Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 1 of 44 PageID #:
`34481
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`C.A. No. 17-1407-CFC
`(CONSOLIDATED)
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`GENENTECH, INC. and CITY OF HOPE, )
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`AMGEN INC.,
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`Defendant.
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`GENENTECH, INC.,
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`AMGEN INC.,
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`Defendant and
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`Counterclaim Plaintiff.
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`____________________________________)
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`GENENTECH’S LETTER-BRIEF CONCERNING
`CONSTRUCTION OF “FOLLOWING FERMENTATION”
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`C.A. No. 18-924-CFC
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`ME1 32740375v.1
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`PUBLIC VERSION FILED: March 3, 2020
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 2 of 44 PageID #:
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`Dear Judge Connolly,
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`Genentech respectfully submits that for three reasons, it would be error to
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`construe “following fermentation” to mean “after harvesting has begun.”
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`1.
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`Rather than address the meaning of “following fermentation,” the
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`proposed construction elides it, substituting a distinct concept, the beginning of
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`harvest. When something ends and when something else begins are not necessarily
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`the same thing. History “following World War II” is defined by the end of the
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`conflict known by that name (1945), not the beginning of, for example, the Cold
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`War that followed (1947).
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`The rules of claim construction require respect for such distinctions. A
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`claim cannot be construed to “include something more than, or something different
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`from, what its words express,” White v. Dunbar, 119 U.S. 47, 51 (1886). Claim
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`construction must address the language the patentee actually used. Phillips v.
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`AWH Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005) (en banc). The claim
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`construction process involves “better understanding the meaning of the claim” but
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`not “changing it” or “making it different from what it is.” White, 119 U.S. at 51-
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`52.
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`“Following fermentation” must therefore be defined by when fermentation
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`ends rather than when harvest may begin. The parties’ experts agreed that
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`“fermentation” is a biological process whose meaning is well understood. Dr.
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 3 of 44 PageID #:
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`Hauser explained that it is “the use of cells to produce a product,” Ex. 1 (Kao
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`Hearing Transcript (Oct. 16, 2019)) at 57:1-7, such as, in the specific context of the
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`Kao patent, an antibody. See also id. at 108:4-109:23 (explaining that production
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`of the antibody is the second part of “fermentation”). Dr. Glacken understood
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`“fermentation” in the Kao patent’s context to refer to “cell culture processes for
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`making antibodies.” Id. at 144:24-145:19; see also id. at 150:13-16 (“fermentation
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`is used synonymous with mammalian cell culture processes for making antibodies”
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`in the Birch review paper), id. at 151:16-152:14 (agreeing fermentation can refer to
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`mammalian cell culture processes), id. at 161:3-7 (fermentation is “synonymous
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`with the culture”), id. at 164:7-13 (agreeing with Dr. Hauser that “production is a
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`subset of fermentation”).
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`With this agreement on what “fermentation” means, the absence of any
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`dispute over the meaning of “following” should end of the inquiry: the
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`requirement to sparge “following fermentation” refers to sparging the fluid after
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`the cells have made the antibodies. That is the concept intended by Genentech’s
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`proposed claim construction, and its proposal during the hearing, that “following
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`fermentation” means “after the production phase has ended.” Id. at 167:1-9,
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`170:20-171:12. Alternative phrasings like “after the cells have stopped making
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`antibodies” or “after the cells have stopped producing antibodies” also convey this
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`concept, and any of them would be an appropriate construction of the patent.
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`2.
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`The proposed construction impermissibly nullifies one of the two
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`embodiments the claims explicitly recite—the method of sparging a “pre-harvest
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`culture fluid” following fermentation. Because sparging of “pre-harvest cell
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`culture fluid” obviously cannot occur “after harvesting has begun,” the proposed
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`construction would violate the basic principle of claim construction that “the
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`context of the surrounding words of the claim must also be considered[.]” Wasica
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`Finance GmbH v. Cont. Auto. Sys., Inc., 853 F.3d 1272, 1288 (Fed. Cir. 2017).
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`When the Court previously asked about the meaning of “pre-harvest culture fluid,”
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`Genentech explained that it means “culture fluid that will be harvested.” D.I. 570
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`at 3-4.1 An interpretation that excludes the “pre-harvest” embodiment of the
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`claims cannot be correct. See Wasica, 853 F.3d at 1288 (rejecting claim
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`construction for excluding embodiments “expressly covered by the claim”).
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`This embodiment is important. The parties agree that harvest does not
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`always begin immediately after fermentation ends. A simple and common
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`example, discussed at the hearing, arises when fermentation has ended but the
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`manufacturing facility’s harvest equipment is not yet ready to receive the culture
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`fluid. Ex. 1 at 177:11-178:5. In that scenario fermentation is over, and pre-harvest
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`culture fluid is waiting to be harvested. Id. at 173:8-174:6, 177:11-178:5. During
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`that period the antibodies in the culture fluid are especially susceptible to being
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`1 All D.I. citations are to C.A. No. 17-1407 unless otherwise stated.
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`destroyed by the reducing enzymes in the culture fluid, precisely the problem the
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`claimed methods solve. Id. at 173:8-174:6. This period in time is depicted in the
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`figure below:
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`D.I. 570 at 3-4; Ex. 1 at 173:8-174:6.
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`The expert Amgen presented at the hearing, Dr. Glacken, suggested that he
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`was unaware of activity between fermentation and harvest. Ex. 1 at 165:3-9. But
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`Dr. Chalmers, the scientific expert who Amgen relied upon during briefing,
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`explained there is an additional, required step between fermentation and harvest
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`when antibodies are made using bacterial cells, a manufacturing process that is
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`specifically recited in dependent claim 10. D.I. 326 at 853-56 (¶¶ 42-43, 51).
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`Because bacterial cells generally cannot secrete antibodies into the culture fluid,
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`Dr. Chalmers described how it is necessary to destroy, or “lyse,” these cells in
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`order to release the antibodies that are trapped inside: “the first step following
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`fermentation is ‘lysis’ (necessary to release the antibody into the culture medium),
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`ME1 32740375v.1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 6 of 44 PageID #:
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`which is then followed by ‘harvest’.” Id. at 853 (¶ 43). Indeed he identified this
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`scenario (lysis of bacterial cells) as one in which the claimed methods, following
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`fermentation, sparge a “pre-harvest culture fluid” before harvest has begun. Id. at
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`853-57 (¶¶ 42-43, 51-52). Amgen itself has emphasized that a culture fluid
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`containing cells that “have been lysed ‘following fermentation’” is a “pre-harvest
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`culture fluid” that can be sparged “before harvest.” D.I. 325 at 62 (emphasis
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`added); see also 18-cv-924, D.I. 121 at 83 (discussing sparging of “‘pre-harvest’
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`cell culture fluid” after cells have been lysed). This understanding of the
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`technology (like Genentech’s) cannot be squared with the construction of
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`“following fermentation” as “after harvesting has begun.”
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`This is a plainly correct understanding of the technology, and Amgen has not
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`(yet) made any effort to withdraw or expressly disavow it. Yet based on a recent
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`meet-and-confer, it appears Amgen will encourage the Court to enter the proposed
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`construction despite knowing it is scientifically incorrect.
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`The rules of claim construction prohibit construing a term in a way that
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`excludes material covered by a dependent claim, and as noted dependent claim 10
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`expressly covers the production of antibodies in bacterial cells where the lysis
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`process described by Dr. Chalmers occurs. “[W]here dependent claims have no
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`meaningful difference other than an added limitation . . . construing the
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`independent claim to exclude material covered by the dependent claim would be
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 7 of 44 PageID #:
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`inconsistent.” Columbia Univ. v. Symantec Corp., 811 F.3d 1359, 1370 (Fed. Cir.
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`2016).
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`The Court’s proposed construction does not just eliminate a production
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`scenario the claims identify. It is also inconsistent with numerous scenarios in
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`which scientists in the field undertake activities—waiting for harvest equipment to
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`become available, lysing bacterial cells, or discarding the material because the
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`fermentation resulted in a contaminated or low quality product—that
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`unquestionably occur “following fermentation” but before harvest has begun. The
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`Court should not enter a construction that excludes these scenarios.
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`3.
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`Any concern regarding how the end of fermentation is defined under
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`Genentech’s construction would be misplaced, for two reasons.
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`First, Dr. Hauser explained how the end of fermentation could be measured,
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`as taught in the Kao patent’s written description. Ex. 1 at 70:4-74:16. Amgen
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`adduced no evidence disputing his testimony. Id. at 182:12-183:2. His undisputed
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`testimony should resolve the issue.
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`Second, and more fundamentally, it is neither necessary nor appropriate to
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`resolve at the Markman stage whether fermentation is over under various scenarios
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`identified. As the Federal Circuit has explained, trial courts “need not attempt the
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`impossible task of resolving all questions of meaning with absolute, univocal
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`finality.” Eon Corp. IP Holdings LLC v. Silver Spring Networks, Inc., 815 F.3d
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`ME1 32740375v.1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 8 of 44 PageID #:
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`1314, 1318 (Fed. Cir. 2016). Acumed LLC v. Stryker Corp. illustrates the principle
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`well. 483 F.3d 800 (Fed. Cir. 2007). There, the claimed surgical nail required a
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`“curved shank,” id. at 802-803, which the trial court construed to mean “a shank
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`that has a bend or deviation from a straight line without sharp corners or sharp
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`angles.” Id. at 804. On appeal the defendants argued that the district court should
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`have gone further to “specify precisely how ‘sharp’ is too sharp.” Id. at 806.
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`Affirming the construction, the Federal Circuit explained that a “sound claim
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`construction need not always purge every shred of ambiguity,” and that claim
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`constructions often leave “line-drawing problems” that are “properly left to the
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`trier of fact.” Id. (citing prior cases). Numerous decisions since then have
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`instructed district courts to apply this maxim, observing that were it otherwise, the
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`claim construction inquiry could “proceed ad infinitum.” Rembrandt Wireless
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`Techs. LP v. Samsung Elecs. Co., Ltd., 853 F.3d 1370, 1379 (Fed. Cir. 2017).
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`In any event, the proposed construction simply replaces one factual dispute
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`for another. As discovery has already shown, “when harvest begins” is a question
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`particularly susceptible to factual dispute:
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`ME1 32740375v.1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 9 of 44 PageID #:
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`In the end, Dr. Hauser and Dr. Glacken have served reports debating the
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`factual question of whether
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`. This is the relevant
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`factual dispute, as underscored by the plain language of the claim and undisputed
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`expert testimony about the meaning of “fermentation.” Precedent mandates that
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`the jury resolve it.
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`ME1 32740375v.1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 10 of 44 PageID
`#: 34490
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`Respectfully submitted,
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`
`
` /s/ Daniel M. Silver
`Michael P. Kelly (# 2295)
`Daniel M. Silver (# 4758)
`Alexandra M. Joyce (# 6423)
`MCCARTER & ENGLISH, LLP
`Renaissance Centre
`405 N. King Street, 8th Floor
`Wilmington, Delaware 19801
`Tel.: (302) 984-6300
`Fax: (302) 984-6399
`mkelly@mccarter.com
`dsilver@mccarter.com
`ajoyce@mccarter.com
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`Attorneys for Plaintiffs Genentech, Inc.
`and City of Hope
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`Dated: February 26, 2020
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`
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`OF COUNSEL:
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`Paul B. Gaffney
`David I. Berl
`Thomas S. Fletcher
`Kyle E. Thomason
`Teagan J. Gregory
`Charles L. McCloud
`Kathryn S. Kayali
`WILLIAMS & CONNOLLY LLP
`725 Twelfth St. NW
`Washington, DC 20005
`(202) 434-5000
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`Attorneys for Plaintiff Genentech, Inc.
`(17-1407-CFC)
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`William F. Lee
`Lisa J. Pirozzolo
`Emily R. Whelan
`Kevin S. Prussia
`Andrew J. Danford
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`60 State Street
`Boston, MA 02109
`(627) 526-6000
`william.lee@wilmerhale.com
`lisa.pirozzolo@wilmerhale.com
`emily.whelan@wilmerhale.com
`andrew.danford@wilmerhale.com
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`
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`ME1 32740375v.1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 11 of 44 PageID
`#: 34491
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`
`Robert J. Gunther Jr.
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`7 World Trade Center
`250 Greenwich Street
`New York, NY 10007
`(212) 230-8800
`robert.gunther@wilmerhale.com
`
`Nora Passamaneck
`WILMER CUTLER PICKERING
`HALE AND DORR LLP
`1225 17th Street, Suite 2600
`Denver, CO 80202
`
`Daralyn J. Durie
`Adam R. Brausa
`Eric C. Wiener
`Eneda Hoxha
`DURIE TANGRI
`271 Leidesdorff Street
`San Francisco, CA 94111
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`Attorneys for Plaintiffs Genentech,
`Inc. and City of Hope
`(17-1407-CFC and 18-924-CFC)
`
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`ME1 32740375v.1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 12 of 44 PageID
`#: 34492
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`Exhibit 1
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`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 13 of 44 PageID
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`#: 34493
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`1
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`IN THE UNITED STATES DISTRICT COURT
`IN AND FOR THE DISTRICT OF DELAWARE
`- - -
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`CIVIL ACTION
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`NO. 17-1407 (CFC)
`CIVIL ACTION
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`NO. 18-924 (CFC)
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`::::::::::::::::::::
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`GENENTECH, INC. and CITY OF
`HOPE,
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` Plaintiffs,
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`AMGEN INC.,
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` Defendant.
`---------------------------
`GENENTECH, INC.,
` Plaintiff,
` vs.
`AMGEN, INC.,
` Defendant.
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` Wilmington, Delaware
` Wednesday, October 16, 2019
` 9:00 o'clock, a.m.
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`BEFORE: HONORABLE COLM F. CONNOLLY, U.S.D.C.J.
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` Valerie J. Gunning
` Official Court Reporter
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`1 of 122 sheets
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`Page 1 to 1 of 309
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`10/22/2019 11:55:11 AM
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`2
`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 14 of 44 PageID
`#: 34494
`APPEARANCES:
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`4
`
` P R O C E E D I N G S
`
`(Proceedings commenced in the courtroom,
`beginning at 9:00 a.m.)
`
`THE COURT: Good morning. Please be seated.
`(Counsel respond, "Good morning, Your Honor.")
`THE COURT: Mr. Silver?
`MR. SILVER: Good morning, Your Honor.
`THE COURT: How are you?
`MR. SILVER: I'm good. Thanks. How are you?
`THE COURT: Good.
`MR. SILVER: Your Honor, with me on behalf of
`Genentech today are Thomas Fletcher from Williams &
`Connolly, Paul Gaffney from Williams & Connolly, David Berl
`from Williams & Connolly, Luke McCloud from Williams &
`Connolly, Andrew Danford from Wilmer Hale, Daralyn Durie
`from Durie Tangri, and we've got Rebecca Grant from
`Genentech.
`
`THE COURT: All right. Thank you very much.
`Ms. Ormerod, how are you?
`MS. ORMEROD: Eve Ormerod on behalf of Amgen in
`the 18-924 case.
`With me today from Cooley are Michele Rhyu,
`Eamonn Gardner and Phillip Mao, and from Amgen we Lois
`
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`
` McCARTER & ENGLISH, LLP
` BY: DANIEL M. SILVER, ESQ.
`
` -and-
`
` WILLIAMS & CONNOLLY LLP
`BY: PAUL B. GAFFNEY, ESQ.,
` DAVID J. BERL, ESQ.,
` THOMAS S. FLTECHER, ESQ.,
` TEAGAN J. GREGORY, ESQ.
` CHARLES McCLOUD, ESQ.
` ANDREW DANFORD, ESQ.
` (Washington, D.C.)
`
` -and-
`
`DURIE TANGRI
`BY: DARALYN DURIE, ESQ.
`
` Counsel for Plaintiffs
`
` YOUNG CONAWAY STARGATT & TAYLOR, LLP
` BY: MELANIE K. SHARP, ESQ. and
` JAMES L. HIGGINS, ESQ.
`
` -and-
`
`PROSKAUER ROSE LLP
`BY: SIEGMUND Y. GUTMAN, ESQ.,
` AMIR NAINI, ESQ. and
` DAVID HANNAH, ESQ.
` (Los Angeles, California)
`
` -and-
`
`3
`
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`Cosigrove and Nancy Goettel. We also have Neal Belgam from
`my office.
`
`1
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`THE COURT: All right. Thank you.
`4
`Ms. Sharp?
`5
`MS. SHARP: Good morning, Your Honor. Melanie
`6
`Sharp from Young Conaway Stargatt & Taylor for Amgen in the
`7
`17-14-07-case. Also Jim Higgins from Young Conaway. With
`8
`me are my colleagues Your Honor has met, Siegmund Gutman,
`9
`Amir Naini, David Hanna, and Drew Diamond from Amgen.
`10
`THE COURT: All right. Thank you.
`11
`All right. I guess let's begin. You know, the
`12
`declarations were largely about the intrinsic evidence and
`13
`the briefing. As far as I'm concerned, that is already
`14
`dealt with. You can address it real quickly if you want,
`15
`but I thought the purpose of this hearing was to adduce
`16
`extrinsic evidence so I can make a decision. I think I've
`17
`already ruled that I'm unable based on the intrinsic
`18
`evidence to construe the terms.
`19
`MR. FLETCHER: Yes, Your Honor.
`20
`THE COURT: All right.
`21
`MR. FLETCHER: And I think we will go through
`22
`the extrinsic evidence today.
`23
`THE COURT: I mean, did you have a different
`24
`understanding, because I mean the declaration basically just
`25
`went through the Kao patent. I thought that we did that.
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`APPEARANCES (Continued):
`
` AMGEN INC.
` BY: DREW DIAMOND, ESQ.
`
` Counsel for Defendant
` Amgen Inc.
` (CA No. 17-1407-CFC)
`
` SMITH KATZENSTEIN & JENKINS LLP
` BY: NEAL C. BELGAM, ESQ. and
` EVE H. ORMEROD, ESQ.
`
` -and-
`
` COOLEY LLP.
` BY: MICHELLE RHYU, ESQ.,
` PHILIP S. MAO, ESQ. and
` DANIEL KNAUSS, ESQ.
`
` Counsel for Defendant Amgen
` (CA 18-924-CFC)
`
` - - -
`
`10/22/2019 11:55:11 AM
`
`

`

`56
`
`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 15 of 44 PageID
`54
`#: 34495
`
`Hauser - direct
`1
`information about the cells and the process?
`2
`A.
`That's the main part of this. They have to try out
`3
`what kind of conditions are the best ones, and for that,
`4
`they raise a number of data, yes.
`5 Q.
`Let's take a look at the top line. Can you explain
`6
`briefly what is going on in the top line of Figure 6 in
`7
`Birch?
`8
`A.
`Basically, this is called -- people call it the seed
`9
`train, where the inoculum, this is the little vial of frozen
`10
`cells, is taken out. It's expanded in many stations until
`11
`enough material is produced to inoculate the production
`12
`fermenter, which is the circled material. Here you have a
`13
`situation where three seed trains and three production
`14
`fermenter are used in parallel.
`15 Q.
`And what goes on in the fermenter?
`16
`A.
`Fermenter activity is mainly cell growth, end of
`17
`production.
`18 Q.
`And what happens in the next line of the figure in
`19
`Birch?
`20
`A.
`The next line concerns the harvesting, and this is a
`21
`removal of cells from the cell culture fluid.
`22 Q.
`And do scientists want the cells to continue to grow
`23
`after the fermentation stage and produce antibodies?
`24
`A.
`They don't want to have them grow anymore. They don't
`25
`want to have them produce anymore because, as I mentioned
`
`Hauser - direct
`1
`time point the production and the quality of the antibody
`2
`is changing.
`3 Q.
`And then what do companies do when they actually
`4
`perform a process to end production?
`5
`A.
`Before they, before they perform the process,
`6
`everything is fixed, everything is written down, everything
`7
`is defined. So at a certain, at a point when the production
`8
`is over, or the fermentation is over, there are steps taken
`9
`that end fermentation on purpose.
`10 Q.
`In your experience, have you ever heard of any
`11
`confusion in a manufacturing process about whether
`12
`fermentation is over?
`13
`A.
`I've not heard about that.
`14 Q.
`Have you ever until today heard about a zone of
`15
`uncertainty in your 40 years practicing in this field as to
`16
`whether fermentation has ended?
`17
`A.
`Not talking to these people from the, from the
`18
`company.
`19 Q.
`When fermentation has ended -- sorry. When you say
`20
`that the conditions have changed, what is the purpose of
`21
`changing conditions at the, to end production?
`22
`A.
`Changing conditions is to make clear that the cells
`23
`stop producing the antibody, and that under the changing
`24
`conditions, the byproduct or the variant cannot be made
`25
`anymore or cannot be created anymore.
`
`55
`
`Hauser - direct
`
`57
`
`1 Q.
`
`Hauser - direct
`1
`before, under conditions that are not correctly defined,
`2
`there might be variants produced that are not -- that are
`3
`dangerous for the whole process.
`4 Q.
`So just so it's clear, would the POSA operate in some
`5
`zone of uncertainty as to whether antibody is being produced
`6
`and cells are growing in a manufacturing process?
`7
`A.
`The intent is to have no cell uncertainty. It must be
`8
`clear that the fermentation has ended after it has -- it's
`9
`leaving the fermenter.
`10 Q.
`And what happens at the bottom of the figure in Birch?
`11
`A.
`The two lines on the bottom concerns the purification
`12
`process on different steps.
`13 Q.
`And why can't you just get rid of all of these
`14
`dangerous variants you talked about that can be made when
`15
`conditions are not correct in the purification process?
`16
`A.
`The difficulty is that these variants are very closely
`17
`related to the main product, the antibody, and thus, the
`18
`classical purification methods do not allow to separate
`19
`them, so they will remain mainly in the final product.
`20 Q.
`In developing a process, how do companies know
`21
`that the production phase of the manufacturing process has
`22
`ended?
`23
`A.
`During the development process, there are lots of, we
`24
`mentioned before, there are lots of measurements
`25
`determinations to make sure or to clarify at what
`15 of 122 sheets
`
`8 Q.
`Is that meaning reflected in the literature?
`9
`A.
`It's well reflected in literature.
`10 Q.
`Let's go to tab 3 of your binder, which is an FDA
`11
`inspection guide in the prior art. That's at A223. Have
`12
`you reviewed this document?
`13
`A.
`I have seen that.
`14 Q.
`And we've put on the screen portions of A226 and A227.
`15
` Can you explain to the Court how this is
`16
`relevant to the meaning of fermentation to a person of
`17
`ordinary skill?
`18
`A.
`FDA uses the word fermentation in the process and to
`19
`find that it's the process that is used in the production of
`20
`monoclonal antibodies.
`21 Q.
`And it talks about closely monitoring and controlling
`22
`the bioreactor system. How is that relevant to your
`23
`understanding of fermentation?
`24
`A.
`It emphasizes, as I said before, that fermentation is
`25
`only good if it's closely monitored and quality control.
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`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 16 of 44 PageID
`66
`#: 34496
`
`68
`
`Hauser - direct
`1
`Kao patent at times to speak of the manufacturing process as
`2
`a whole?
`3 A.
`It is also used in an overarching use of weight.
`4 Q.
`And with reference to what's on the screen, claim 1 at
`5
`claim 42 to 51 and claim 2 at 10 through 14, can you explain
`6
`to the Court the other way in which production is being used
`7
`in the patent?
`8 A.
`Here it's meant, as I said, an overarching, the whole
`9
`process of the making biopharmaceutical products.
`10 Q.
`And in the definition that you have proposed for
`11
`fermentation, the growth and production phases, what does
`12
`production mean in your definition?
`13 A.
`Production means the phase or the protein is made by
`14
`the cells.
`15 Q.
`Is there a scientific or technical term for that?
`16 A.
`The other technical term which is also reflected in
`17
`claim 1 is expression.
`18 Q.
`Expression means what?
`19 A.
`Expression means, again, the realization of the
`20
`genetic information to get the protein.
`21 Q.
`To make the protein?
`22 A.
`To make the protein.
`23 Q.
`I'd like to look at claim 29 briefly at line 4 through
`24
`8, which was addressed in the Court's opinion where it says,
`25
`fermentation, recovery and purification and production
`
`Hauser - direct
`1 Q.
`And how is fermentation generally ended in your
`2
`opinion?
`3 A.
`Different technologies. One we have already been
`4
`discussing here is the chilling of the culture. Another one
`5
`is the centrifugation. The third one would be the addition
`6
`of chemical that is essentially also terminus fermentation
`7
`or changing conditions.
`8 Q.
`And who decides which technique to use to end
`9
`fermentation?
`10 A.
`That's a decision that is made during the development
`11
`process.
`12 Q.
`Does that make it subjective whether fermentation has
`13
`ended?
`14 A.
`No. When it's defined and the -- it's implemented,
`15
`there is no uncertainty anymore.
`16 Q.
`Now, you talked about ending cell growth and antibody
`17
`production. I want to talk about those separately.
`18
`First, let's talk about cell growth. Have you
`19
`looked at literature addressing the question of when cell
`20
`growth ends upon a reduction in temperature?
`21 A.
`I have looked at it.
`22 Q.
`And is one of those articles the Matjasevic article
`23
`that's at tab 11 in A354 of the appendix?
`24 A.
`I see that.
`25 Q.
`Can you explain with reference to Figure 1 of the
`
`67
`
`69
`
`Hauser - direct
`1
`recovery and purification.
`2
` Have you reviewed that portion of the
`3
`specification?
`4 A.
`I've seen that.
`5 Q.
`Okay.
`6 A.
`Yes.
`7 Q.
`And is there any difference between the end of
`8
`production and the end of fermentation as it's being used
`9
`here in claim 29?
`10 A.
`End of fermentation and end of production is the same.
`11 Q.
`It's the exact same thing?
`12 A.
`It's exactly the same point.
`13 Q.
`I want to discuss one final point with you, Dr.
`14
`Hauser, which is determining when fermentation has ended.
`15
` First of all, if the conditions that you've been
`16
`describing that are suitable for production and growth
`17
`continue, how long will fermentation continue?
`18 A.
`Continue -- fermentation continues as long as these
`19
`conditions are kept.
`20 Q.
`And so why if you're trying to make antibody, why
`21
`wouldn't you try to keep these conditions going forever?
`22 A.
`During the, during the development process, it has
`23
`been defined that at a certain time point, problems getting
`24
`up, the byproducts, and the decision is made at what stage
`25
`fermentation will be ended, so it has to be ended.
`10/22/2019 11:55:11 AM
`
`Hauser - direct
`1
`Matjasevic article the relationship between temperature
`2
`reduction and cell growth?
`3 A.
`The experiment, what we see here on the left side is
`4
`the number of viable cells over time of about 15 hours in
`5
`cultivation. You see in the open circles that the cells
`6
`grow very fast and produce more and more viable cells.
`7
`If you go down to 33, these are the closed
`8
`circles. We see it's much less. It's even more less. It's
`9
`even less at 31 degrees, and you also see that at
`10
`28 degrees, and this is the yellow line, there is no
`11
`increase anymore. So there is no indication for cell growth
`12
`at that temperature.
`13 Q.
`And if you're curious about whether there is cell
`14
`growth, if you want to make sure whether there is cell
`15
`growth at a certain temperature, what kind of experiment
`16
`would the POSA conduct?
`17 A.
`Well, that's what's on the right-hand side. It's just
`18
`the control, where the cells have been reactivated after
`19
`having been at four degrees, they have been brought up to
`20
`37, and you can see that the cells can grow again.
`21 Q.
`And if you are curious about whether the cells will
`22
`grow at 28, what experiment would you conduct consistent
`23
`with the literature?
`24 A.
`It's measuring the cell density over time. What's
`25
`given here, viable cell density is measured over time.
`Page 66 to 69 of 309
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`

`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 17 of 44 PageID
`70
`#: 34497
`
`Hauser - direct
`
`72
`
`Hauser - direct
`1 Q.
`Have you seen other literature that also makes those
`2
`measurements?
`3
`A.
`Yes.
`4 Q.
`And let's take a look at tab 12. That's the Hunt
`5
`article. Did you review this prior art article?
`6
`A.
`I did.
`7 Q.
`In connection with your work?
`8
`And can you please explain to the Court what
`9
`Figure 5C shows of the Hunt article?
`10
`A.
`
`Hauser - direct
`
`Hauser - direct
`
`71
`
`73
`
`1
`
`6 Q.
`
`15 Q.
`
`20 Q.
`
`
`
`1
`
`4 Q.
`
`And they do it so by lowering, and this is at the time
`frame between six hours and 78 hours while the chilling or
`the pausing is initiated at 12 and 24 degrees as the
`controls they use, seven degrees and 70.
`
`
`16
`17
`18
`19
`20
`
`1
`
`3 Q.
`Just so the record is clear, you're REFERRING to the
`4
`part on the X axis in Figure 5C between 6 and 78 hours?
`5
`A.
`Yes.
`6 Q.
`Where there was no cell growth?
`7
`A.
`Yes.
`8 Q.
`
`10 Q.
`
`20 Q.
`
`25 Q.
`19 of 122 sheets
`
`17 Q.
`Now, let's talk about antibody production briefly.
`18
`Have you looked at literature regarding the end of antibody
`19
`production and chilling?
`20
`A.
`I have done so.
`21 Q.
`Okay. And can you explain what the Hunt article again
`22
`at tab 12, Figure 5D shows in that regard?
`23
`A.
`5C concerns what you have determined from the 5C, and
`24
`the difference is here that the expression that is the
`25
`production of antibody is measured and again has the same
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`
`

`

`Case 1:18-cv-00924-CFC-SRF Document 524 Filed 03/03/20 Page 18 of 44 PageID
`74
`#: 34498
`
`Hauser - direct
`experiment as described before over time.
`Q.
`
`12
`
`12 Q.
`And what is the relationship of that test to what the
`13
`patent discloses at claim 48 about the HPLC method to
`14
`measure titer values?
`15
`A.
`The HPLC method is a classical test method that's
`16
`typically used in the production of antibodies.
`17 Q.
`We've been seeing in the literature tests about
`18
`reducing temperature and whether production and growth have
`19
`ended by reduction in temperature.
`20
`Are there other techniques to stop cell growth
`21
`in antibody production?
`22
`A.
`I mentioned that already. In the technical area, it's
`23
`typically done by centrifugation. It's done by adding, for
`24
`example, assays to the extent the cells are destroyed.
`25 Q.
`Does the fact that you've used a different technique
`
`76
`
`Hauser - cross
`in an industrial surrounding.
`MR. BERL: Thank you. No further questions, Dr.
`
`Hauser.
`
`1
`2
`3
`4
`THE COURT: Excellent timing.
`5
`MR. BERL: I tried.
`6
`THE COURT: All right. Mr. Gutman, or somebody
`7
`from the defense.
`8
`MS. SHARP: May we approach, Your Honor?
`9
`THE COURT: Yes.
`10
`(Binder handed to the Court.)
`11
`