throbber
Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 1 of 234 PageID #:
`13526
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`)
`
`
`
`
`
`
`
`GENENTECH, INC. and CITY OF HOPE, )
`)
`Plaintiffs and Counterclaim Defendants, )
`)
`)
`)
`)
`)
`)
`)
`
`v.
`
`
`AMGEN INC.,
`
`Defendant and Counterclaim Plaintiff.
`
`
`
`v.
`
`SAMSUNG BIOEPIS CO., LTD,
`
`Defendant and Counterclaim Plaintiff.
`
`
`
`C.A. No. 18-924-CFC
`
`C.A. No. 18-1363-CFC
`
`REVISED APPENDIX C TO JOINT CLAIM CONSTRUCTION CHART
`VOLUME III
`
`Neal C. Belgam (No. 2721)
`Eve H. Ormerod (No. 5369)
`SMITH KATZENSTEIN & JENKINS LLP
`1000 West Street, Suite 1501
`Wilmington, DE 19801
`(302) 652-8400
`nbelgam@skjlaw.com
`eormerod@skjlaw.com
`
`Attorneys for Defendant Amgen Inc.
`
`Michael P. Kelly (#2295)
`Daniel M. Silver (#4758)
`MCCARTER & ENGLISH, LLP
`405 North King Street, 8th Floor
`Wilmington, DE 19801
`(302) 984-6300
`mkelly@mccarter.com
`dsilver@mccarter.com
`
`Attorneys for Plaintiffs
`Genentech, Inc. and City of Hope
`in C.A. No. 18-924-CFC
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 2 of 234 PageID #:
`13527
`
`Frederick L. Cottrell, III (#2555)
`Jason J. Rawnsley (#5379)
`Alexandra M. Ewing (#6407)
`RICHARDS, LAYTON & FINGER, P.A.
`920 North King Street
`Wilmington, DE 19801
`(302) 651-7700
`cottrell@rlf.com
`rawnsley@rlf.com
`ewing@rlf.com
`
`Attorneys for Plaintiffs
`Genentech, Inc. and City of Hope
`in C.A. No. 18-1363-CFC
`
`David E. Moore (#3983)
`Bindu Palapura (#5370)
`POTTER ANDERSON & CORROON LLP
`Hercules Plaza, 6th Floor
`1313 North Market Street
`P.O. Box 951
`Wilmington, DE 19801
`(302) 984-6000
`dmoore@potteranderson.com
`bpalapura@potteranderson.com
`
`Attorneys for Defendant
`Samsung Bioepis Co., Ltd.
`
`
`
`
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 3 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 395 of 749 PageID #: 7872
`13528
`chromatography . . . lowering the temperature of the composition prior to
`
`subjecting the composition to protein A affinity chromatography, e.g. by lowering
`
`the temperature of harvested cell culture fluid (HCCF)”); 20:61 (“[t]he temperature
`
`of the HCCF”), 24:36 (“controlling the HCCF temperature”).
`
`61.
`
`The experiments summarized in Figures 1–2 reinforce this
`
`understanding. The Fahrner Patent explains that the temperature on the x-axis of
`
`these figures refers to the temperature of the water bath employed in the
`
`experiments, id. at 2:56–3:40, which was used to control the temperature of the
`
`composition as it flowed through the column, id. at 20:35–58. The Materials and
`
`Methods section explains:
`
`The temperature was controlled by immersing the
`column and the 5 ml stainless steel upstream line in a
`water bath controlled to the desired temperature of the
`run. The inlet line acted as a heat exchanger cooling or
`heating the HCCF prior to entering the protein A column,
`similar to the effect of chilling the HCCF in a tank at
`manufacturing scale. The outlet temperature was
`measured to be sure the desired temperature was
`achieved.
`
`Id. at 20:36–43. In other words, to the POSA the relevant temperature disclosed in
`
`the specification is the temperature of the composition, which was controlled in the
`
`experiments by a water bath, rather than the temperature of the laboratory itself,
`
`27
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 27 of 109
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`JA00004107
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`

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`13529
`which would not necessarily have been the same as that of the composition (hence
`
`the need for the water bath).
`
`62.
`
`The Fahrner Patent demonstrates that “controlling the temperature of
`
`the HCCF during loading could control protein A leaching.” Id. at 24:46–48. As
`
`the summary of the invention explains, “the invention further provides a method
`
`for reducing leaching of protein A during protein A affinity chromatography
`
`comprising reducing protease activity in a composition subjected to protein A
`
`chromatography. . . .” Id. at 2:48–51. The POSA would have understood from
`
`these disclosures that the reduction in leaching is achieved by reducing
`
`temperature, which reduces the activity of proteases. But this reduction in activity
`
`requires that the composition being purified—i.e., the cell culture fluid and the
`
`proteases in it—be at a reduced temperature, not that the laboratory generally be at
`
`a reduced temperature.
`
`63.
`
`For all of the reasons set forth above, the POSA would have
`
`understood from the Fahrner Patent’s claims and specification that the claimed
`
`temperature range of “about 10° C. to about 18° C.” refers to the temperature of the
`
`composition being purified.
`
`“About”
`C.
`64. Hospira contends that the POSA would have understood the term
`
`“about” in the phrase “about 10° C. to about 18° C.” to mean ±3°C. I disagree.
`
`28
`
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 28 of 109
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`JA00004108
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`

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`13530
`The POSA would have understood the ordinary meaning of the term
`
`65.
`
`“about” to mean “approximately.” This is the ordinary meaning in English and
`
`within the field of industrial protein purification. And the POSA would interpret
`
`“approximately” to exclude temperatures 3°C above 18°C.
`
`66.
`
`The specification of the Fahrner Patent further confirms this
`
`understanding. The specification is clear that, as the term “about” is used in the
`
`Fahrner Patent, “about” 18° C. and “about 20° C.” are both “below room
`
`temperature.” Id. at 18:4–9 (“Preferably, the method comprises reducing the
`
`temperature of the composition subjected to the protein A affinity chromatography,
`
`e.g. Where the temperature of the composition is reduced below room temperature,
`
`for instance in the range from about 3° C. to about 20° C., e.g. from about 10° C. to
`
`about 18° C.”). If “about” means ±3°C as Hospira urges, then “about 20° C.”—a
`
`temperature the Fahrner Patent indicates is “below room temperature”—means
`
`17°C to 23°C. This cannot be correct because 23°C (73.4°F) is well within the
`
`range of “room temperature.” Likewise, 21°C (69.8°F)—a temperature Hospira
`
`contends is within the scope of “about 18° C.”—is “room temperature,” not “below
`
`room temperature.”
`
`67. Hospira’s proposed construction of “about” results in the claimed
`
`method encompassing the purification of HCCF that is at “room temperature”
`
`(e.g., 21°C), not “below room temperature,” as the invention is described in
`
`29
`
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 29 of 109
`
`JA00004109
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`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 6 of 234 PageID #:
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`13531
`column 18. Because Hospira’s construction causes the claim to contradict the
`
`specification’s teaching—to chill the HCCF “below room temperature”—the
`
`POSA would not consider it to be a “reasonable” construction.
`
`68.
`
`I understand Hospira has argued that an experiment described in the
`
`specification of the Fahrner Patent suggests “about” should be interpreted to mean
`
`±3°C. Pet. 19–20; Ex. 1002 ¶¶ 81–82. I disagree. Hospira’s argument ignores the
`
`context in which “about” is used in the claim—it is used to modify the endpoints of
`
`a range, not to modify a single point. When the specification describes the
`
`invention as involving chilling the HCCF to “about 10° C. to about 18° C.,” it is
`
`describing the temperature of the composition in a way different from a single
`
`point with an associated error.
`
`69. Dr. Przybycien states that, “[i]n view of this, a POSA could
`
`understand that in the context of the ’799 patent, ±3° C reflects an acceptable
`
`temperature fluctuation during the purification process.” Ex. 1002 ¶ 82. The
`
`±3° C variation associated with this experiment is “acceptable” only because it
`
`falls entirely within the range of “about 10° C. to about 18° C.” This does not
`
`mean that the POSA would have understood ±3° C to be an appropriate
`
`interpretation of “about” in the context of the claim.
`
`70.
`
`I understand Hospira has also argued its proposed construction of
`
`“about” is supported by the prosecution history of two other Genentech patents.
`
`30
`
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 30 of 109
`
`JA00004110
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 7 of 234 PageID #:
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`13532
`Pet. 20. Specifically, Hospira points out that, during the prosecution of U.S. Patent
`
`No. 7,485,704 and European Patent No. EP 1 648 940 B1, claims directed to a
`
`temperature range of “about 3° C to about 20° C” were rejected over prior art
`
`disclosing protein A affinity chromatography performed at 22 °C (i.e., room
`
`temperature). Id. Hospira argues that the applicants, by amending the claims to
`
`recite a range of “about 3°C to about 18°C,” “implicitly acknowledged that ‘about’
`
`means at least ±2° C but less than ±4° C.” Id. This argument makes no sense, and
`
`the POSA would not adopt Hospira’s reasoning. Hospira appears to ignore that
`
`Genentech expressly did not “acquiesce[] to the rejection,” in making its initial
`
`amendment in the prosecution of the ’704 patent (“about 3°C to 20°C”), Ex. 1010
`
`at 55, 59, or in making its subsequent amendment (“about 3°C to about 18°C”), id.
`
`at 74, 76 (“All amendments and cancellations were made without prejudice or
`
`disclaimer.”). The same is true of its amendment during prosecution of EP ’940.
`
`Ex. 1012 at 21 (“Any amendments made during the prosecution of this application
`
`are intended solely to expedite prosecution of the application and are not to be
`
`interpreted as acknowledgement of the validity of any objection raised earlier in
`
`prosecution, nor as acknowledgement that any citation made against the
`
`application is material to the patentability of the application prior to amendment.”).
`
`The POSA would draw no conclusions from this history of amendments in these
`
`31
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 31 of 109
`
`JA00004111
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 8 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 400 of 749 PageID #: 7877
`13533
`related patents; certainly the POSA would not conclude from them that the
`
`inventors were claiming a temperature range that captured room temperature..
`
`VI. THE PRIOR ART DOES NOT DISCLOSE THE CLAIMED
`METHODS.
`71.
`I have reviewed the Board’s Institution Decision, and I understand
`
`that the Board concluded that there was a reasonable likelihood that both WO
`
`95/22389 (Exhibit 1003) and van Sommeren (Exhibit 1004) disclose the claimed
`
`methods and thus anticipate the claims of the Fahrner Patent. As explained in
`
`more detail, I disagree.
`
`72.
`
`Fundamentally, both Exhibits 1003 and 1004 fail to disclose the step
`
`of chilling the composition to be purified—the harvested cell culture fluid—to a
`
`temperature within the claimed range of “about 10 °C. to about 18 °C.” Neither
`
`reference suggests, let alone discloses, chilling the cell culture fluid. Therefore,
`
`neither reference teaches the claimed methods.
`
`A. WO ’389 (Ex. 1003)
`73.
`Exhibit 1003, WO 95/22389, entitled “Antibody Purification,” names
`
`SmithKline Beecham Corporation as the applicant and discloses various protocols
`
`for purifying antibodies and provides data for the results of those protocols as
`
`applied to two antibodies, RSHZ-19 (Example IA-D) and CH-CD14 (Example
`
`IIA-C). The first step in each of these protocols is protein A affinity
`
`32
`
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 32 of 109
`
`JA00004112
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 9 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 401 of 749 PageID #: 7878
`13534
`chromatography. In the following sections, I analyze particular aspects of the
`
`reference.
`
`1.
`
`The Temperature of the HCCF Subject to Protein A
`Chromatography
`The reference states that “[a]ll steps are carried out at room
`
`74.
`
`temperature (18 – 25 °C).” Ex. 1003 at 15. I understand that the Board, in its
`
`analysis of whether the reference teaches the claimed method step of “subjecting a
`
`composition . . . to protein A chromatography at a temperature in the range from
`
`about 10 °C to about 18 °C,” cited this disclosure in concluding that the reference
`
`discloses an overlapping range. Institution Decision at 11. In my opinion the
`
`Board’s conclusion is incorrect. There is an important distinction between the
`
`temperature at issue in the claim—the temperature of the harvested cell culture
`
`fluid—and the temperature disclosed in the reference, which is the temperature of
`
`the lab.
`
`75.
`
`The cited portion of Exhibit 1003—“All steps are carried out at room
`
`temperature (18 – 25 °C)”—would have been understood by the POSA as
`
`disclosing the temperature of the laboratory in which the research was conducted.1
`
`1 I note that this is a very broad range for “room temperature.” I typically consider
`
`“room temperature” to be approximately 21 to 25°C. The POSA would have
`
`33
`
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 33 of 109
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`JA00004113
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 10 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 402 of 749 PageID #: 7879
`13535
`I attended the deposition of Hospira’s expert, Dr. Todd Przybycien—a colleague of
`
`mine whom I have known for many years—and he agreed that this disclosure
`
`concerns the temperature of the lab. Ex. 2010 at 82:10–22. I do not believe
`
`anyone skilled in the art could interpret this disclosure any differently.
`
`76. Dr. Przybycien and I also agree that Exhibit 1003 does not include
`
`any disclosures about the temperature of the harvested cell culture fluid that the
`
`SmithKline Beecham researchers used in their protein A chromatography
`
`experiments. Id. at 89:16–90:5. In this regard, there is a stark difference between
`
`Exhibit 1003 and the Fahrner Patent’s disclosure of multiple experiments
`
`performed with cell culture fluid chilled or warmed to various temperatures. This
`
`lack of disclosure in Exhibit 1003 also contrasts with the Fahrner Patent’s teaching
`
`concerning the logistics of achieving this temperature control. I discussed these
`
`mechanisms above in section V.C in the context of the meaning of “about.”
`
`77.
`
`In both examples in Exhibit 1003, the antibodies are made by cell
`
`culture processes. Ex. 1003 at 14, 34. The POSA would have understood that
`
`harvested cell culture fluid comes from a bioreactor in which cells are typically
`
`understood such a broad definition of “room temperature” to suggest that authors
`
`of WO ’389 were essentially unconcerned about temperature control and
`
`considered it unimportant to their research.
`
`34
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 34 of 109
`
`JA00004114
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 11 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 403 of 749 PageID #: 7880
`13536
`cultured around 37°C. (This is common ground with Dr. Przybycien too. Ex.
`
`2010 at 66:17–24.) The reference does not disclose any intermediate step between
`
`the harvest of cell culture fluid from the bioreactor and the harvested cell culture
`
`fluid being subjected to protein A affinity chromatography. Ex. 1003 at 16. This
`
`contrasts with the reference’s disclosure concerning subsequent steps, for example,
`
`that between a viral inactivation step and cation exchange chromatography, the
`
`solution containing the product is chilled to 4°C or held at -70°C. Ex. 1003 at 16–
`
`17.
`
`78.
`
`I have considered whether it is necessarily the case that the harvested
`
`cell culture fluid in Exhibit 1003 would have cooled to ambient temperature prior
`
`to being subjected to protein A chromatography. I cannot say that this would
`
`inevitably have happened, nor do I believe the POSA would have concluded that
`
`this inevitably happened. (Dr. Przybycien agrees. Ex. 2010 at 90:18–20.) As
`
`noted above, the reference discloses no intermediate process step or hold time
`
`between harvest of the cell culture fluid and protein A chromatography. Efficiency
`
`is typically a goal of industrial processes, and absent an instruction to wait to allow
`
`the harvested cell culture fluid to cool to room temperature, the POSA would have
`
`interpreted Exhibit 1003 as allowing the disclosed process to be performed with
`
`harvested cell culture fluid that was potentially warmer than room temperature.
`
`35
`
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 35 of 109
`
`JA00004115
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 12 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 404 of 749 PageID #: 7881
`13537
`In sum, there are two critical points: (1) the POSA would not have
`
`79.
`
`read Exhibit 1003 as disclosing the temperature of the harvested cell culture fluid;
`
`and (2) the POSA would not have considered the disclosure of the temperature of
`
`the lab as inherently disclosing the temperature of the harvested cell culture fluid.
`
`Accordingly, Exhibit 1003 does not disclose the claimed method step of
`
`“subjecting a composition . . . to protein A chromatography at a temperature in the
`
`range from about 10 °C to about 18 °C.” Exhibit 1003 should therefore not be
`
`found to anticipate any claim of the Fahrner Patent.
`
`Leached Protein A
`2.
`Exhibit 1003 discloses that, “Although Protein A affinity column
`
`80.
`
`chromatography is widely used, it is also appreciated that elution of antibody from
`
`such columns can result in leaching of residual Protein A from the support.” Ex.
`
`1003 at 6 (emphasis added). The POSA would have understood three points from
`
`this sentence. First, the POSA would have understood the leached protein A was a
`
`known impurity introduced by the purification process itself. Second, the POSA
`
`would have understood that the cause of leaching was believed to be the acidic
`
`wash that elutes the antibody from the protein A ligand. Third, the POSA would
`
`have understood that this cause was “appreciated” by those field—i.e., the
`
`widespread belief in the field was that leaching was caused by forcing a low pH
`
`36
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`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 36 of 109
`
`JA00004116
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`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 13 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 405 of 749 PageID #: 7882
`13538
`buffer through the column, which could degrade the matrix and/or degrade the
`
`linkage between the matrix and the protein A ligand of the column.
`
`81.
`
`In the next sentence, Exhibit 1003 teaches that the art already
`
`contained methods for addressing leached protein A: either size exclusion
`
`chromatography or anion exchange chromatography. Id. These are both
`
`downstream purification steps. Exhibit 1003 then teaches that it provides a third
`
`solution: hydrophobic interaction chromatography. Id. Hydrophobic interaction
`
`chromatography (“HIC”) is another form of downstream processing.
`
`82.
`
`The POSA would have considered the data provided in Exhibit 1003
`
`when evaluating this contention. The data indicate that the disclosed HIC methods
`
`result in significant reductions in leached protein A. The “ProSep A eluate” is the
`
`solution collected following protein A chromatography that contains the antibody
`
`of interest. It contained 20.2 ng/mg of leached protein A. Ex. 1003 at 24, 27.
`
`Following a cation exchange chromatography step and different hydrophobic
`
`interaction chromatography steps, the level of leached protein A was reduced to
`
`3.5 ng/mg (using the Phenyl-650M column, id. at 24) and 0.7 ng/mg (using the
`
`Butyl-650M column, id. at 27). In the scaled-up example of the process, the
`
`ProSep A eluate contained 11.7 ng/mg of leached protein A, which was “not
`
`detectable” in the Phenyl-650M eluate and reduced to 1.7 ng/mg in the formulated
`
`product. Id. at 34. Based on these results, the POSA would have agreed with the
`
`37
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`Hospira, Inc. v. Genentech, Inc.
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`Page 37 of 109
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`JA00004117
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`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 14 of 234 PageID #:
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`13539
`suggestion in Exhibit 1003 that “HIC can be usefully employed to remove
`
`contaminating Protein A from IgG mixtures eluted from Protein A
`
`chromatographic support.” Ex. 1003 at 6.
`
`83.
`
`In later sections, I analyze whether the POSA would have been
`
`motivated to modify the methods disclosed in Exhibit 1003 to reduce levels of
`
`leached protein A. As discussed further below, it would not have made sense for
`
`the POSA to modify the process disclosed in Exhibit 1003 to reduce levels of
`
`leached protein A because the processes disclosed in Exhibit 1003 already address
`
`the problem of leached protein A.
`
`B.
`84.
`
`Van Sommeren (Ex. 1004)
`Exhibit 1004, “Effects of Temperature, Flow Rate and Composition of
`
`Binding Buffer on Adsorption of Mouse Monoclonal IgG1 Antibodies to Protein A
`
`Sepharose 4 Fast Flow,” Preparative Biochemistry, 22(2) 135-149 (1992),
`
`discloses a series of experiments using a Sepharose 4 Fast Flow protein A column
`
`to purify various mouse antibodies. In the following sections, I analyze particular
`
`aspects of the reference.
`
`1.
`
`The Temperature of the HCCF Subject to Protein A
`Chromatography
`The reference states that “The effect of temperature, 4 °C versus
`
`85.
`
`ambient temperature (AT) (20-25 °C) was studied . . . .” Ex. 1004 at 16. I
`
`understand that the Board concluded that this reference teaches the claimed method
`
`38
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`Hospira, Inc. v. Genentech, Inc.
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`Page 38 of 109
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`JA00004118
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`

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`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 15 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 407 of 749 PageID #: 7884
`13540
`step of “subjecting a composition . . . to protein A chromatography at a
`
`temperature in the range from about 10 °C. to about 18 °C.” by disclosing an
`
`overlapping range, based upon the Board’s citation to pages 33–37, Institution
`
`Decision at 19, which in turn contains a claim chart that cites the disclosure quoted
`
`above, Pet. 34.
`
`86.
`
`I disagree for two reasons. First, the temperature ranges are not
`
`overlapping applying the construction of the word “about” discussed above.
`
`Second, the reference’s disclosure concerning temperature does not disclose the
`
`temperature of the composition subjected to chromatography, as the Fahrner Patent
`
`does.
`
`The Disclosed Temperatures
`a.
`The POSA would have understood van Sommeren to exemplify the
`
`87.
`
`performance of protein A chromatography in two different environments—a cold
`
`room (4°C) and in the “ambient temperature” of the authors’ laboratory (disclosed
`
`to be 20–25°C). The reference does not disclose any effort to adjust the
`
`temperature of the harvested cell culture fluid directly and does not disclose any
`
`mechanisms for achieving temperatures other than a cold room or ambient
`
`temperature.
`
`88.
`
`In section V.C above, I explained the basis for my opinion concerning
`
`the correct construction of the word “about” in the context of the Fahrner Patent.
`
`39
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 39 of 109
`
`JA00004119
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 16 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 408 of 749 PageID #: 7885
`13541
`Applying that construction, there is no overlap between the range claimed in the
`
`Fahrner Patent and the temperatures disclosed in the van Sommeren reference,
`
`even if one were to assume that the temperatures disclosed in van Sommeren were
`
`the temperature of the harvested cell culture fluid subjected to protein A
`
`chromatography.
`
`89.
`
`I understand the Petitioner to argue that the “POSA would
`
`immediately appreciate from this disclosure that protein A chromatography could
`
`be conducted at temperatures between 4 °C and 20 to 25 °C as well.” Pet. 35. I
`
`have considered Dr. Przybycien’s opinion that van Sommeren “teaches that protein
`
`A chromatography can be conducted at temperatures from 4 °C to 25 °C.” Ex.
`
`1002 ¶ 97. I disagree with these positions.
`
`90. Van Sommeren does not disclose any example of performing protein
`
`A chromatography using harvested cell culture fluid that had been chilled to “about
`
`10 °C. to about 18 °C.” It provides no suggestion to modify the temperature of the
`
`harvested cell culture fluid to this range and no disclosure of how to achieve these
`
`temperatures. It nowhere suggests that performing protein A chromatography
`
`within this temperature range would result in any benefit.
`
`91. At most, van Sommeren notes that the dynamic binding capacity of
`
`the protein A column may differ in a cold room where the column is at 4 °C from
`
`its dynamic binding capacity at ambient temperature. Ex. 1004 at 15 (Table V),
`
`40
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 40 of 109
`
`JA00004120
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 17 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 409 of 749 PageID #: 7886
`13542
`16–18. However, the difference observed was unpredictable—sometimes binding
`
`capacity increased, sometimes it decreased. Ex. 1004 at 15–18. Thus, van
`
`Sommeren concludes that, using buffers identified in the reference, the
`
`“temperature effect on the IgG1 binding capacity becomes of minor importance.”
`
`Ex. 1004 at 18. The POSA would have understood that the point of van Sommeren
`
`is that when the exemplified buffers are used, whether protein A chromatography
`
`is performed in a cold room or in an ambient temperature laboratory is irrelevant.
`
`Dr. Przybycien suggested in his declaration that researchers were eager to “step out
`
`of the cold room and conduct protein A chromatography at ambient temperatures.”
`
`Ex. 1002 ¶ 34. I agree with this sentiment—any bioprocessing engineer would
`
`prefer to perform processes at ambient temperature because of the inconvenient
`
`and expense of changing temperature (whether in the form of maintaining a cold
`
`room or in the form of chilling relatively large amounts of water). Thus, the
`
`teaching the POSA would take from van Sommeren was not a suggestion to
`
`perform protein A chromatography at 4°C, 20–25°C, or any temperature in
`
`between—the teaching of van Sommeren is that with the exemplified buffers,
`
`temperature is irrelevant, and that there is no good reason to conduct protein A
`
`chromatography at anything other than ambient temperature.
`
`92. Nor would the POSA have understood van Sommeren to disclose the
`
`performance of protein A chromatography at “about 10 °C. to about 18 °C.” As
`
`41
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 41 of 109
`
`JA00004121
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 18 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 410 of 749 PageID #: 7887
`13543
`noted, van Sommeren includes no such example. And to the extent that van
`
`Sommeren teaches that temperature can affect dynamic binding capacity, it does
`
`not suggest that temperatures between those of a cold room and ambient
`
`temperature would be optimal. If the authors of van Sommeren subscribed to that
`
`belief, it would have made sense to test intermediate temperatures methodically.
`
`But no such experiments are disclosed in Exhibit 1004. (Nor, for that matter, does
`
`any reference cited in the Petition disclose any such series of experiments—
`
`presumably because, as I discuss throughout this declaration, controlling
`
`temperature is time-consuming, expensive, and challenging.) I therefore disagree
`
`with the notion that van Sommeren discloses to the POSA the performance of
`
`protein A chromatography at any and all temperatures in between the cold room
`
`and ambient temperature. On the contrary, it discloses to the POSA the
`
`performance of protein A chromatography only in the cold room and in an ambient
`
`temperature laboratory.
`
`93. Because van Sommeren, Exhibit 1004, does not disclose the claimed
`
`method step of “subjecting a composition . . . to protein A chromatography at a
`
`temperature in the range from about 10 °C. to about 18 °C.,” it should not be found
`
`to anticipate any claim of the Fahrner Patent.
`
`b.
`
`The Temperature of the HCCF
`
`42
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 42 of 109
`
`JA00004122
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 19 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 411 of 749 PageID #: 7888
`13544
`94. Van Sommeren does not disclose the claimed methods for the
`
`additional reason that it does not teach anything about the temperature of the cell
`
`culture fluid. As I noted above, I believe the Board, as it did with Exhibit 1003,
`
`has incorrectly conflated the temperature at issue in the claim—i.e., the
`
`temperature of the composition being purified (harvested cell culture fluid)—with
`
`the temperature disclosed in the reference—i.e., the temperature of the lab. .
`
`95.
`
`The cited portion of van Sommeren—“The effect of temperature, 4 °C
`
`versus ambient temperature (AT) (20-25 °C) was studied . . . .” Ex. 1004 at 16—
`
`would have been understood by the POSA as disclosing the temperature of the cold
`
`room and the laboratory in which the research was conducted.
`
`96.
`
`Exhibit 1004 does not include any disclosures about the temperature
`
`of the harvested cell culture fluid specifically. This lack of disclosure contrasts
`
`with the Fahrner Patent, which provides data from multiple experiments performed
`
`with cell culture fluid chilled or warmed to various temperatures. This lack of
`
`disclosure also contrasts with the Fahrner Patent’s teaching concerning the
`
`logistics of achieving this temperature control. (I discussed these mechanisms
`
`above in section V.C in the context of the meaning of “about.”)
`
`97.
`
`In the experiments disclosed in Exhibit 1004, the antibodies are made
`
`by cells cultures in hollow fibers and obtained by dialysis. Ex. 1004 at 7. The
`
`POSA would have understood that the cells, and by extension, the fluid from
`
`43
`
`Genentech 2008
`Hospira, Inc. v. Genentech, Inc.
`IPR2016-01837
`Page 43 of 109
`
`JA00004123
`
`

`

`Case 1:18-cv-01363-CFC Document 95-3 Filed 04/10/19 Page 20 of 234 PageID #:
`Case 1:18-cv-00924-CFC Document 60-12 Filed 12/11/18 Page 412 of 749 PageID #: 7889
`13545
`which the antibodies were dialyzed would typically be around 37°C. Ex. 2034 at
`
`2. The van Sommeren reference does not disclose any intermediate step between
`
`the harvest of cell culture fluid from the bioreactor and the harvested cell culture
`
`fluid being subjected to protein A affinity chromatography. Ex. 1004 at 7.
`
`98.
`
`I have considered whether it is necessarily the case that the harvested
`
`cell culture fluid in Exhibit 1004 would have cooled to “ambient temperature” (20–
`
`25°C) prior to being subjected to protein A chromatography. I cannot say that this
`
`would inevitably have happened, nor do I believe the POSA would have concluded
`
`that this inevitably happened. As noted above, the reference discloses no
`
`intermediate process step or hold time between harvest of the cell culture fluid and
`
`protein A chromatography. Efficiency is typically a goal of industrial processes,
`
`and absent an instruction to wait to allow the harvested cell culture fluid to cool to
`
`room temperature, the POSA would have interpreted Exhibit 1004 as suggesting,
`
`and at a minimum allowing, the disclosed process to be performed with harvested
`
`cell culture fluid

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