Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 1 of 20 PageID #: 34874
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Plaintiffs,
`
`Civ. No. 17-1407- CFC, Consol.
`
`v.
`
`AMGEN INC.,
`
`Defendant.
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Plaintiffs,
`
`V.
`
`AMGEN INC.,
`
`Defendant.
`
`Civ. No. 18-924-CFC
`
`Michael P. Kelly, Daniel M. Silver, Alexandra M. Joyce, MCCARTER
`&ENGLISH, LLP, Wilmington, Delaware; Daralyn J. Durie, Adam R. Brausa, Eric
`C. Wiener, Eneda Hoxha, DURIE TANGRI LLP, San Francisco, California.
`Counsel for Plaintiffs Genentech, Inc. and City of Hope. (C.A. No. 17-1407-CFC
`and C.A. No. 18-924-CFC).
`
`Paul B. Gaffney, David I. Berl, Thomas S. Fletcher, Kyle E. Thomason, Teagan J.
`Gregory, Charles L. McCloud, Kathryn S. Kayali, WILLIAMS & CONNOLLY
`LLP, Washington, D.C. Counsel for PlaintiffGenentech, Inc. (C.A. No. 17-1407-
`CFC).
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Plaintiffs,
`
`Civ. No. 17-1407- CFC, Consol.
`
`v.
`
`AMGEN INC.,
`
`Defendant.
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Plaintiffs,
`
`V.
`
`AMGEN INC.,
`
`Defendant.
`
`Civ. No. 18-924-CFC
`
`Michael P. Kelly, Daniel M. Silver, Alexandra M. Joyce, MCCARTER
`&ENGLISH, LLP, Wilmington, Delaware; Daralyn J. Durie, Adam R. Brausa, Eric
`C. Wiener, Eneda Hoxha, DURIE TANGRI LLP, San Francisco, California.
`Counsel for Plaintiffs Genentech, Inc. and City of Hope. (C.A. No. 17-1407-CFC
`and C.A. No. 18-924-CFC).
`
`Paul B. Gaffney, David I. Berl, Thomas S. Fletcher, Kyle E. Thomason, Teagan J.
`Gregory, Charles L. McCloud, Kathryn S. Kayali, WILLIAMS & CONNOLLY
`LLP, Washington, D.C. Counsel for PlaintiffGenentech, Inc. (C.A. No. 17-1407-
`CFC).
`
`
`
`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 2 of 20 PageID #: 34875
`
`William F. Lee, Lisa J. Pirozzolo, Emily R. Whelan, Kevin S. Prussia, Andrew J.
`Danford, WILMER CUTLER PICKERING HALE AND DORR LLP, Boston,
`Massachusetts; Robert J. Gunther Jr., WILMER CUTLER PICKERING HALE
`AND DORR LLP, New York, New York; Nora Passamaneck, WILMER CUTLER
`PICKERING HALE AND DORR LLP, Denver, Colorado. Counsel for Plaintiff
`Genentech, Inc. (C.A. No. 18-924-CFC).
`
`Melanie K. Sharp, James L. Higgins, YOUNG CONAWAY STARGATT &
`TAYLOR, LLP, Wilmington, Delaware. Counsel for Defendant Amgen Inc. (C.A.
`No. 17-1407-CFC).
`
`Neal C. Belgam, Eve H. Ormerod, Jennifer M. Rutter, SMITH KATZENSTEIN &
`JENKINS LLP, Wilmington, Delaware. Counsel for Defendant Amgen Inc. (C.A.
`No. 18-924-CFC).
`
`MEMORANDUM OPINION
`
`March 9, 2020
`Wilmington, Delaware
`
`
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 3 of 20 PageID #: 34876
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`CONNOLLY, UNITED STATEolSTRICT JUDGE
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`Genentech, Inc. and City of Hope (collectively, Genentech) brought these
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`patent infringement actions against Amgen, Inc. pursuant to the Biologics Price
`
`Competition and Innovation Act (BPCIA), 42 U.S.C. § 262. Pending before me is
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`the matter of the construction of the disputed claim term "following fermentation"
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`in United States Patent Number 8,574,869 (the Kao or #869 patent). The Kao
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`patent teaches methods and means of preventing disulfide bond reduction during
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`the manufacturing of therapeutic antibodies. #869 patent at 1: 17-22.
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`I initially heard argument on the meaning of"following fermentation" and
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`other disputed claim terms at two Markman hearings convened in April 2019.
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`C.A. No. 17-1407, D.I. 340; C.A. No. 18-924, D.I. 182. 1 In memorandum
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`opinions issued in June 2019, I explained that I was unable to construe "following
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`fermentation" based solely on the intrinsic evidence, and I ordered a hearing "to
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`determine if' following fermentation' can be construed by resort to extrinsic
`
`evidence or is invalid for indefiniteness." D.I. 256 at 19.2
`
`1 See Markman v. Westview Instruments, Inc., 517 U.S. 370,372 (1996) ("[T]he
`construction of a patent, including terms of art within its claim, is exclusively
`within the province of the court").
`
`2 Identical documents were usually filed in both cases. In addition, the
`memorandum opinions' discussions of "following fermentation" are identical.
`Accordingly, all citations are to the docket for C.A. No. 18-924 unless otherwise
`noted.
`
`1
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`
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`The parties thereafter presented me with extrinsic evidence in the form of
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`affidavits, treatises, articles, reports, and competing expert testimony at an
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`evidentiary hearing on October 16, 2019. D.I. 372; D.I. 373. Based on the
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`extrinsic evidence and my reconsideration of the intrinsic evidence in light of that
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`extrinsic evidence, I have concluded that a person of ordinary skill in the art
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`(POSIT A) would understand "following fermentation" to mean "after the earlier of
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`harvesting or purification has begun," and I will construe the term accordingly.
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`I set forth the legal standards that govern claim construction in my earlier
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`memorandum opinions. See D.I. 256 at 3-5. Rather than repeat those standards
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`here, I incorporate by reference the earlier memorandum opinions. I write
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`primarily for the parties and, to a large degree, presume familiarity with the
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`underlying technology.
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`Claim 1 of the Kao patent teaches
`
`I.
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`[a] method for the prevention of the reduction of a
`disulfide bond in an antibody expressed in a recombinant
`host cell,
`
`compnsmg, following fermentation, sparging the pre(cid:173)
`harvest or harvested culture fluid of said recombinant host
`cell with air,
`
`wherein the amount of dissolved oxygen ( dO2) in the pre(cid:173)
`harvest or harvested culture fluid is at least I 0%.
`
`2
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`
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`#869 patent at 107:44-49 (reformatted for clarity and emphasis added). As I
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`explained in my earlier memorandum opinions, the construction of "following
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`fermentation" involves two questions. First, what is "fermentation?" And second,
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`when does "fermentation" end? D.I. 256 at 15.
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`Unfortunately, as I also discussed in my earlier memorandum opinions, the
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`Kao patent neither defines fermentation nor allows for a cogent inference of
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`fermentation's meaning, let alone when it ends. The patent is plagued by
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`typographical errors and sloppy language; it suggests at times that fermentation is
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`synonymous with "production" and "manufacturing" and at other times that
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`fermentation is distinct from these concepts. Id. at 16, 19 n.6. To add to the
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`confusion, the patent does not consistently use or assign meaning to "production"
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`and "manufacturing." Id. at 19 n.6. As Genentech's counsel conceded (to his
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`credit) at oral argument, "certain words like manufacturing and production may not
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`be used quite as precisely as one would like in the Kao patent." C.A. No. 17-1407,
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`D.I. 340 at 25 :20-22. Resort to extrinsic evidence is therefore necessary. See
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`Digital Biometrics, Inc. v. Identix, Inc., 149 F.3d 1335, 1344 (Fed. Cir. 1998) ("[I]f
`
`after consideration of the intrinsic evidence there remains doubt as to the exact
`
`meaning of the claim terms, consideration of extrinsic evidence may be necessary
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`to determine the proper construction.").
`
`3
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`
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 6 of 20 PageID #: 34879
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`IL
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`Genentech argues that "fermentation" refers to "the growing of the cells and
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`the producing of the protein [i.e., antibody]" in the manufacturing process. D.I.
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`528 at 13:20-22; see also id. at 66: 13-22.3 Amgen insists that I should reject this
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`definition, D.I. 373 at 4, but it has used "fermentation" in the context of antibody
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`manufacturing to mean exactly what Genentech says the term means. Specifically,
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`in its 2011 Annual Report, Amgen stated that the "[b ]ulk manufacturing" of its
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`biological products "includes fermentation and/or cell culture, processes by which
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`our proteins are produced." D.I. 376-2 at Appx. 449 (emphasis added). In
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`addition, Amgen's expert, Dr. Glacken, admitted during cross-examination at the
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`evidentiary hearing that "[w]ithin the context of the Kao patent, the person of
`
`ordinary skill would understand the term fermentation to refer to cell culture
`
`processes for making antibodies." D.I. 528 at 145:14-19; see also id. at 152:7-9
`
`(Glacken) (admitting that "using fermentation synonymous[ly] with mammalian
`
`cell culture is becoming more common").
`
`Genentech's proposed definition of fermentation is well supported by other
`
`extrinsic evidence. For instance, Kemp states that therapeutic antibodies "are
`
`produced ... via mammalian cell fermentation." D.I. 376 at Appx. 248. And
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`3 The parties used "protein" and "antibody" interchangeably, and I will therefore do
`the same.
`
`4
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`
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`Geigert states that "fermentation" is used interchangeably with "cell culture,"
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`which the parties equate with cell growth and antibody production. See C.A. No.
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`17-1407, D.I. 271-2, Ex. 9 at 119 (Geigert) ("In this CMC book, the terms
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`'fermentor' and 'bioreactor' will be used interchangeably; as well as the terms
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`'fermentation' and 'cell culturing."'); D.I. 374 ,I 1 (Hauser) (stating that "cell
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`culture technology is "the science of isolating cells from their natural environment
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`and growing them in a controlled, artificial environment" and that "cell culture
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`processes [are] used to manufacture biotherapeutics, such as therapeutic
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`antibodies"); D.I. 375 at ,I 56 (Glacken) (noting that for some skilled artisans "[t]he
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`term 'fermentation' refers to a process in which organisms growing in a liquid or
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`solid medium produce an industrial product." (quoting U.S. Patent Appl.
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`2007/0141687Al)).
`
`Support for Genentech's proposed definition of fermentation can also be
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`found in the written description of the Kao patent. See #869 patent at 29:4-8
`
`( discussing "fermentation, recovery and purification" in the sentence that
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`immediately precedes discussion of"production, recovery and purification,"
`
`thereby suggesting that fermentation and production are synonymous); id. at
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`26:29-41 (using "following fermentation" immediately after a description of the
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`"production phase," thereby suggesting that fermentation and production are
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`5
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 8 of 20 PageID #: 34881
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`synonymous). The ref ore, I will adopt Genentech' s definition of "fermentation"(cid:173)
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`i.e., the growing of the cells and producing of the protein.
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`III.
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`Neither side was able to point me to a treatise, dictionary, or other reference
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`that expressly defines when fermentation ends in the antibody manufacturing
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`process. Both parties, however, effectively conceded that "harvesting" marks the
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`end of fermentation for proteins secreted into the cell culture fluid. I will therefore
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`construe "following fermentation" for those antibodies to mean "after harvesting
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`has begun."
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`Amgen's expert, Dr. Glacken, testified that "following fermentation is just
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`harvest, really. If [the term] comes up at all, that's the context it comes up in."
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`D.I. 528 at 165:6-9.
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`For its part, Genentech describes the end of fermentation as being
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`coterminous with the end of antibody production. See id. at 13:20-23
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`(Genentech's counsel explaining that "[t]ermentation includes both the growing of
`
`the cells and the producing of the protein, and so in context, the end of production
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`and the end of fermentation are coterminous, at the same time."). And Genentech
`
`describes the manufacture of therapeutic antibodies secreted from cells as follows:
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`Therapeutic antibodies ... are manufactured by growing
`or "culturing" genetically engineered cells inside large
`tanks called "bioreactors" ( or "production fermenters" as
`referred to by [ a defendant in a related civil case]). The
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`6
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 9 of 20 PageID #: 34882
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`cells produce the antibody and then secrete it into the
`surrounding culture fluid. Once the antibodies have been
`produced in sufficient quantity,
`the culture fluid
`containing the antibodies is "harvested" and then the
`antibodies are purified from the fluid.
`
`D.I. 121 at 62 (citations omitted) (emphasis added). Thus, Genentech concedes
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`that in the manufacture of antibodies secreted by the cells in the culture fluid,
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`harvesting immediately follo':VS fermentation.
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`That harvesting immediately follows-and thus can be said to mark the end
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`of-fermentation, is supported by the extrinsic evidence. Wurm, for example,
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`states that "the timing of the termination (that is, harvest) of a culture is driven
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`mainly by plant capacity and productivity kinetics." D.I. 375-4, Ex. 5 at 1397.
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`And the inventors of the Kao patent, along with other Genentech employees,
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`acknowledged in a 2009 article that " [ a ]t the end of the production phase, the
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`feedstock is usually harvested by disc stacked centrifugation followed by depth
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`filtration or by tangential flow microfiltration." D.I. 376 at Appx. 130.
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`Construing "following fermentation" for secreted proteins to mean "after
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`harvesting has begun" also finds support in the intrinsic evidence. The patent's
`
`written description, for example, explains that "[ w ]hen the cells grow to sufficient
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`numbers, they are transferred to large-scale production tanks to begin the
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`production phase, and grown for a longer period of time. At this point in the
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`process, the recombinant protein can be harvested." #869 patent at 1 :64-67
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`7
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`( emphasis added). Figure 23 of the patent similarly depicts "harvest" as the step
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`that immediately follows cell growth and antibody production:
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`Typical Batch or Fed-Batch Culture Process
`
`Seed Train
`Multiple Passages in
`Selective Medium
`
`lnoculum Train
`Multiple Passages in
`Non-Selective Medium
`
`Production
`Non-Selective
`Production Medium
`
`Harvest -
`
`d02, pH, Temperature
`Parameter shifts & timing
`Osmolality
`Batch feed addition
`Seeding density
`Culture duration
`
`Temperature
`Seeding density
`Culture duration
`
`d02, pH, Temperature
`Seeding density
`Culture duration
`
`FIG. 23
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`The parties agree that for proteins that are secreted by the cells into the
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`culture fluid, "harvesting" is, to use Genentech' s words, "the process of separating
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`the culture fluid (which contains antibody) from cells or cellular debris." D.I. 449
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`at 1 ( citations omitted); see also C.A. No. 17-1407, D.I. 325 at 61 (Amgen
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`acknowledging that "[ w ]hen 'the cells are engineered to secrete the [antibody] into
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`the cell culture media, ... the first step in the purification process is to separate the
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`cells from the media,' which is harvesting") (quoting #869 patent at 1 :67-2:4)
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`(second alteration and ellipses in original)). And although the extrinsic evidence
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`showed that there is no universal first step for every harvesting process, Genentech
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`8
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 11 of 20 PageID #: 34884
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`agrees that a POSIT A "readily could determine the first step of harvest in that
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`process." D.I. 449 at 2. Accordingly, it makes sense to define the end of
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`fermentation for proteins secreted into the cell culture fluid in terms of the
`
`beginning of harvesting.
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`Genentech argues that my construction is erroneous for two reasons. First, it
`
`states that
`
`'following
`the meaning of
`than address
`[r]ather
`fermentation,' [my] construction elides it, substituting a
`distinct concept, the beginning of harvest. When
`something ends and when something else begins are not
`necessarily the same thing. History "following World War
`II" is defined by the end of the conflict known by that
`name ( 1945 ), not the beginning of, for example, the Cold
`War that followed (1947).
`
`D.I. 514 at 1. It is of course true that "when something ends and when something
`
`begins are not necessarily the same thing." But sometimes they are the same thing,
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`and we often meaningfully define the end of something with the beginning of
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`something else. A marriage ends when a spouse dies or obtains a divorce. A
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`pregnancy ends when a birth, miscarriage, or abortion occurs. And, most relevant
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`here, crops end their growth when they are harvested. Gen en tech' s World War II
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`analogy misses the point. The end of World War II is defined by the beginning of
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`another event-the surrender of Japan in August 1945. It is (clearly) not defined
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`by the beginning of the Cold War two years after that surrender.
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`9
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`Second, Genentech argues that my construction "impermissibly nullifies one
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`of the two embodiments the claims explicitly recite-the method of sparging a
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`'pre-harvest culture fluid' following fermentation." D.I. 514 at 3. But the premise
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`of this argument-that "sparging of 'pre-harvest cell culture fluid' obviously
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`cannot occur 'after harvesting has begun," id.-is neither obvious nor correct.
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`Sparging of pre-harvest culture fluid can occur after harvesting of secreted
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`antibodies has begun. If, for example, a harvesting were initiated by moving into
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`another vessel culture fluid containing cells that had secreted their proteins directly
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`into the fluid and then sparging were immediately begun in the new vessel, a pre(cid:173)
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`harvest fluid would be sparged after harvesting had begun.
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`IV.
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`There remains the issue of construing "following fermentation" when the
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`antibodies are not made by secretion into the cell culture but are instead produced
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`"intracellularly." See #869 patent at 26:43-45 (distinguishing antibodies "secreted
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`directly from the cell into the surrounding growth media" from antibodies "made
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`intracellularly"); see also C.A. No. 17-1407, D.I. 271-2, Ex. 9 at 119 (same).
`
`The written description of the Kao patent states that "[t]ollowing
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`fermentation proteins are purified," and it states further that when proteins are
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`"made intracellularly ... the first step of a purification process involves lysis of
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`10
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 13 of 20 PageID #: 34886
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`cells." #869 patent at 26:41-47.4 But the specification does not state expressly
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`whether purification immediately follows fermentation.
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`Certain language in the written description could be read to suggest that
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`purification does not immediately follow fermentation. The patent, for example,
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`speaks of "the fermentation, recovery and purification methods described herein."
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`#869 patent at 29:4-5; see also id. at 25:40-41 (describing "protocol for the
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`production, recovery and purification of recombinant antibodies"); id. at 28:38-39
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`(referring to "[m]ethods for the production, recovery and purification of
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`recombinant proteins"). Genentech cites this clause as evidence that the "antibody
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`manufacturing process involves three steps," D.I. 325 at 65, and it argues that
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`purification is the third step and is temporally separated from the first step
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`(fermentation) by the second step (recovery, which the parties agree is the same
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`thing as harvest), id. at 65-67; C.A. No. 17-1407 at 11:12-14; id. at 25:18-19; id.
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`at 58:6-7 ("Well, Your Honor, so I think we agree that recovery is harvest.").
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`But other language in the written description can be read to suggest that
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`harvesting is part of, not separate from, purification. Specifically, the written
`
`description provides:
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`4 Lysis refers to processes that disrupt the cell wall or membrane, thereby releasing
`the entire contents of the cell, including the proteins, into the culture medium. #869
`patent at 26:43-45. Lysis can be done by a variety of methods, including mechanical
`shear, osmotic shock, or enzymatic treatments. Id.
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`11
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`When the cells grow to sufficient numbers, they are transferred to
`large-scale production tanks and grown for a longer period of time.
`At this point in the process, the recombinant proteins can be
`harvested. Typically, the cells are engineered to secrete the
`[antibody] into the cell culture media, so the first step in the
`purification process is to separate the cells from the media.
`Typically, harvesting includes centrifugation and filtration to
`produce a Harvested Cell Culture Fluid (HCCF). The media is then
`subjected to additional purification steps that remove any cellular
`debris, unwanted proteins, salts, minerals, or other undesirable
`elements. At the end of the purification process, the recombinant
`[antibody] is highly pure and is suitable for human therapeutic use.
`
`#869 patent at 1 :64-2:9 (italics and underlining added).
`
`Both sides agree that the italicized language describes "harvesting." See D.I.
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`449 at 1 (Genentech citing sentence containing italicized language in support of its
`
`proposed definition of "harvest" as "the process of separating the culture fluid
`
`(which contains the antibody) from cells or cellular debris"); C.A. No. 17-1407,
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`D.I. 325 at 61 (Amgen citing sentencing containing italicized language in support
`
`of its contention that "harvesting" is the "first step in the purification process" and
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`involves the "separat[ion] [ of] the cells from the media."). And thus, they agree
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`that harvesting is the first step in the purification process for proteins secreted from
`
`the cells into the culture fluid. The written description's subsequent reference to
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`"additional purification steps" confirms that "harvesting" is a purification step.
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`#869 patent at 2:5-6.
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`If harvesting is deemed to be part of purification, then the antibody
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`manufacturing process consists of two steps, not three steps, as Genentech argues.
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`12
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`And if antibody manufacturing consists of only two steps-fermentation and
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`purification-then it can be said that fermentation ends when purification begins.
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`Like the Kao patent, the extrinsic evidence adduced by the parties does not
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`uniformly describe the steps of the antibody manufacturing process. See, e.g., D.I.
`
`376 at Appx. 179 (Fahrner) (describing antibody manufacturing process as "cell
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`banking and cell culture, recovery, filling ... , finishing, and packaging."); id. at
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`Appx. 214 (Birch) (describing antibody manufacturing process as "inoculum prep,"
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`"production," "clarification," and "purification"); C.A. No. 17-1407, D.I. 27~-1 at
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`530 (Dwiveldi) (referring to the antibody manufacturing steps as "cell expansion,"
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`"fermentation," "harvest," "cell free harvest," and "concentration"); id. at 562
`
`(Nelson) (identifying the basic steps of the antibody manufacturing process as
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`"inoculum prep," "production," "recovery," "purification," and "bulk fill"); C.A.
`
`No. 17-1407, D.I. 271-2, Ex. 9 at 117 (Geigert) (identifying the steps of the antibody
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`manufacturing process as "expansion of master/working bank aliquot," "expression
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`of the biopharmaceutical," "harvest"). Nor does the extrinsic evidence uniformly
`
`use the terms "purification" or "recovery" (which the parties agree is synonymous
`
`with harvesting). See, e.g., C.A. No. 17-1407, D.I. 271-1 at 442 (Bates) (stating that
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`"initial purification" involves "filtration, centrifugation, precipitation, [ and] large(cid:173)
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`bead adsorption chromatography"); id. at 566 (Nelson) (stating that purification is
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`"typically a mixture of chromatography and ultrafiltration"); D.I. 376 at Appx. 179
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`13
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 16 of 20 PageID #: 34889
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`(Fahrner) (stating that "[p]roduct recovery includes harvest ... , chromatography for
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`antibody purification, and formulation by tangential flow filtration."); C.A. No. 17-
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`1407, D.I. 271-1 at 442 (Bates) (describing the entire downstream process as
`
`"recovery," and depicting "recovery" as the steps of "initial purification,"
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`"intermediate processing," and "final polishing"); id. at 565 (Nelson) (stating that
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`"recovery operations clarify and remove cell debris," and that "[ c] larification
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`operations may be done using centrifugation, depth filtration, dead-end sterile
`
`filtration, or tangential flow microfiltration.").
`
`In sum, the intrinsic and extrinsic evidence is conflicting. But my overall
`
`impression of the evidence taken as a whole is that a POSIT A would understand
`
`for purposes of the Kao patent that harvesting is part of purification and that
`
`antibody manufacturing consists of two steps-fermentation (i.e., cell culturing or
`
`antibody production) and purification. I find three things especially informative.
`
`First, as noted above, the Kao patent describes both harvesting and lysing as
`
`"the first step" of purification, depending on whether the proteins are made by
`
`secretion or intracellularly. This suggests that the inventors ultimately viewed
`
`antibody manufacturing as consisting of two main processes-fermentation and
`
`purification. Second, Genentech's expert, Dr. Hauser, conceded at his deposition
`
`that POSIT As use "purification" in "a broad sense" to describe the "downstream
`
`processing" in the manufacturing of antibodies. See D.I. 326-4 at J.A. 1600,
`
`14
`
`
`
`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 17 of 20 PageID #: 34890
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`138: 10-12) ("I admit that people sometimes use 'purification' in a broad sense,
`
`like downstream processing"); id. at 139:2-4 ("purification is from time to time
`
`used in a very general way that [is] identical [to] or identically understood [as]
`
`downstream processing"). As there is only an upstream and a downstream, this
`
`concession also suggests a two-step manufacturing process. Third, the same
`
`sentence in Amgen's 2011 Annual Report cited by Genentech as evidence that
`
`Amgen understands "fermentation" to mean what Genentech says it means also
`
`makes clear that Amgen understands the "bulk manufacturing" of antibodies to
`
`consist of two steps: fermentation and purification. See D.I. 376-2 at Appx. 449
`
`("Bulk manufacturing includes fermentation and/or cell culture, processes by
`
`which our proteins are produced, and also includes purification of the proteins to a
`
`high quality.").
`
`Accordingly, I will construe "following fermentation" for the proteins made
`
`intracellularly in terms of the beginning of purification. Furthermore, because
`
`claim 1 of the patent (in which "following fermentation" appears) applies to
`
`proteins made by either secretion or intracellularly and because of the inconsistent
`
`and overlapping uses of "harvest" ( or recovery) and "purification" in the Kao
`
`patent and the extrinsic evidence, I will construe "following fermentation" to mean
`
`"after the earlier of harvesting or purification has begun."
`
`15
`
`
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 18 of 20 PageID #: 34891
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`V.
`
`Genentech proposes that I construe "following fermentation" to mean "after
`
`the end of the cell growth and antibody production phases (which is indicated by a
`
`change in the cell culture environment that substantially ends cell growth and
`
`antibody production)." D.I. 121 at 63-64. This definition is problematic for five
`
`reasons.
`
`First, it is essentially a tautology. It defines the end of fermentation (i.e., cell
`
`growth and antibody production) as a change that "substantially ends"
`
`fermentation (i.e., cell growth and antibody production).
`
`Second, nothing in the patent's claims, figures, or written description
`
`suggests that fermentation ends when cell growth and antibody production
`
`substantially end.
`
`Third, the prosecution history contradicts Genentech' s construction.
`
`Substantially means largely, but not wholly; and thus Genentech's construction
`
`would allow for continued cell growth following fermentation. But during
`
`prosecution, in overcoming a non-final rejection by the patent examiner,
`
`Genentech stated that a prior art reference did not anticipate the claims in question
`
`because the reference "describes sparging the culture medium during the cell
`
`growth" but "does not describe sparging the pre-harvest or harvested culture fluid
`
`of the recombinant host cell with air following fermentation." C.A. No. 17-1407,
`
`16
`
`
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 19 of 20 PageID #: 34892
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`D.I. 326-2 at J.A. 612 (emphasis added) (underlines removed). Thus, Genentech
`
`disclaimed the possibility of cell growth following fermentation. Omega Eng 'g,
`
`Inc. v. Raytek Corp., 334 F.3d 1314, 1323 (Fed. Cir. 2003) ("The doctrine of
`
`prosecution disclaimer ... preclud[ es] patentees from recapturing through claim
`
`interpretation specific meanings disclaimed during prosecution.").
`
`Fourth, nothing in the patent teaches a POSIT A how to determine when cell
`
`growth and antibody production substantially ends. "When a word of degree is
`
`used the district court must determine whether the patent's specification provides
`
`some standard for measuring that degree." Datamize, LLC v. Plumtree Software,
`
`Inc., 417 F.3d 1342, 4351 (Fed. Cir. 2005). The Kao patent provides no standard
`
`to ascertain when the end of cell growth and antibody production has been
`
`substantially reached.
`
`And finally, Genentech's expert admitted that the analytical methods by
`
`which Genentech proposes to measure the substantial end of cell growth and
`
`antibody production are "theoretical[]" and that he is unaware of any occasion
`
`when such methods were actually used in an antibody manufacturing process. D.I.
`
`106-5, Ex. 12 at 85:17-86:11; see also D.l. 528 at 81:6-10.
`
`17
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`
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`Case 1:18-cv-00924-CFC-SRF Document 530 Filed 03/09/20 Page 20 of 20 PageID #: 34893
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`VI.
`
`Wherefore, for the reasons discussed above, I will construe "following
`
`fermentation" in the Kao patent to mean "after the earlier of harvesting or
`
`purification has begun."
`
`The Court will issue an order consistent with this Memorandum Opinion.
`
`18
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`
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