harvest
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