Case 0:15-cv-61631-JIC Document 77 Entered on FLSD Docket 12/11/2015 Page 1 of 23
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF FLORIDA
`Case No. 15-cv-61631-JIC/BSS
`
`AMGEN INC. and AMGEN
`MANUFACTURING LIMITED,
`
`Plaintiffs,
`
`vs.
`
`APOTEX INC. and APOTEX CORP.,
`
`Defendants.
`
`PLAINTIFFS’ OPENING CLAIM CONSTRUCTION BRIEF
`
`APOTEX EX1038
`
`Page 1
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`TABLE OF CONTENTS
`
`I.
`
`A.
`
`II.
`III.
`
`A.
`
`B.
`
`C.
`
`1.
`2.
`3.
`4.
`5.
`6.
`7.
`
`1.
`2.
`
`Introduction..........................................................................................................................1
`Patents-in-Suit................................................................................................................1
`The ’138 Patent....................................................................................................... 1
`1.
`The ’427 Patent....................................................................................................... 2
`2.
`The ’784 Patent....................................................................................................... 3
`3.
`Law of Claim Construction..................................................................................................4
`Construction of Disputed Terms..........................................................................................5
`’138 Patent .....................................................................................................................5
`“a protein . . . present in a volume at a concentration of 2.0 g/L or greater”.......... 5
`“refold buffer”......................................................................................................... 7
`“redox component” ................................................................................................. 8
`“final thiol-pair ratio” ............................................................................................. 8
`“redox buffer strength” ........................................................................................... 9
`“2 mM or greater”................................................................................................. 10
`“refold mixture”.................................................................................................... 11
`’427 Patent ...................................................................................................................12
`“chemotherapeutic agent”..................................................................................... 12
`“disease treating-effective amount”...................................................................... 14
`’784 Patent ...................................................................................................................15
`“substantially homogenous” ................................................................................. 15
`“the sequence identified in SEQ. ID No. 1”/“the amino acid sequence
`identified in SEQ. ID No. 1”................................................................................. 16
`“pH sufficiently acidic to selectively activate the alpha amino group”................ 17
`
`1.
`2.
`
`3.
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`CASES
`
`TABLE OF AUTHORITIES
`
`AllVoice Computing PLC v. Nuance Commc’ns, Inc.,
`504 F.3d 1236 (Fed. Cir. 2007)................................................................................................13
`Cias, Inc. v. All. Gaming Corp.,
`504 F.3d 1356 (Fed. Cir. 2007)..............................................................................................7, 8
`Datamize, LLC v. Plumtree Software, Inc.,
`417 F.3d 1342 (Fed. Cir. 2005)..................................................................................................5
`Eli Lilly & Co. v. Aradigm Corp.,
`376 F.3d 1352 (Fed. Cir. 2004)................................................................................................15
`Epos Techs. Ltd. v. Pegasus Techs. Ltd.,
`766 F.3d 1338 (Fed. Cir. 2014)............................................................................................4, 10
`Gillette Co. v. Energizer Holdings, Inc.,
`405 F.3d 1367 (Fed. Cir. 2005)..............................................................................................7, 8
`Hoffer v. Microsoft Corp.,
`405 F.3d 1326 (Fed. Cir. 2005)................................................................................................17
`Kruse Tech. P’ship v. Volkswagen AG,
`544 F. App’x 943 (Fed. Cir. 2013) ............................................................................................7
`Markman v. Westview Instruments, Inc.,
`517 U.S. 370 (1996)...................................................................................................................4
`Nautilus, Inc. v. Biosig Instruments, Inc.,
`134 S. Ct. 2120 (2014).........................................................................................................5, 15
`Novo Indus., L.P. v. Micro Molds Corp.,
`350 F.3d 1348 (Fed. Cir. 2003)................................................................................................17
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005)........................................................................................ passim
`Syngenta Seeds, Inc. v. Monsanto Co.,
`231 F. App’x 954 (Fed. Cir. 2007) ..........................................................................................15
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`135 S. Ct. 831 (2015)...........................................................................................................4, 12
`Vitronics Corp. v. Conceptronic, Inc.,
`90 F.3d 1576 (Fed. Cir. 1996)....................................................................................................4
`
`STATUTES
`
`35 U.S.C. § 112, ¶ 2 (2006) .............................................................................................................5
`42 U.S.C. § 262(l)................................................................................................................1, 14, 15
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`Leahy-Smith America Invents Act,
`Pub. L. No. 112-29, 125 Stat. 284 (2011)..................................................................................5
`
`iii
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`Pursuant to this Court’s Supplemental Scheduling Order [D.E. 58], Plaintiffs Amgen Inc.
`and Amgen Manufacturing Limited (collectively “Amgen”) respectfully submit this brief in
`support of their proposed claim constructions for the patents-in-suit in this case. Pursuant to 42
`U.S.C. § 262(l)(6)(A), the parties agreed that the following three patents owned by Amgen
`would be the subject of this suit. U.S. Patent No. 8,952,138 (“the ’138 Patent”) is entitled
`“Refolding Proteins Using a Chemically Controlled Redox State,” and issued on February 10,
`2015. It is attached hereto as Exhibit 1. U.S. Patent No. 6,162,427 (“the ’427 Patent”), is
`entitled “Combination of G-CSF with a Chemotherapeutic Agent for Stem Cell Mobilization,”
`and issued on December 19, 2000. It is attached hereto as Exhibit 2. U.S. Patent No. 5,824,784
`(“the ’784 Patent”), is entitled “N-Terminally Chemically Modified Protein Compositions and
`Methods,” and issued on October 20, 1998. It is attached hereto as Exhibit 3.
`I.
`Introduction
`A.
`Patents-in-Suit
`1.
`The ’138 Patent
`The use of recombinant DNA technology began in earnest in the early 1980s and was the
`basis of the biotechnology revolution. For the first time, scientists could harness the natural
`mechanisms by which bacterial cells make their own proteins and engineer those bacteria to
`make therapeutically useful non-bacterial proteins. However, while bacteria could be
`manipulated into producing non-bacterial (usually mammalian) proteins, the proteins so
`produced were often non-functional. Proteins are usually produced as chains of amino acids, but
`generally the protein chain must fold into a specific configuration to be functional—a process
`referred to as “protein folding.” In many instances, bacteria can produce non-bacterial protein
`chains but lack the ability to properly fold those chains. The proteins are misfolded and/or
`aggregated with other bacterial proteins and must be artificially unfolded and refolded after
`being separated from the bacteria. The ’138 patent is directed to improved methods for refolding
`proteins made in bacterial or “non-mammalian” cells.1
`As the patent specification notes, prior means of refolding recombinant proteins generally
`relied on the use of very dilute protein solutions and thus necessitated the use of very large
`volumes. ’138 Patent, 1:18–67; Ex. 4 at ¶ 24. However, the need to use very dilute solutions
`
`1 The technical background of the ’138 Patent is further discussed in the Declaration of Dr. Richard Willson
`(“Willson Declaration”), attached as Exhibit 4 to this brief, the contents of which are incorporated herein by
`reference.
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`posed a significant limitation on the production of recombinant proteins on an industrial scale,
`because of the need for huge refolding tanks and the facilities to house them. Ex. 4 at ¶ 24. The
`inventors of the ’138 Patent discovered that efficient refolding of proteins expressed in non-
`mammalian expression systems is impacted by the protein concentration, and by the particular
`conditions relating to breaking (“reducing”) and forming (“oxidizing”) bonds within the protein
`(referred to as “redox” chemistry in the patent). Ex. 4 at ¶ 25 & n.3. Their patent teaches how to
`choose these parameters and others (e.g., the inclusion of one or more chemicals that serve as a
`denaturant, aggregation suppressor, or protein stabilizer) to optimize and enhance the efficiency
`of refolding proteins at concentrations significantly higher, i.e., significantly less dilute, than
`those typically employed in the prior art. Ex. 4 at ¶¶ 30–50. The invention claimed in the ’138
`Patent is, thus, an improved, redox chemistry-based methodology for efficiently refolding
`proteins at high concentration.
`2.
`The ’427 Patent
`The ’427 Patent discloses and claims methods of treatment of diseases that require
`peripheral hematopoietic stem cell transplantation. More specifically, the inventors of the ’427
`Patent discovered that administration of granulocyte colony-stimulating factor (“G-CSF”),
`followed by a chemotherapeutic agent enhances stem cell mobilization.
`Certain cancer therapies are so severe that a patient’s bone marrow—the source of stem
`cells that make up our blood and immune system—is destroyed or “ablated.” The destruction of
`the bone marrow can be reversed by reconstituting the bone marrow with transplanted
`hematopoietic stem cells. Hematopoietic stem cells are the progenitor cells that can differentiate
`and mature into all of the cells that make up the blood and immune system. To reconstitute the
`bone marrow, the hematopoietic stem cells must first be mobilized and collected from the patient
`prior to their undergoing the severe cancer therapy. Before the invention of the ’427 Patent, it
`was known in the art that hematopoietic stem cells could be collected from peripheral blood (i.e.,
`the blood circulating through our veins and arteries) by a process known as leukapheresis.
`Before the invention of the ’427 Patent, it was also known that administering G-CSF alone, a
`chemotherapeutic agent alone, or a chemotherapeutic agent followed by G-CSF could enhance
`the mobilization of stem cells from bone marrow to peripheral blood for collection by
`leukapheresis and subsequent transplantation back to the patient. ’427 Patent, 1:32–54.
`
`2
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`As the ’427 Patent discloses, the prior art approaches typically required several
`leukapheresis sessions to collect sufficient stem cells for a successful transplantation, and these
`sessions are extremely stressful for the patient. ’427 Patent, 1:24–27, 55–57. However, certain
`patients fail to mobilize sufficient stem cells necessary for successful transplant using the prior
`art mobilization approaches. The inventors of the ’427 Patent surprisingly discovered that when
`G-CSF was administered first followed by administration of a chemotherapeutic agent, the yield
`of hematopoietic stem cells in peripheral blood was enhanced compared to the prior art
`approaches. This, in turn, leads to more efficient collection of stem cells in the run-up to ablative
`cancer treatment, i.e., fewer leukaphareses, and, consequently, greater patient comfort. Thus, the
`invention disclosed and claimed in the ’427 Patent is an improved method of treating diseases
`requiring peripheral stem cell transplantation, in which G-CSF and a chemotherapeutic agent (or
`agents), in that order, are administered to enhance stem cell mobilization.
`3.
`The ’784 Patent
`The ’784 Patent discloses and claims modified forms of G-CSF having polyethylene
`glycol (“PEG”) attached to the N-terminus (“N-terminally pegylated G-CSF”), as well as
`methods of making such modified proteins.2
`As discussed in the specification, prior art approaches taught that chemically attaching
`PEG molecules to proteins, referred to as “pegylation,” led to greater stability of the pegylated
`protein, but that the techniques were non-selective, and could attach PEG molecules to any
`reactive group on the protein. ’784 Patent, 1:20–3:5.
`Thus, reaction conditions in the prior art produced heterogeneous populations of
`pegylated proteins, having multiple states of pegylation at various reactive groups. ’784 Patent,
`3:5–15. The production of a heterogeneous population of pegylated proteins was a limitation to
`the use of such proteins in pharmaceutical therapeutic applications, because the lot-to-lot
`biological activity of such a heterogeneous population was unpredictable. ’784 Patent, 3:16–39.
`The invention disclosed and claimed in the ’784 Patent allows the selective pegylation of the N-
`terminus of the G-CSF protein, minimizing the production of G-CSF pegylated at other reactive
`sites. See, e.g., ’784 Patent, 3:47–4:22, claim 1.
`
`2 The chemical structure of filgrastim, which is a non-pegylated, recombinant form of human G-CSF, is provided in
`the Willson Declaration at ¶ 22.
`
`3
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`II.
`
`Law of Claim Construction
`Patent claims define the scope of the patent right. See Phillips v. AWH Corp., 415 F.3d
`1303, 1312 (Fed. Cir. 2005) (en banc) (“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.”) (internal
`quotation marks omitted). Claim construction is an issue of law. Markman v. Westview
`Instruments, Inc., 517 U.S. 370, 376 (1996). It begins with consideration of the intrinsic
`evidence of record: i.e., the text of the claims, the specification, and (if in evidence) the
`prosecution history. Phillips, 415 F.3d at 1313, 1317. Claim terms “are generally given their
`ordinary and customary meaning,” which is “the meaning that the term would have to a person
`of ordinary skill in the art in question at the time of the invention.” Id., 415 F.3d at 1312–13.
`Claims “must be read in view of the specification, of which they are a part,” and the
`specification is usually “the single best guide to the meaning of a disputed term.” Id., 415 F.3d
`at 1315; see also Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996)
`(“[I]t is always necessary to review the specification to determine whether the inventor has used
`any terms in a manner inconsistent with their ordinary meaning.”). When considering the
`specification “it is improper to read limitations from a preferred embodiment described in the
`specification—even if it is the only embodiment—into the claims absent a clear indication in the
`intrinsic record that the patentee intended the claims to be so limited.” Epos Techs. Ltd. v.
`Pegasus Techs. Ltd., 766 F.3d 1338, 1341 (Fed. Cir. 2014).
`While the Court can also consider the patent’s prosecution history (which is intrinsic
`evidence), in addition to the specification, the prosecution history is often “less useful for claim
`construction purposes” than the specification, and because it is an “ongoing negotiation between
`the PTO and the applicant, rather than the final product of that negotiation, it often lacks the
`clarity of the specification.” Philips, 415 F.3d at 1317.
`Courts may also rely on expert testimony, which is extrinsic evidence, to determine the
`state of the art at the time of the invention, and how a person of ordinary skill would have
`understood certain terms of art at that time. Teva Pharm. USA, Inc. v. Sandoz, Inc., 135 S. Ct.
`831, 841 (2015). The court may then use these factual determinations in its legal determination
`of how the person of ordinary skill in the art would have understood such terms as used in the
`patent at issue. Id.
`Claims must “particularly point[] out and distinctly claim[] the subject matter which the
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`applicant regards as [the] invention.” 35 U.S.C. § 112, ¶ 2 (2006).3 This affords “clear notice of
`what is claimed, thereby ‘appris[ing] the public of what is open to them.’ ” Nautilus, Inc. v.
`Biosig Instruments, Inc., 134 S. Ct. 2120, 2129 (2014) (quoting Markman, 517 U.S. at 373). The
`Supreme Court has held that Section 112, second paragraph, requires that claims must, when
`read “in light of the specification and prosecution history, inform those skilled in the art about
`the scope of the invention with reasonable certainty,” or be invalid for indefiniteness. Id. “A
`determination of indefiniteness is a legal conclusion that is drawn from the court’s performance
`of its duty as the construer of claims.” Datamize, LLC v. Plumtree Software, Inc., 417 F.3d
`1342, 1347 (Fed. Cir. 2005).
`III.
`Construction of Disputed Terms
`A.
`’138 Patent
`1.
`“a protein . . . present in a volume at a concentration of 2.0 g/L or
`greater”
`Claim Term
`“a protein . . . present in a
`volume at a concentration of
`2.0 g/L or greater” (claim 1)
`
`Amgen’s Construction
`A protein as it exists in a
`volume before contacting the
`volume with a refold buffer.
`The protein concentration in
`the volume is 2.0 g/L or
`greater.
`Amgen’s proposed construction reflects the clear language of claim 1, set forth below:
`1. A method of refolding a protein expressed in a non-mammalian expression system and
`present in a volume at a concentration of 2.0 g/L or greater comprising:
`(a) contacting the protein with a refold buffer comprising
`a redox component comprising
`a final thiol-pair ratio having a range of 0.001 to 100 and a redox buffer strength
`of 2 mM or greater
`and one or more of:
`(i) a denaturant;
`(ii) an aggregation suppressor; and
`(iii) a protein stabilizer;
`to form a refold mixture;
`(b) incubating the refold mixture; and
`(c) isolating the protein from the refold mixture.
`’138 Patent, claim 1 (emphasis added).
`
`Apotex’s Construction
`A protein . . . present at a
`concentration of 2.0 g/L or
`greater after dilution in a
`refold buffer
`
`3 The pre-America Invents Act statutory provisions apply to the patents-in-suit, as they were filed before September
`16, 2012. Leahy-Smith America Invents Act, Pub. L. No. 112-29, § 9(e), 125 Stat. 284, 297 (2011).
`
`5
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`Claim 1 clearly recites a “volume” that contains the protein at a concentration of 2.0 g/L
`or greater. The claim also recites a “refold buffer,” comprising several elements. These are
`“contacted” with one another, or combined, to form the “refold mixture.” Prior to formation of
`the refold mixture, the volume containing the protein at 2.0 g/L or greater is necessarily separate
`from the refold buffer, otherwise it would not need to be “contacted” with the refold buffer.
`Amgen’s proposed construction matches this logical necessity; Apotex’s proposed construction
`does not.
`The specification fully supports Amgen’s proposed construction. In one instance, “a
`protein is expressed in a non-mammalian expression system” and is further processed to be
`“present in a volume at a concentration of 10 g/L or greater.” ’138 Patent, 10:17–22. This
`results in a protein-containing volume, with a protein concentration of 2.0 g/L or greater, prior to
`any combining step—consistent with Amgen’s proposed construction. This protein-containing
`volume “is then contacted with a refold buffer,” representing the combining step that forms the
`refold mixture. ’138 Patent, 10:22–23. As noted by Prof. Willson, the protein concentration in
`the initial volume, as well as the concentrations of the components of the refold buffer, become
`diluted when contacted with one another. Ex. 4 ¶ 30. The specification twice discloses that after
`such a dilution, the protein concentration in the refold mixture can be as low as 1 g/L (’138
`Patent, 12:40–53, 10:12–16), further condemning Apotex’s proposed construction, which is
`inconsistent with these passages of the specification.
`The specification contains another, similar disclosure, where “a protein is expressed in a
`non-mammalian expression system and is present in a volume at a concentration of 2.0 g/L or
`greater.” ’138 Patent, 11:6–20. This protein is then “contacted with a refold buffer,” and “[a]fter
`the protein has been contacted,” the resulting “refold mixture is then incubated.” ’138 Patent,
`11:9, 64–67; see also ’138 Patent, 14:66–15:8 (describing the combination of the refold buffer
`and an elution volume containing the protein to form a “diluted mixture”); 15:4762 (describing
`the combination of a volume of solubilized inclusion bodies and a refold buffer to form a
`“diluted mixture”). Thus, consistent with the logical import of the claim language, the
`specification repeatedly describes one volume having a protein concentration of 2.0 g/L or
`greater prior to being combined with the refold buffer, to form the refold mixture. Claims “must
`be construed so as to be consistent with the specification, of which they are a part.” Phillips, 415
`
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`F.3d at 1316. The Court should, therefore, adopt Amgen’s proposed construction, which directly
`mirrors this disclosure.
`2.
`“refold buffer”
`Claim Term
`Amgen’s Construction
`“refold buffer”
`A preparation that supports the renaturation of
`(claim 1)
`protein to a biologically active form. The refold
`buffer comprises (1) a redox component and (2)
`one or more of (i) a denaturant, (ii) an
`aggregation suppressor, and (iii) a protein
`stabilizer.
`
`Apotex’s Construction
`A preparation that supports
`the renaturation of protein
`to biologically active form
`
`The parties agree that the “refold buffer” is “a preparation that supports the renaturation
`of protein to a biologically active form,” which is taken directly from the specification. See ’138
`Patent, 1:46–47. Because step (a) of claim 1 contains the word “comprising” twice, the second
`sentence of Amgen’s proposed construction actually reiterates the claim language itself to
`emphasize which elements the refold buffer comprises, specifically a redox component,4 and one
`or more of a denaturant, an aggregation suppressor and a protein stabilizer. ’138 Patent, claim 1.
`This construction is consistent with principles of English grammar. See Kruse Tech. P’ship v.
`Volkswagen AG, 544 F. App’x 943, 949 (Fed. Cir. 2013) (“[A] claim must be read in accordance
`with the precepts of English grammar.” (quoting In re Hyatt, 708 F.2d 712, 714 (Fed. Cir.
`1983))). To the extent that Apotex’s proposed construction would not require the refold buffer
`as recited in claim 1 to comprise the specific elements listed above, it would be improper
`because it would contradict the express claim language. “In the patent claim context the term
`‘comprising’ is well understood to mean ‘including but not limited to.’ ” Cias, Inc. v. All.
`Gaming Corp., 504 F.3d 1356, 1360 (Fed. Cir. 2007); see also Gillette Co. v. Energizer
`Holdings, Inc., 405 F.3d 1367, 1372–74 (Fed. Cir. 2005) (noting that “comprising” indicates that
`the recited feature includes at least the listed elements).
`
`4 As discussed below, the redox component “comprises” its own elements.
`
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`3.
`Claim Term
`“redox component”
`(claim 1)
`
`Apotex’s Construction
`Any thiol-reactive chemical or
`solution comprising such a
`chemical that facilitates a
`reversible thiol exchange with
`another thiol or the cysteine
`residues of a protein
`
`“redox component”
`Amgen’s Construction
`Any thiol-reactive chemical or
`combinations of such chemicals, or
`solution comprising such a chemical or
`chemicals that facilitates a reversible thiol
`exchange with another thiol or the
`cysteine residues of a protein. The redox
`component comprises a final thiol-pair
`ratio in the range of 0.001–100 and a
`redox buffer strength of 2 mM or greater.
`The parties at least agree that the “redox component” is “any thiol-reactive chemical or
`solution comprising such a chemical, . . . that facilitates a reversible thiol exchange with another
`thiol or the cysteine residues of a protein,” as set forth in the specification. See ’138 Patent,
`6:63–66. Amgen’s proposed construction further reflects that thiol-reactive chemicals may be
`used in combination, as indicated by the specification. See ’138 Patent, 6:66–7:2, 11:57–63
`(noting the recited compounds or “combinations thereof” could make up the redox component);
`see also ’138 Patent, 3:38–42, 8:30–33, 10:53–54, and 12:49. Furthermore, to ensure that the
`second use of the term “comprising” in step (a) is clear, the second sentence of Amgen’s
`proposed construction reiterates the claim language itself to explicitly note that it is the “redox
`component” that comprises the “final thiol-pair ratio” and the “redox buffer strength,” two
`calculated terms as discussed below. Amgen’s proposed construction reflects this express claim
`language, and should therefore be adopted. See Cias, Inc., 504 F.3d at 1360; see also Gillette
`Co., 405 F.3d at 1372–74.
`4.
`“final thiol-pair ratio”
`Claim Term
`Amgen’s Construction
`“final thiol-pair ratio”
`Defined by the following
`(claim 1)
`
`Apotex’s Construction
`The relationship of the reduced and
`oxidized redox species used in the
`refold buffer as defined in Equation 1:
`
`[reductant]ଶ
`,
`[oxidant]
`
`Where the ratio is the ratio in the refold
`mixture
`The parties agree the final thiol-pair ratio is defined by Equation 1 set forth at column 6,
`lines 23–28, but they dispute whether the final thiol-pair ratio refers to a ratio of concentrations
`
`equation:[ݎ݁݀ݑܿݐܽ݊ݐ]ଶ
`,
`[݋ݔ݅݀ܽ݊ݐ]
`
`where the concentrations are
`the concentrations in the redox
`component.
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`of the oxidant and reductant in the redox component, as in Amgen’s proposed construction, or in
`the refold mixture, as in Apotex’s proposed construction. The plain language of claim 1 recites a
`redox component that is not initially part of the refold mixture, and in that context, the claim
`recites the final thiol-pair ratio as being an element of the redox component. See Phillips, 415
`F.3d at 1314 (“[T]he context of the surrounding words of the claim also must be considered in
`determining the ordinary and customary meaning of those term.”). Thus, the plain language of
`claim 1 recites the final thiol-pair ratio of the redox component prior to the formation of the
`refold mixture. Amgen’s proposed construction mirrors this plain language of the claim. The
`specification also recites the final thiol-pair ratio of the redox component prior to the formation
`of the refold mixture, consistent with Amgen’s proposed construction. See, e.g., ’138 Patent,
`11:64–67 (“After the protein has been contacted with a redox component having the recited thiol
`pair ratio and redox buffer strength to form a refold mixture, the refold mixture is then incubated
`for a desired period of time.”); see also ’138 Patent, 10:24–30, 11:11–17, 11:40–46. Apotex’s
`construction requires that the final thiol-pair ratio is that after formation of the refold mixture.
`This improperly contradicts the plain language of the claim.
`5.
`“redox buffer strength”
`Claim Term
`Amgen’s Construction
`“redox buffer
`Also called “buffer thiol strength,” “thiol-pair
`strength” (claim
`buffer strength,” or “thiol-pair strength,”
`1)
`defined by the following equation:
`
`2[݋ݔ݅݀ܽ݊ݐ]+[ݎ݁݀ݑܿݐܽ݊ݐ],
`
`Apotex’s Construction
`
`where the concentrations are
`the concentrations in the
`refold mixture
`
`2[݋ݔ݅݀ܽ݊ݐ]+[ݎ݁݀ݑܿݐܽ݊ݐ],
`
`where the concentrations are the
`concentrations in the redox component.”
`The parties agree the redox buffer strength is defined by Equation 2 set forth at column 6,
`lines 35–38, but they dispute whether the redox buffer strength refers to concentrations of the
`oxidant and reductant in the redox component, as in Amgen’s proposed construction, or in the
`refold mixture, as in Apotex’s proposed construction. The plain language of claim 1 recites a
`redox component that is not initially part of the refold mixture, and in that context, the claim
`recites the redox buffer strength as being an element of the redox component. See Phillips, 415
`F.3d at 1314 (“[T]he context of the surrounding words of the claim also must be considered in
`determining the ordinary and customary meaning of those term.”). Thus, the plain language of
`claim 1 recites the redox buffer strength of the redox component prior to the formation of the
`refold mixture. Amgen’s proposed construction mirrors this plain language of the claim. The
`
`9
`
`Page 13
`
`

`

`Case 0:15-cv-61631-JIC Document 77 Entered on FLSD Docket 12/11/2015 Page 14 of 23
`
`Apotex’s Construction
`“2 mM or greater, wherein the redox buffer
`strength is effectively bounded at a maximum of
`100 mM”
`
`specification also recites the redox buffer strength of the redox component prior to the formation
`of the refold mixture, consistent with Amgen’s proposed construction. See, e.g., ’138 Patent,
`11:64–67 (“After the protein has been contacted with a redox component having the recited thiol
`pair ratio and redox buffer strength to form a refold mixture, the refold mixture is then incubated
`for a desired period of time.”); see also ’138 Patent, 10:24–30, 11:11–17, 11:40–46. Apotex’s
`construction improperly contradicts the plain language of the claim.
`6.
`“2 mM or greater”
`Claim Term
`Amgen’s Construction
`“2 mM or
`No construction is
`greater” (claim 1)
`necessary. The term
`should be given its plain
`and ordinary meaning.
`A person of ordinary skill in the art at the time of the invention would understand that “2
`mM or greater” has a plain meaning, and refers to a redox buffer strength of 2 millimolar or
`greater. “[W]ords of a claim are generally given their ordinary and customary meaning” which
`is “the meaning that the term would have to a person of ordinary skill in the art in question at the
`time of the invention.” Phillips, 415 F.3d at 1312 (internal quotation marks omitted). The Court
`should, therefore, apply this plain meaning to the term “2 mM or greater.”
`The Court should reject Apotex’s proposed construction because it reads in the limitation
`“redox buffer strength is effectively bounded at a maximum of 100 mM” from the specification,
`which is improper. See Epos Techs. Ltd., 766 F.3d at 1341. Rather than representing intentional
`limits on the scope of the claim, the embodiments that describe upper limits on the redox buffer
`strength are merely demonstrative of particular conditions used in the examples, and not an
`absolute limit on range of concentration. Phillips, 415 F.3d at 1323 (“One of the best ways to
`teach a person of ordinary skill in the art how to make and use the invention is to provide an
`example of how to practice the invention in a particular case.”). The specification explains that
`the method can be applied to “any type of protein,” ’138 Patent, 4:23–24, and that the
`“[o]ptimization of the buffer thiol strength and system thiol pair ratio can be tailored to a
`particular protein.” ’138 Patent, 4:55–58; 9:10–30. This indicates to a person of ordinary skill in
`the art that, depending on the protein to be refolded, the optimal redox buffer strength will need
`to be determined empir