Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 1 of 33 PageID #: 14826
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Plaintiffs and Counterclaim
`Defendants,
`
`V.
`
`AMGEN INC.,
`
`Defendant and Counterclaim
`Plaintiff.
`
`GENENTECH, INC. and ClTY OF
`HOPE,
`
`Plaintiffs and Counterclaim
`Defendants,
`
`v.
`
`SAMSUNG BIOEPSIS CO., LTD.,
`
`Defendant and Counterclaim
`Plaintiff.
`
`Civ. No. 18-924-CFC
`
`Civ. No. 18-1363-CFC
`
`Michael P. Kelly, Daniel M. Silver, MCCARTER &ENGLISH, LLP, Wilmington,
`Delaware. Counsel for Plaintiffs in C.A. No. 18-924-CFC.
`
`Frederick L. Cottrell, Ill, Jason J. Rawnsley, RICHARDS, LAYTON & FINGER,
`P.A., Wilmington, Delaware. Counsel for Plaintiffs in C.A. No. 18-1363-CFC.
`
`William F. Lee, Lisa J. Pirozzolo, Emily R. Whelan, Kevin S. Prussia, Andrew J.
`Danford, WILl\,1ER CUTLER PICKERING HALE AND DORR LLP, Boston,
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELAWARE
`
`GENENTECH, INC. and CITY OF
`HOPE,
`
`Plaintiffs and Counterclaim
`Defendants,
`
`V.
`
`AMGEN INC.,
`
`Defendant and Counterclaim
`Plaintiff.
`
`GENENTECH, INC. and ClTY OF
`HOPE,
`
`Plaintiffs and Counterclaim
`Defendants,
`
`v.
`
`SAMSUNG BIOEPSIS CO., LTD.,
`
`Defendant and Counterclaim
`Plaintiff.
`
`Civ. No. 18-924-CFC
`
`Civ. No. 18-1363-CFC
`
`Michael P. Kelly, Daniel M. Silver, MCCARTER &ENGLISH, LLP, Wilmington,
`Delaware. Counsel for Plaintiffs in C.A. No. 18-924-CFC.
`
`Frederick L. Cottrell, Ill, Jason J. Rawnsley, RICHARDS, LAYTON & FINGER,
`P.A., Wilmington, Delaware. Counsel for Plaintiffs in C.A. No. 18-1363-CFC.
`
`William F. Lee, Lisa J. Pirozzolo, Emily R. Whelan, Kevin S. Prussia, Andrew J.
`Danford, WILl\,1ER CUTLER PICKERING HALE AND DORR LLP, Boston,
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 2 of 33 PageID #: 14827
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`Massachusetts; Robert J. Gunther Jr., WILMER CUTLER PICKERING HALE
`AND DORR LLP, New York, New York; Daralyn J. Durie, Adam R. Brausa,
`DURIE TANGRI LLP, San Francisco, California. Counsel for Plaintiffs in C.A. No.
`18-924-CFC and C.A. No. 18-1363-CFC.
`
`Neal C. Belgam, Eve H. Ormerod, SWTH KATZENSTEIN & JENKINS LLP,
`Wilmington, Delaware; Michelle Rhyu, Susan Krumplitsch, Daniel Knauss,
`COOLEY LLP, Palo Alto, California; Orion Armon, COOLEY LLP, Broomfield,
`Colorado; Eamonn Gardner, COOLEY LLP, San Diego, California. Counsel for
`Defendant Amgen Inc.
`
`David E. Moore, Bindu Palapura, POTTER ANDERSON & CORROON LLP,
`Wilmington, Delaware; Dimitrios T. Drivas, Scott T. Weingaertner, Amit H.
`Thakore, Holly Tao, WHITE & CASE LLP, New York, New York. Counsel for
`Defendant Samsung Bioepis Co., Ltd.
`
`MEMORANDUM OPINION
`
`June 14, 2019
`
`Wilmington, Delaware
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 3 of 33 PageID #: 14828
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`Ol@C~
`
`CONNOLLY, UNITED ST SoisTRICT JUDGE
`
`This action arises under the Biologics Price Competition and Innovation Act
`
`("BPCIA"), 42 U.S.C. § 262, and involves biosimilar versions of Herceptin®, a
`
`drug used to treat breast cancer. Pending before me is the matter of claim
`
`construction pursuant to Markman v. Westview Instruments, Inc., 517 U.S. 3 70
`
`(1996). Plaintiffs Genentech, Inc. and City of Hope (collectively, "Genentech")
`
`and Defendants Amgen, Inc. ("Amgen") and Samsung Bioepsis Co., Ltd.
`
`("Samsung," and collectively with Amgen, "Defendants") have asked me to
`
`construe the meaning of terms set forth in U.S. Patent Nos. 7,993,834 ("the '834
`
`patent"); 8,076,066 ("the '066 patent"); 8,574,869 ("the '869 patent"); 8,512,983
`
`("the '983 patent"); and 7,390,660 ("the '660 patent"). D.I. 60; D.I. 121.1
`
`I held a Markman hearing on April 24, 2019.2 D.I. 182. I ruled from the
`
`bench with respect to one of the disputed terms. See Id. at 12:3-14:14 (adopting
`
`Genentech's proposed construction of"A method for increasing likelihood of
`
`1 All citations are to the docket for C.A. No. 18-924 unless stated otherwise.
`
`2 Two of the terms at issue in this case are also at issue in Genentech v. Amgen,
`C.A. 17-1407 (the "Avastin case"). Oral argument on the overlapping terms was
`held in the Avastin case on April 2, 2019 and April 23, 2019. See C.A. 17-1407,
`D.I. 340 at 5:8-83:10 ("following fermentation") and D.I. 345 at 18:18-96:21
`("glutamine-free"). Samsung appeared in the Avastin case to state that it has "the
`same position as Amgen" on glutamine-free, "so we don't need to ... argue it on
`[April] 24th." D.I. 345 at 96:5-8.
`
`2
`
`
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 4 of 33 PageID #: 14829
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`effectiveness of breast cancer treatment with humanized anti-ErbB2 antibody
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`huMAb4D5-8"). The parties also agreed during the hearing that I could assign
`
`another disputed term ("Pre-Harvest [Culture Fluid]") its plain and ordinary
`
`meaning. See id. at 90. I address in this Memorandum Opinion the remaining
`
`disputed terms.
`
`I.
`
`STANDARD OF REVIEW
`
`"It is a bedrock principle of patent law that the claims of a patent define the
`
`invention to which the patentee is entitled the right to exclude." Phillips v. AWH
`
`Corp., 415 F.3d 1303, 1312 (Fed. Cir. 2005). "'[T]here is no magic formula or
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`catechism for conducting claim construction.' Instead, the court is free to attach
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`the appropriate weight to appropriate sources 'in light of the statutes and policies
`
`that inform patent law."' SoftView LLC v. Apple Inc., 2013 WL 4758195, at *1 (D.
`
`Del. Sept. 4, 2013) (quoting Phillips, 415 F.3d at 1324). Construing the claims in a
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`patent is a question of law. Markman v. Westview Instruments, Inc., 52 F.3d 967,
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`977-78 (Fed. Cir. 1995), aff'd, 517 U.S. 370, 388-90 (1996).
`
`Unless a patentee acts as his own lexicographer by setting forth a special
`
`definition or disavows the full scope of a claim term, the words in a claim are to be
`
`given their ordinary and accustomed meaning. Thorner v. Sony Comput. Entm 't
`
`Am. LLC, 669 F.3d 1362, 1365 (Fed. Cir. 2012). "[T]he ordinary and customary
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`3
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`
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 5 of 33 PageID #: 14830
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`meaning of a claim term is the meaning that the term would have to a person of
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`ordinary skill in the art in question at the time of the invention, i.e., as of the
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`effective filing date of the patent application." Phillips, 415 F.3d at 1313. A
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`person of ordinary skill in the art ("POSIT A") "is deemed to read the claim term
`
`not only in the context of the particular claim in which the disputed term appears,
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`but in the context of the entire patent, including the specification." Id. at 1313.
`
`"[T]he specification is always highly relevant to the claim construction analysis.
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`Usually, it is dispositive; it is the single best guide to the meaning of a disputed
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`term." Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir.
`
`1996).3
`
`The court may also consider extrinsic evidence, which "consists of all
`
`evidence external to the patent and prosecution history, including expert and
`
`inventor testimony, dictionaries, and learned treatises." Phillips, 415 F.3d at 1317.
`
`3 Section 112(b) of Title 35 provides that "[t]he specification shall conclude with
`one or more claims[.]" This language makes clear that the specification includes
`the claims asserted in the patent, and the Federal Circuit has so held. See
`Markman, 52 F.3d at 979 ("Claims must be read in view of the specification, of
`which they are part"). The Federal Circuit and other courts, however, have also
`used "specification" on occasion to refer to the written description of the patent as
`distinct from the claims. See, e.g., id. ("To ascertain the meaning of claims, we
`consider three sources: The claims, the specification, and the prosecution
`history."). To avoid confusion, I will refer to the portion of the specification that is
`not the claims as "the written description."
`
`4
`
`
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 6 of 33 PageID #: 14831
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`"Extrinsic evidence is to be used for the court's understanding of the patent, not for
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`the purpose of varying or contradicting the terms of the claims." Markman, 52
`
`F.3d at 981. "The construction that stays true to the claim language and most
`
`naturally aligns with the patent's description of the invention will be, in the end,
`
`the correct construction." Renishaw PLC v. Marposs Societa 'per Azioni, 158 F.3d
`
`1243, 1250 (Fed. Cir. 1998).
`
`II. CONSTRUCTION OF DISPUTED TERMS
`
`A. "Wherein The Patient's Cancer Cells Express HER2 At AO Or 1+
`Level By Immunohistochemistry" ('066 patent)4
`
`Genentech's
`"wherein the patient's cancer cells have an antigen level
`Construction corresponding to a 0 or 1 + score for HER2 by any
`immunohistochemistry test"
`
`Amgen's
`"wherein the patient's cancer cells have been found to express
`Construction HER2 at a 0 or 1 + level by any immunohistochemistry test"
`
`Court's
`"wherein the patient's cancer cells have been found to express
`Construction HER2 at a 0 or 1 + level by any immunohistochemistry test"
`
`1. Background
`
`Claim 1 of the '066 patent, reformatted for clarity, recites:
`
`A method of identifying and treating a breast cancer patient disposed
`to respond favorably to a HER2 antibody, huMAb4D5-8,
`
`which method comprises detecting her2 gene amplification in cancer
`cells in a breast tissue sample from the patient and treating the patient
`
`4 This term is not at issue in the case between Genentech and Samsung.
`5
`
`
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 7 of 33 PageID #: 14832
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`with her2 gene amplification with the HER2 antibody in an amount
`effective to treat the breast cancer,
`
`wherein the patient's cancer cells express HER2 at a O or I+ level by
`immunohistochemistry.
`
`'066 patent at 22:22-64 (emphasis added).
`
`Some technical background is helpful in understanding the intrinsic
`
`evidence. Trastuzumab, the active ingredient in Herceptin®, is an antibody that
`
`binds to the protein HER2, a receptor on the surface of a cell, and slows the growth
`
`of "HER2-positive" cancer cells. The HER2 protein is encoded by the HER2 gene.
`
`A normal cell has two copies of the HER2 gene. In patients with certain types of
`
`breast cancer, cells have extra copies of the HER2 gene. The relevant field of art
`
`refers to the extra copies of the HER2 gene as "amplification." Having extra
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`copies of the HER2 gene results in a higher than normal level (i.e.,
`
`"overexpression") of the HER2 protein. Thus, amplification of the HER2 gene is
`
`said to result in the overexpression of the HER2 protein.
`
`At the time of the invention, there were two ways to test a sample of breast
`
`cancer tissue: (i) immunohistochemistry ("IHC") tests, which measured antigen
`
`levels (i.e., overexpression of the HER2 protein), and (ii) fluorescence in-situ
`
`hybridization ("FISH") tests, which measured the number DNA copies of the
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`HER2 gene (i.e., amplification). In general, pathologists evaluated IHC assays
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`using a 0, 1+, 2+, and 3+ scoring system. A score ofO to I+ was considered
`6
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 8 of 33 PageID #: 14833
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`HER2-negative. A score of 2+ was considered "borderline" or "equivocal." A
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`score of 3+ was considered HER2-positive. At the time of the invention, it was
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`known in the art that IHC tests could yield false negative results that excluded
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`patients from treatment who might otherwise have benefitted from it.
`
`2. Analysis
`
`Genentech and Amgen dispute the meaning of"wherein the patient's cancer
`
`cells express HER2 at a O or l+ level by immunohistochemistry." The crux of the
`
`dispute is whether this "wherein" clause requires that an IHC test be performed as
`
`a step in the claimed method. Amgen argues that an IHC test is required.
`
`Genentech contends the test is not necessary. I agree with Amgen.
`
`First, claim 1 describes a "method of identifying and treating a breast cancer
`
`patient disposed to respond favorably to a HER2 antibody ... wherein the patient's
`
`cancer cells express HER2 at a O or l+ level by immunohistochemistry." Id. at
`
`22:22 (emphasis added). To identify a patient with an IHC score of O or 1+, an
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`IHC test has to be performed on that patient's cancer cells.
`
`Genentech admits that the "wherein" clause is "a substantive claim
`
`requirement" and that infringement of claim 1 requires "that the patient's cancer
`
`cells express HER2 at a zero or one-plus level." D.I. 182 at 43: 19-20. It argues,
`
`however, that
`
`7
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 9 of 33 PageID #: 14834
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`[ t ]here are multiple ways that one might determine that.
`One might do a test and one might go back and look at
`patient samples as patients who were screened using FISH
`and who were then treated with Herceptin and determine
`what the IHC result for those patients would be. One might
`also perform a statistical analysis, which is common in
`patent cases in evaluating the scope of infringement.
`
`Id. at 24:22-25:3.
`
`There are two problems with this argument. First, conducting an IHC test
`
`after a patient's treatment effectively reads "identifying" out of the claimed
`
`method. "[I]t is well settled that claims are not to be interpreted so as to render
`
`claim language meaningless." Dade Behring Marburg GmbH v. Biosite
`
`Diagn,ostics, Inc., 1998 WL 552962, at* 15 (D. Del. July 24, 1998). If"identifying
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`... a breast cancer patient disposed to respond favorably to a HER2 antibody" is to
`
`have meaning, the identification of the patient must be part of the claimed method.
`
`And if the "wherein" clause is, as Genentech admits, a substantive requirement,
`
`then the ascertainment of the patient's HER2 level "by immunohistochemistry"
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`must be part of the identification.
`
`Second, the claim calls for the identification and treatment of "a breast
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`cancer patient." This reference to the singular patient makes clear that the method
`
`does not contemplate the use of statistical analysis of "samples [ of] patients who
`
`were screened using FISH." Genentech may be correct that "around 9 to 10
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`8
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 10 of 33 PageID #: 14835
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`percent" of patients with a FISH+ test result "will score a O or 1 + by [ICH]." D.I.
`
`121 at 58. But that does not mean that a particular patient with a FISH+ test
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`result will have an ICH score ofO or l+. Indeed, accepting Genentech's cited
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`statistic as true, the odds are that a particular patient with a FISH+ score will not
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`have an ICH score of O or 1 +.
`
`The patent's written description also largely supports Amgen' s reading of
`
`claim 1. It states that "[a] particular advantage of the invention is that it permits
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`selection of patients for treatment who, based on immunohistochemical criteria,
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`would be excluded." '066 patent at 3:22-24; id. at 21 :65-67. This sentence makes
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`clear that the invention is directed towards the identification (i.e., selection) of
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`patients whose ICH scores (i.e., immunohistochemical criteria) would hitherto
`
`have excluded them from treatment because of false-negative ICH test results. The
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`fact that the written description repeatedly refers to an ICH "O or 1 + level" as "a
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`score," see, e.g., id. at 3:26, 4:2, 18:24, and equates scores with "results," see, e.g.,
`
`id. at 18 :54, provides further evidence that the patent contemplates the selection of
`
`a patient based on the results determined by an actual ICH test.
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`The prosecution history also makes clear that the claimed method requires
`
`the performance of an IHC test. Claim 1 originally did not have the "wherein"
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`clause and, therefore, described a method that relied solely on FISH to "detect[ ]
`
`9
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 11 of 33 PageID #: 14836
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`HER2 gene amplification" in a breast tissue sample taken from the patient. D.I.
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`60-5 at J .A. 1719. The Examiner rejected the claim as obvious in light of Baselga,
`
`Pauletti, and Persons. Id. at J.A. 1729-30. Baselga taught that breast cancer
`
`patients "should be screened for overexpression ofHer2 before treatment." Id. at
`
`1730 ( emphasis added). Pauletti and Persons taught that "detection of Her2 gene
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`amplification using FISH is superior to immunochemistry [sic] for assessing Her2
`
`status in patients with breast cancer." Id. Thus, the Examiner concluded that one
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`would have been motivated to use FISH instead ofIHC to assess HER2 status
`
`before treatment, because both Pauletti and Persons taught the advantages of the
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`FISH technique. Id. Genentech overcame the rejection by adding the "wherein"
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`clause to claim 1. Id. at J.A. 1735-36. The Examiner accepted Genentech's
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`amendment, because the "wherein" clause "chang[ ed] the scope of the claims to a
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`method for treating patients that express HER2 at 0 or I+ level by
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`immunohistochemistry and also have a HER2 gene amplification." Id. at J.A.
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`17 40-41 ( emphasis added).
`
`In its remarks to the Examiner, Genentech stated that support for the
`
`amendment could be found in the written description's statement that
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`"[i]dentification of FISH+ patients in the 1 + and O sub-groups might identify
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`subjects who, though failing the IHC criteria for HERCEPTIN® treatment, would
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`10
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 12 of 33 PageID #: 14837
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`likely benefit from HERCEPTIN® treatment" See Id. at J.A. 1736 (asserting that
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`the "wherein" clause amendment is "supported ... by page 28, line 27-29" of the
`
`original specification, which ultimately became lines 19:42-47 of the '066 patent).
`
`Thus, Genentech specifically linked patients who received a failing IHC score to
`
`the disputed claim limitation. Having disclaimed a method that did not require
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`IHC testing, Genentech cannot now recapture claim scope it relinquished during
`
`prosecution. See 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.").
`
`Genentech relies heavily on the following excerpt from the written
`
`description:
`
`[T]he present invention is a powerful adjunct to IHC
`assays for target protein expression level-based selection
`It can also be employed on its own, i.e.,
`of patients.
`without IHC, to provide initial screening and selection of
`patients.
`
`D.I. 138 at 50 (citing '066 patent at 4:34-37) (emphasis added). This statement,
`
`however, was in the original written description before Genentech added the
`
`"wherein" clause to overcome the Examiner's obviousness rejection just discussed.
`
`See D.I. 60-5 at J.A. 1469. Thus, the "present invention" referred to in the quoted
`
`11
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`
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 13 of 33 PageID #: 14838
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`passage describes the method taught by claim 1 before the claim was amended(cid:173)
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`i.e., a method claim that required only FISH testing and not IHC testing.
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`I also do not find compelling Genentech' s two claim differentiation
`
`arguments. First, Genentech argues that language in dependent claim 3 of the '066
`
`patent would be rendered surplusage under Amgen's construction of independent
`
`claim 1. D .I. 13 8 at 51. It points specifically to claim 3 's requirement that "the
`
`patient's breast cancer cells ha[ve] been subjected to immunohistochemistry assay
`
`andfoundto express HER2 at 0 and 1+ level." '066 patent at 23:2-4 (emphasis
`
`added). The doctrine of claim differentiation, however, does not apply when other
`
`claim language distinguishes the claim scope. Mantech Envtl. Corp. v. Hudson
`
`Envtl. Servs., Inc., 152 F.3d 1368, 1376 (Fed. Cir. 1998). Dependent claim 3 states
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`in its entirety: "the method of claim 1 wherein a formaldehyde-fixed tissue sample
`
`containing the patient's breast cancer cells has been subjected to
`
`immunohistochemistry assay and found to express HER2 at a 0 or 1 + level." '066
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`patent at 23: 1-4. Thus, dependent claim 3 is distinguished from and narrower than
`
`independent claim 1 based on the use of a formaldehyde-fixed tissue sample. Id. at
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`1 :30-44, 2:21-35.
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`Second, Genentech argues that the difference between claim 2 of the related
`
`'834 patent-which includes a "wherein" clause that expressly states that a
`
`12
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 14 of 33 PageID #: 14839
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`patient's cells "have been found to express" HER2 at a 0 or 1 + level-and claim 1
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`of the '066 patent-which does not include the past tense language "have been
`
`found"-means that the '066 patent does not require that the patient's cells were
`
`"found to express" such ICH test results. See D.I. 121 at 68. But the "wherein"
`
`clauses of both patents were added by Genentech in response to same objection by
`
`the patent examiner. Compare D.I. 60-5 at J.A. 1526, 1531-34 (the '834 patent)
`
`with D.I. 60-6 at J.A. 2147-49 (the '066 patent). Thus, the slight difference in
`
`wording between the two "wherein" clauses should not be interpreted to suggest
`
`different meanings. See Multiform Desiccants, Inc. v. Medzam, Ltd. 133 F.3d
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`1473, 1480 (Fed. Cir. 1998) ("[T]he doctrine of claim differentiation cannot
`
`broaden claims beyond their correct scope, determined in light of the specification
`
`and the prosecution history and any relevant extrinsic evidence."). The common
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`written description and prosecution history of the '834 and '066 patents suggest
`
`that both sets of claims are properly construed to cover the same subject matter.
`
`See Nystrom v. TREX Co., Inc., 424 F.3d 1136, 1143 (Fed. Cir. 2005) ("Different
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`terms or phrases in separate claims may be construed to cover the same subject
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`matter where [ the intrinsic evidence indicates] that such a reading of the terms or
`
`phrases is proper.").
`
`13
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 15 of 33 PageID #: 14840
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`Accordingly, I will adopt Amgen's proposed construction. The disputed
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`claim limitation in claim 1 of the '066 patent, which states "wherein the patient's
`
`cancer cells express HER2 at a 0 or 1+ level by immunohistochemistry," means
`
`"wherein the patient's cancer cells have been found to express HER2 at a 0 or 1 +
`
`level by any immunohistochemistry test."
`
`B. "Following Fermentation" ('869 patent)
`
`Genentech's "After the end of the cell growth and antibody production phases
`construction
`( which is indicated by a change in the cell culture environment
`that substantially ends cell growth and antibody production)"
`
`Amgen's
`construction
`
`Samsung's
`construction
`
`Court's
`construction
`
`"steps starting with initiation of purification"
`
`"after all the steps that occur in the production fermenter''
`
`I am unable to construe the limitation at this time
`
`1. Background
`
`Claim 1 of the '869 patent, reformatted for clarity, teaches
`
`[a] method for the prevention of the reduction of a disulfide bond in
`an antibody expressed in a recombinant host cell,
`
`comprising, following fermentation, sparging the pre-harvest or
`harvested culture fluid of said recombinant host cell with air,
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`wherein the amount of dissolved oxygen ( dO2) in the pre-harvest or
`harvested culture fluid is at least 10%.
`
`14
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`
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`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 16 of 33 PageID #: 14841
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`'869 patent at 107:44-49 (emphasis added). As stated, the goal of the invention is
`
`to prevent the reduction of disulfide bonds in the antibody expressed in a
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`recombinant host cell.
`
`2. Analysis
`
`The construction of "following fermentation" involves two questions. First,
`
`what is "fermentation?" And second, when does "fermentation" end?
`
`Amgen dodges the first question. It argues that "following fermentation" is
`
`indefinite, because the phrase does not "provide clear guidance for when
`
`'fermentation' ends and 'following fermentation' begins[.]" D.I. 121 at 68.
`
`Amgen does not say that the term "fermentation" itself is indefinite; and although
`
`Amgen argues that the '869 patent "does not use 'fermentation' in the ordinary
`
`way," id., it makes no attempt to explain "the way" the patent does use the term.
`
`Samsung defines "fermentation" as "the steps that occur in the production
`
`fermenter." Id. at 63. Genentech equates "fermentation" with "the cell growth and
`
`antibody production phases." Id.
`
`Although the '869 patent has a lengthy section titled "Definitions," it does
`
`not provide definitions for "fermentation," "fermenter,"5 or "production."
`
`5 "Fermenter" does not appear in the patent. The patent uses but does not define
`"fermentor."
`
`15
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 17 of 33 PageID #: 14842
`
`Language in column 9 of the patent suggests that "fermentation" is synonymous
`
`with "production":
`
`It is emphasized that the fermentation, recovery and
`purification methods described herein are only for
`illustration purposes. The methods of the present invention
`can be combined with any manufacturing process
`developed for the production, recovery and purification of
`recombinant proteins.
`
`'869 patent at 29:4-8 (emphasis added). The use of the words "following
`
`fermentation" immediately after a description of the "production phase" in another
`
`portion of the patent's written description provides further evidence that the
`
`patentee understood fermentation and production to mean the same thing. See id.
`
`at 26:29-41.
`
`Language in column 22 of the patent, however, suggests that fermentation is
`
`not synonymous with production. Specifically, lines 10 through 13 of column 22
`
`provide that "non-specific methods can also be used to prevent the reduction [sic]
`
`of disulfide bond reduction [sic] following fermentation during the recombinant
`
`production of recombinant proteins." This sloppy language is unfortunately typical
`
`of the patent. Because of its two references to "reduction," the sentence describes
`
`an invention that does the exact opposite of what is described in the patent's
`
`Abstract and taught by Claim I-that is, the sentence literally teaches a method to
`
`achieve the prevention of "the reduction of the reduction" of disulfide bonds. I
`
`16
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 18 of 33 PageID #: 14843
`
`assume, therefore, that either the phrase "the reduction of' that precedes "disulfide
`
`bond" or the word "reduction" that follows "disulfide bond" is a typographical
`
`error.
`
`Correcting that error, however, does not cure the sentence's ambiguities.
`
`The corrected sentence (i.e., with only one reference to "reduction") can be read in
`
`two different ways with respect to the relationship between fermentation and
`
`production: either ( 1) the prevention of disulfide bond reduction occurs during a
`
`production process that comes after fermentation, or (2) the prevention of disulfide
`
`bond reduction occurs after the completion of a fermentation process that itself
`
`occurs and is completed during production. In the first case, fermentation occurs
`
`before production. In the second case, fermentation occurs during production. In
`
`both cases, fermentation is neither coterminous with nor the same thing as
`
`production.
`
`Language in Column 1 of the patent only adds to the confusion over the
`
`relationship between fermentation and production:
`
`Usually, to begin the production cycle, a small number of
`transformed recombinant host cells are allowed to grow in
`culture for several days (see, e.g., FIG. 23). Once the cells
`have undergone several rounds of replication, they are
`transferred to a larger container where they are prepared
`to undergo fermentation. The media in which the cells are
`grown and the levels of oxygen, nitrogen and carbon
`
`17
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 19 of 33 PageID #: 14844
`
`dioxide that exist during the production cycle may have a
`significant impact on the production process.
`
`Id. at 1 :52-2:9 ( emphasis added). It is clear from this quoted passage that
`
`fermentation occurs after "several rounds of replication" and that "replication"
`
`refers to the initial growing "in culture for several days" of a small number of
`
`transformed recombinant host cells. Because of the ambiguous phrase ''to begin
`
`the production cycle," however, it is unclear whether this replication is the
`
`beginning of the production cycle or whether it precedes ( and lays the foundation
`
`for) the production cycle. Thus, it is not clear whether the production cycle begins
`
`before fermentation takes place. To compound the confusion, the quoted passage
`
`refers in one sentence to "the production cycle" and "the production process," and
`
`it does not make clear whether these terms refer to the same thing. The confusion
`
`is further compounded because the patent variably uses "production" throughout
`
`18
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 20 of 33 PageID #: 14845
`
`its written description. 6 And although the passage describes the transfer of cells to
`
`a larger container where they are ''prepared to undergo fermentation," it does not
`
`indicate when fermentation begins, let alone when it ends or what it encompasses.
`
`In sum, the patent neither defines fermentation nor allows for a cogent
`
`inference of the term's meaning. Moreover, the parties have not identified any
`
`prior art cited in the patent or anything from the prosecution history that would
`
`enable me, based solely on the intrinsic evidence, to construe reasonably the
`
`meaning of"fennentation" (and, consequently, the meaning of"following
`
`fermentation"). Accordingly, I cannot construe the term based on the intrinsic
`
`evidence and therefore will a convene a hearing to determine if "following
`
`fermentation" can be construed by resort to extrinsic evidence or is invalid for
`
`indefiniteness.
`
`6 For example, at times, the patent equates "production" with "manufacturing."
`Compare '869 patent at 2:17-19 (referring to a "manufacturing, recovery and
`purification process" (emphasis added)) with id. at 25:40-41, 28:38-39 (referring to
`a ''production, recovery and purification" process ( emphasis added)). At other
`times, the patent describes "production" as encompassing "manufacturing" and
`other processes. See, e.g., id. at 2:13-19 ("[D]uring the recombinant production of
`polypeptides ... , it is essential to protect and retain the disulfide bonds throughout
`the manufacturing, recovery and purification process." ( emphasis added)). And at
`other times the patent describes "manufacturing" as encompassing "production"
`and other processes. See, e.g., id. at 29:6-8 (stating that "[t]he methods of the
`present invention can be combined with any manufacturing process developed for
`the production, recovery and purification of recombinant proteins" ( emphasis
`added)).
`
`19
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 21 of 33 PageID #: 14846
`
`C. "A glutamine-free production culture medium" ('983 patent)
`
`Genentech's Construction:
`
`"A production culture medium that is essentially
`free of glutamine"
`
`Defendants' Construction:
`
`Court's Construction:
`
`"culture medium used in the production phase
`that does not contain glutamine when
`formulated"
`
`"a culture medium used in the production phase
`that is not formulated or supplemented with
`glutamine"
`
`1. Background
`
`Claim 1 of the '983 patent, reformatted for clarity, teaches:
`
`A process for producing a polypeptide in a mammalian host cell
`expressing said polypeptide,
`
`comprising culturing the mammalian host cell in a production phase
`of the culture in a glutamine-free production culture medium
`· containing asparagine,
`
`wherein the asparagine is added at a concentration in the range of 7 .5
`mMto 15 mM.
`
`'983 patent at 49:12-17 (emphasis added).
`
`Antibodies, like trastuzumab, are polypeptides, manufactured by culturing
`
`genetically-engineered cells inside tanks called bioreactors. The cells in the
`
`bioreactor are suspended in a solution called a "cell culture medium," which
`
`supplies, among other things, various nutrients for the cells to consume. Cell
`
`culture media are comprised of "base media" ( also sometimes called "basal
`
`20
`
`
`
`Case 1:18-cv-01363-CFC Document 156 Filed 06/14/19 Page 22 of 33 PageID #: 14847
`
`media") and "feed media." Id. at 1 :33-36. A base medium is the initial medium
`
`added to the bioreactor. Feed media are periodically added to the bioreactor to
`
`supplement ( or replenish) the nutrients in the base medium. Base media and feed
`
`media are "formulated" (i.e., made or prepared).
`
`The amino acid glutamine is a nutrient frequently used in the formulation of
`
`base and feed media. Cells not only consume glutamine, they also produce their
`
`own glutamine. As a result, the concentration of glutamine in a cell culture
`
`medium is dynamic, as cells are continually consuming and adding to the
`
`glutamine in the cell culture medium and a manufacturer can also add glutamine at
`
`any time through feed media.
`
`2. Analysis
`
`Defendants assert that "a glutamine-free production culture medium" refers
`
`to a cell culture medium used in the production phase of the antibodies that omits
`
`glutamine from the formulation of the base media and/or feed media. D.I. 121 at
`
`91. Genentech takes the position that "a glutamine-free production culture
`
`medium" refers to the concentration of glutamine in the bioreactor at any point
`
`during the production phase. Id. Because cells themselves
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