Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 1 of 7 PageID #:
`32726
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`
`v.
`
`AMGEN INC.,
`
`
`Plaintiffs,
`
`Defendant.
`
`
`
`GENENTECH, INC.,
`
`
`Plaintiff,
`
`v.
`
`AMGEN INC.,
`
`Defendant.
`
`
`
`
`
`
`C.A. No. 17-1407-CFC
`(CONSOLIDATED)
`
`
`
`
`
`
`C.A. No. 18-924-CFC
`
`
`
`
`
`AMGEN INC.’S RESPONSES TO COURT’S QUESTIONS REGARDING
`HARVESTING AND “PRE-HARVEST CULTURE FLUID”
`
`C.A. No. 18-924-CFC:
`
`SMITH, KATZENSTEIN &
`JENKINS, LLP
`Neal C. Belgam (No. 2721)
`Eve H. Ormerod (No. 5369)
`Jennifer M. Rutter (No. 6200)
`1000 West Street, Suite 1501
`Wilmington, DE 19801
`P (302) 652-8400
`nbelgam@skjlaw.com
`eormerod@skjlaw.com
`jrutter@skjlaw.com
`
`Attorneys for Defendant Amgen Inc.
`
`C.A. No. 17-1407-CFC:
`
`YOUNG, CONAWAY, STARGATT
`& TAYLOR LLP
`Melanie K. Sharp (No. 2501)
`James L. Higgins (No. 5021)
`Rodney Square
`1000 North King Street
`Wilmington, DE 19801
`P (302) 571-6600
`msharp@ycst.com
`jhiggins@ycst.com
`
`Attorneys for Defendant Amgen Inc.
`
`Dated: October 25, 2019
`
`25475796.1
`
`
`
`
`
`32726
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`
`v.
`
`AMGEN INC.,
`
`
`Plaintiffs,
`
`Defendant.
`
`
`
`GENENTECH, INC.,
`
`
`Plaintiff,
`
`v.
`
`AMGEN INC.,
`
`Defendant.
`
`
`
`
`
`
`C.A. No. 17-1407-CFC
`(CONSOLIDATED)
`
`
`
`
`
`
`C.A. No. 18-924-CFC
`
`
`
`
`
`AMGEN INC.’S RESPONSES TO COURT’S QUESTIONS REGARDING
`HARVESTING AND “PRE-HARVEST CULTURE FLUID”
`
`C.A. No. 18-924-CFC:
`
`SMITH, KATZENSTEIN &
`JENKINS, LLP
`Neal C. Belgam (No. 2721)
`Eve H. Ormerod (No. 5369)
`Jennifer M. Rutter (No. 6200)
`1000 West Street, Suite 1501
`Wilmington, DE 19801
`P (302) 652-8400
`nbelgam@skjlaw.com
`eormerod@skjlaw.com
`jrutter@skjlaw.com
`
`Attorneys for Defendant Amgen Inc.
`
`C.A. No. 17-1407-CFC:
`
`YOUNG, CONAWAY, STARGATT
`& TAYLOR LLP
`Melanie K. Sharp (No. 2501)
`James L. Higgins (No. 5021)
`Rodney Square
`1000 North King Street
`Wilmington, DE 19801
`P (302) 571-6600
`msharp@ycst.com
`jhiggins@ycst.com
`
`Attorneys for Defendant Amgen Inc.
`
`Dated: October 25, 2019
`
`25475796.1
`
`
`
`
`
`
`Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 2 of 7 PageID #:
`32727
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`
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`Pursuant to the Court’s Oral Order dated October 17, 2019, Amgen Inc.
`
`provides the following responses to the Court’s two questions regarding U.S.
`
`Patent No. 8,574,869 (the “’869 Patent”).
`
`What is the first step of harvesting?
`
`The purported invention concerns “prevention of disulfide bond reduction
`
`during harvesting of disulfide-containing polypeptides, including antibodies, from
`
`recombinant host cell cultures.” ’869 Patent at 1:19-22 (emphasis added). The
`
`’869 Patent explains that such “disulfide bond reduction occurs during processing
`
`of the Harvested Cell Culture Fluid (HCCF) produced during manufacturing of
`
`recombinant proteins that contain disulfide bonds” and that, “[t]ypically, this
`
`reduction is observed after cell lysis, especially mechanical cell lysis during
`
`harvest operations….” Id. at 20:17-22 (emphasis added).
`
`The ’869 Patent explains that harvest operations occur after the bioreactor
`
`production operations: “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 protein can be harvested.” Id. at 1:64-
`
`67 (emphasis added). See also id. at Fig. 23 (the term “Harvest” highlighted in
`
`reproduction below).
`
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`Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 3 of 7 PageID #:
`32728
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`Harvest thus initially requires transfer of the contents of the bioreactor to the
`
`equipment specifically designed for harvesting. The first step of harvesting the
`
`protein is then using such equipment to separate the cells from the media in which
`
`the cells were grown: “Typically, harvesting includes centrifugation and filtration
`
`to produce a Harvested Cell Culture Fluid (HCCF).” Id. at 2:3-4. If, however, the
`
`protein is not secreted into the media by the cells, equipment might also be needed
`
`to break open the cells (i.e., cause “lysis”) “which can be done by a variety of
`
`methods, including mechanical shear, osmotic shock, or enzymatic treatments,” id.
`
`at 26:46-49, but specifically exemplified in the patent by using a “homogenizer”
`
`device. See id. at 48:55-64. Indeed, as Genentech’s counsel noted, the experts and
`
`parties all agree that while “harvesting” may be a multiple step process, across
`
`multiple pieces of equipment, “harvesting” begins in the first piece of equipment
`
`used to separate cells from media. 10/16/2019 Hearing Tr. at 173:8-18.
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`Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 4 of 7 PageID #:
`32729
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`How should the Court construe the term “pre-harvest culture fluid”?
`
`As Amgen indicated in the Joint Claim Construction Chart, “pre-harvest
`
`culture fluid,” like “following fermentation,” renders the claims indefinite. D.I.
`
`225 at 18 (C.A. No. 17-cv-1407-CFC). “Pre-harvest” is not defined in the ’869
`
`Patent. Nor is it used in any context that permits its scope to be ascertained with
`
`reasonable certainty. Instead, the patent simply refers to addition of thioredoxin
`
`inhibitors to “pre-harvest culture fluid” without explaining what constitutes “pre-
`
`harvest.” ’869 Patent at 2:27; 2:31; 2:50; 3:18.1
`
`The minimal guidance provided by the patent does not clarify the
`
`characteristic attributes of a “pre-harvest culture fluid” that allows it to be
`
`distinguished from culture fluid or harvested culture fluid. Only if the Court
`
`expressly directs its application of extrinsic evidence to potentially maintain
`
`validity of the claims does a possible construction arise based on a manufacturing
`
`operation.
`
`
`
` 1
`
` Unlike for “harvested culture fluid,” there is no data in the patent that even
`purports to demonstrate that the inventors used air sparging of a “pre-harvest
`culture fluid” to prevent the reduction of a disulfide bond in an antibody. The only
`data presented is in Example 8, which purports to show the prevention of the
`reduction of a disulfide bond in an antibody using air sparging of “HCCF,” i.e.,
`harvested cell culture fluid. ’869 Patent at 55:24-56:16.
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`Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 5 of 7 PageID #:
`32730
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`The Court has provided guidance that, based on extrinsic expert testimony as
`
`to the physical operations involved in antibody manufacture, it may provisionally
`
`direct construction proposals for otherwise indefinite terms like “following
`
`fermentation” and “pre-harvest” based on discrete physical locations within those
`
`operations (e.g., construing “following fermentation” to mean “after the fluid has
`
`left the production bioreactor”). Applying this guidance and following the Court’s
`
`mandate, “pre-harvest culture fluid” could potentially be construed based on
`
`extrinsic testimony from both experts as “culture fluid present in the harvesting
`
`(e.g., centrifugation and filtration) equipment.” See 10/16/2019 Hearing Tr. at
`
`112:11-113:2 (Genentech expert Dr. Hauser); 156:5-12 and 166:2-19 (Amgen
`
`expert Dr. Glacken).
`
`While finding no explicit support in the intrinsic record, this extrinsic-based
`
`construction would eliminate the zone of uncertainty with regard to the conditions
`
`under which sparging may or may not be potentially infringing. Thus, under this
`
`construction, what happens to culture fluid after leaving the bioreactor would be
`
`“following fermentation,” the culture fluid within the harvesting equipment would
`
`be “pre-harvest culture fluid,” and the culture fluid after having left the harvesting
`
`equipment would be “harvested culture fluid.”
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`Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 6 of 7 PageID #:
`32731
`
`
`
`Dated: October 25, 2019
`
`YOUNG CONAWAY STARGATT &
`TAYLOR, LLP
`
`/s/ James L. Higgins
`Melanie K. Sharp (No. 2501)
`James L. Higgins (No. 5021)
`Rodney Square
`1000 North King Street
`Wilmington, DE 19801
`(302) 571-6600
`msharp@ycst.com
`jhiggins@ycst.com
`
`
`Attorneys for Defendant Amgen Inc. in
`C.A. No. 17-1407-CFC
`
`
`SMITH, KATZENSTEIN & JENKINS
`LLP
`
`/s/ Neal C. Belgam
`Neal C. Belgam (No. 2721)
`Eve H. Ormerod (No. 5369)
`Jennifer M. Rutter (No. 6200)
`1000 West Street, Suite 1501
`Wilmington, DE 19801
`(302) 652-8400
`nbelgam@skjlaw.com
`eormerod@skjlaw.com
`jrutter@skjlaw.com
`
`Attorneys for Defendant Amgen Inc. in
`C.A. No. 18-924-CFC
`
`
`25475796.1
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`- 6 -
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`Case 1:18-cv-00924-CFC-SRF Document 448 Filed 10/25/19 Page 7 of 7 PageID #:
`32732
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`WORD COUNT CERTIFICATION
`
`The undersigned counsel hereby certify that Amgen Inc.’s Responses to the
`
`Court’s Questions Regarding Harvesting and “Pre-harvest Culture Fluid” contains
`
`315 and 408 words with respect to the first and second questions respectively,
`
`which were counted by Neal C. Belgam and James L. Higgins by using the word
`
`count feature in Microsoft Word, in 14-point Times New Roman font. The
`
`foregoing word count does not include the cover page or the counsel blocks.
`
`
`
`Dated: October 25, 2019
`
`/s/ Neal C. Belgam
`Neal C. Belgam
`
`/s/ James L. Higgins
`James L. Higgins
`
`
`
`
`25475796.1
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