Case 0:15-cv-61631-JIC Document 119 Entered on FLSD Docket 04/07/2016 Page 1 of 12
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`UNITED STATES DISTRICT COURT
`SOUTHERN DISTRICT OF FLORIDA
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`CASE NO. 15-61631-CIV-COHN/SELTZER
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`AMGEN, INC., and AMGEN
`MANUFACTURING LIMITED,,
`
`Plaintiffs,
`
`v.
`
`APOTEX INC. and APOTEX CORP.,
`
`Defendants.
`______________________________/
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`CLAIM CONSTRUCTION ORDER
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`THIS CAUSE has come before the Court upon the parties’ motions and briefs
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`(DE [76], [77], [82], [83], [89], and [90]) for the construction of certain claim language in
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`U.S. Patents Nos. 8,952,138 (the “’138 Patent”) and 6,162,427 (the “’427 Patent”). 1
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`The ’138 patent is entitled “Refolding Proteins Using a Chemically Controlled Redox
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`State” and was issued on February 10, 2015. The ’427 patent is entitled “Combination
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`of G-SF with a Chemotherapeutic Agent for Stem Cell Mobilization” and was issued on
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`December 19, 2000. The patents are owned by Amgen, Inc., and Amgen
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`Manufacturing Limited (collectively “Amgen”).
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`Amgen develops, manufactures, and markets biologic therapy products
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`including Neulasta (a pegylated filgrastim product) and Neupogen (a filgrastim product).
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`Neulesta and Neupogen are, in the simplest of terms, biologic therapies which consist
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`A third patent, Patent No. 5,824,784 (the “’784 Patent”) has expired and is not
`1
`considered in this Order.
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`APOTEX EX1037
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`of bacterial proteins that stimulate production of white blood cells in patients
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`undergoing chemotherapy and/or stem cell transplants. The ’138 patent is directed to
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`improved methods for refolding the proteins made in bacterial cells, allowing for
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`industrial scale protein production. The ’427 patent provides an improved means of
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`enhancing the mobilization of hematopoietic stem cells in patients undergoing stem cell
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`transplants. Amgen has asserted patent claims against Apotex Inc. and Apotex Corp.
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`(collectively “Apotex”) based upon Apotex’s filings with the U.S. Food & Drug
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`Administration seeking approval to market biosimilar versions of Amgen’s products.
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`The parties dispute the meaning of several claim terms in the ’138 and ’427
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`patents. The Court held a hearing on February 5, 2016, at which both parties
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`presented extensive argument. The parties agreed to rely upon the evidence and
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`affidavits in the record and, therefore, did not present any testimony.
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`I.
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`LEGAL STANDARD
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`The fundamental purpose of a patent is to give notice to others of the subject
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`matter as to which the inventor claims exclusive rights. See Oakley Inc. v. Sunglass
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`Hut Int’l, 316 F.3d 1331, 1340 (Fed. Cir. 2003). Thus, the focus of claim construction is
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`ascertaining how one of ordinary skill in the relevant art would have understood the
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`claim language at the time of the invention. See Phillips v. AWH Corp., 415 F.3d 1303,
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`1312-13 (Fed. Cir. 2005) (en banc).
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`With two exceptions not relevant here, the words used in a patent are evaluated
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`by determining their “ordinary and customary meaning.” Id. To ascertain that meaning,
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`the Court “looks to ‘those sources available to the public that show what a person of
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`skill in the art would have understood disputed claim language to mean.’” Id. at 1314
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`Case 0:15-cv-61631-JIC Document 119 Entered on FLSD Docket 04/07/2016 Page 3 of 12
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`(quoting Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111,
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`1116 (Fed. Cir. 2004)). Those sources include “the words of the claims themselves, the
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`remainder of the specification, the prosecution history, and extrinsic evidence
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`concerning relevant scientific principles, the meaning of technical terms, and the state
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`of the art.” Phillips, 415 F.3d at 1314 (quoting Innova, 381 F.3d at 1116).
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`The Court may also rely on expert testimony, which is extrinsic evidence, to
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`determine the state of the art at the time of the invention, and how a person of ordinary
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`skill would have understood certain terms of art at that time. Teva Pharm. USA, Inc. v.
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`Sandoz, Inc., 135 S. Ct. 831, 841 (2015). The Court may then use these factual
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`determinations in its legal determination of how the person of ordinary skill in the art
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`would have understood such terms as used in the patent at issue. Id.
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`“It is a ‘bedrock principle’ of patent law that ‘the claims of a patent define the
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`invention to which the patentee is entitled the right to exclude.’” Phillips, 415 F.3d at
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`1312 (quoting Innova, 381 F.3d at 1115). Because the Court must examine the patent
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`as a whole, there is a presumption that claim terms normally will be used consistently
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`throughout a patent, such that “the usage of a term in one claim can often illuminate the
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`meaning of the same term in other claims.” Id. at 1314. Terms also must be construed
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`in light of the entirety of the patent, not just in the context of the particular claim(s) in
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`which they appear. Phillips, 415 F.3d at 1313. The claim language must be read in
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`conjunction with the description in the specification. “‘Usually, [the specification] is
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`dispositive; it is the single best guide to the meaning of a disputed term.’” Id. at 1315
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`(quoting Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996)).
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`Even so, the Court must be careful not to import limitations from the specification’s
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`embodiment(s) into the claims. Phillips, 415 F.3d at 1319-20.
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`II.
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`ANALYSIS
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`A.
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`The ’138 Patent
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`The parties identified seven disputed claim terms in the ’138 Patent. The terms
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`appear in claim 1, which reads as follows:
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`1. A method of refolding a protein expressed in a non-mammalian expression
`system and present in a volume at a concentration of 2.0g/L or greater
`comprising:
`(a) contacting the protein with a refold buffer comprising a
`redox component comprising a redox component comprising
`a final thiol-pair ratio having a range of 0.001 to 100 and a
`redox buffer strength of 2mM or greater and one or more of:
`(i)
`a denaturant;
`(ii)
`an aggregation suppressor; and
`(iii)
`a protein stablizer;
`to form a refold mixture;
`(b)
`incubating the refold mixure; and
`(c)
`isolating the protein from the refold mixture.
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`The first term at issue is “a protein . . . present in a volume at a concentration of
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`2.0g/L or greater. . . .” Amgen’s construction is: “A protein as it exists in a volume
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`before contacting the volume with a refold buffer. The protein concentration in the
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`volume is 2.0g/L or greater.” Apotex’s construction is: “a protein . . . present at a
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`concentration of 2.0g/L or greater after dilution in a refold buffer.” The sole point of
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`difference between the parties is whether the concentration of the protein is determined
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`before or after it is contacted with the refold buffer.
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`The Court agrees with Amgen that the concentration of the protein is determined
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`before it is contacted with the refold buffer. This construction is consistent with the
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`language of the claim itself, as well as the specification. Phillips, 415 F.3d at 1316.
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`Under the terms of the claim, the protein which is being refolded, is “expressed in a
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`non-mammalian expression and present in a volume at a concentration of 2.0g/L or
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`greater. . . .” DE [77-1] ’138 Patent 2:52-54 (emphasis added). The specification
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`makes clear that the protein in a volume at a concentration of 2.0g/L or greater “is
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`contacted with a refold buffer . . . “ ’138 Patent 11:6-9. This is also consistent with the
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`Background of the Invention, which states that “[u]ntil the present disclosure, these
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`types of complex molecules could not be refolded at high concentrations, i.e.,
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`concentrations of 2.0g/L and higher, with any meaningful degree of efficiency on a
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`small scale, and notably not on an industrial scale.” DE [77-1], ’138 Patent 2:17-21.
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`Accordingly, the Court construes the claim term “a protein . . . present in a volume at a
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`concentration of 2.0g/L or greater. . . .” as “A protein as it existed in a volume before
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`contacting the volume with a refold buffer. The protein concentration in the volume is
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`2.0g/L or greater.”
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`The second disputed claim term is “refold buffer.” Amgen’s construction is: “A
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`preparation that supports the renaturation of protein to a biologically active form. The
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`refold buffer comprises (1) a redox component and (2) one or more of (i) a denaturant,
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`(ii) an aggregation suppressor, and (iii) a protein stabilizer.” Apotex’s construction is: “A
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`preparation that supports the renaturation of protein to a biologically active form.”
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`Apotex argues that the components of the refold buffer are already expressly recited as
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`limitations within claim 1, and so their inclusion in the construction of “refold buffer” is
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`redundant and unnecessary.
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`The Court finds that Amgen’s construction of the claim term “refold buffer” is
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`consistent with the language of the claim and the principles of English grammar, and
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`that Apotex’s proposed construction could lead to the creation of a refold buffer that
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`does not contain the components required by the claim itself. This would be improper.
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`Gillette Co. v. Energizer Holdings, Inc., 405 F.3d 1367, 1372-74 (Fed. Cir. 2005) (the
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`word “comprising” indicates that the recited feature includes at least the listed
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`elements). For this reason, the Court construes the term “refold buffer” as “a
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`preparation that supports the renaturation of protein to a biologically active form. The
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`refold buffer comprises (1) a redox component and (2) one or more of (i) a denaturant,
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`(ii) an aggregation suppressor, and (iii) a protein stabilizer.”
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`The third disputed claim term is “redox component.” Amgen construes this term
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`to mean “any thiol-reactive chemical or combinations of such chemicals, or solution
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`comprising such a chemical or chemicals that facilitates a reversible thiol exchange with
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`another thiol or the cysteine residues of a protein. The redox component comprises a
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`final thiol-pair ratio in the range of 0.001-100 and a redox buffer strength of 2mM or
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`greater.” Apotex’s construction is: “Any thiol-reactive chemical or solution comprising
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`such a chemical that facilitates a reversible thiol exchange with another thiol or the
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`cysteine residues of a protein.”
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`Again, Apotex argues that Amgen’s construction is redundant, because it
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`contains terms already expressed in the claim itself. As stated above, the construction
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`offered by Amgen is consistent with the terms of the claim and reflects the express
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`claim language. Amgen’s construction does not render any other portion of the claim
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`superfluous. Accordingly, the Court construes the term “redox component” as “Any
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`thiol-reactive chemical or combinations of such chemicals, or solution comprising such
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`a chemical or chemicals that facilitates a reversible thiol exchange with another thiol or
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`the cysteine residues of a protein. The redox component comprises a final thiol-pair
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`ratio in the range of 0.001-100 and a redox buffer strength of 2mM or greater.”
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`The fourth disputed claim term is “final thiol-pair ratio.” Amgen’s construction is:
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`“Defined by the following equation:
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`[reductant]2
`[oxidant]
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`where the concentrations are the concentrations in the redox component.”
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`Apotex’s construction is: “The relationship of the reduced and oxidized redox species
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`used in the refold buffer as defined in Equation 1:
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`[reductant]2
`[oxidant]
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`where the ratio is the ratio in the refold mixture.” The parties agree that the final thiol-
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`pair ratio is based on the concentrations of the reductant and the oxidant in a solution,
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`as defined by Equation 1 set forth at column 6, lines 23-28, but they disagree as to
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`whether the ratio applies to the redox component (Amgen) or the refold mixture
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`(Apotex).
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`Again, the plain language of the claim reveals that the redox component is
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`comprised of a final thiol-pair ratio and one or more listed elements, combined “to form
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`a refold mixture.” This indicates that the ratio applies to the redox component and not
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`to the refold mixture. The specification supports this conclusion as well, where it states:
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`“After the protein has been contacted with a redox component having the recited thiol-
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`pair ratio and redox buffer strength to form a refold mixture, the refold mixture is then
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`incubated for a desired period of time.” DE [77-1], ’138 Patent 11:64-67. For this
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`reason, the Court constructs the term “final thiol-pair ratio” to mean “Defined by the
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`following equation:
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`[reductant]2
`[oxidant]
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`where the concentrations are the concentrations in the redox component.”
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`The fifth disputed claim term is “redox buffer strength.” Amgen’s construction is:
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`“Also called ‘buffer thiol strength,’ ‘thiol-pair buffer strength,’ or ‘thiol-pair strength,’
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`defined by the following equation: 2[oxidant] + [reductant] where the concentrations are
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`the concentrations in the redox component.” Apotex’s construction is: “2[oxidant] +
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`[reductant] where the concentrations are the concentrations in the refold mixture.” The
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`parties agree on the equation for defining the redox buffer strength, but dispute which
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`solution (the redox component or the refold mixture) should be used as the basis for
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`calculating the redox buffer strength.
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`The Court finds that the plain language of claim 1 recites the redox buffer
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`strength of the redox component prior to the formation of the refold mixture; the claim
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`language is careful to say which value is measured at which stage. Adopting Apotex’s
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`proposed construction would require the Court to re-write the claim. Additionally,
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`Apotex’s proposed construction is contradicted by the teachings of the specification and
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`the rebuttal declaration of Richard C. Willson, Ph.D DE [83-1]. The values of the
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`concentrations of oxidants and reductants used in the equations in the specification are
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`based on the volume of the redox component, and not the refold mixture. Accordingly,
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`based upon the language of the claim and the specification, the Court construes the
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`term “redox buffer strength” as follows: “Also called ‘buffer thiol strength,’ ‘thiol-pair
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`buffer strength,’ or ‘thiol-pair strength,’ defined by the following equation: 2[oxidant] +
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`[reductant] where the concentrations are the concentrations in the redox component.”
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`The sixth claim term in dispute is the term “refold mixture.” Amgen’s construction
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`is: “A mixture formed from contacting (1) the volume in which the concentration of
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`protein is 2.0g/L or greater with (2) the refold buffer. The refold mixture has a high
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`protein concentration, where “high protein concentration” is at or above about 1g/L
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`protein.” Apotex’s construction is: “A mixture formed from contacting the protein and
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`the refold buffer.” Apotex’s proposed construction of the term “refold mixture” derives
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`from its proposed construction that the term “a protein . . . present in a volume at a
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`concentration of 2.0g/L or greater. . . .” is “a protein . . . present at a concentration of
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`2.0g/L or greater after dilution in a refold buffer.” The Court has rejected that
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`construction and rejects Apotex’s construction of the term “refold mixture” as well. The
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`language of the claim, the specification and the state of the prior art support the
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`conclusion that the refold mixture of claim 1 of the ’138 Patent would be interpreted by
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`a person of ordinary skill in the art to have a minimum or “floor” concentration at or
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`above about 1g/L. Thus, the Court constructs the term “refold mixture” as “a mixture
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`formed from contacting (1) the volume in which the concentration of protein is 2.0g/L or
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`greater with (2) the refold buffer. The refold mixture has a high protein concentration,
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`where “high protein concentration” is at or above about 1g/L protein.”
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`The seventh, and last, disputed claim term of the ’138 Patent is the term “2mM
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`or greater.” Amgen’s construction is: “No construction necessary. The term should be
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`given its plain and ordinary meaning.” Apotex’s construction is: “2mM or greater,
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`wherein the redox buffer strength is effectively bounded at a maximum of 100mM.”
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`Apotex argues that the specification repeatedly states that the “thiol-pair buffer strength
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`is effectively bounded at a maximum of 100mM” and, therefore, “the specification
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`makes it abundantly clear to one skilled in the art that the patent is using the term ‘2mM
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`or greater’ to describe a redox buffer strength between 2mM and 100mM.” DE [76, p.
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`19]. To the contrary, Amgen argues that the maximum of 100mM referred to in the
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`specification is merely an embodiment, which does not impose a limitation on the
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`language of the claim. Thus, argues Amgen, the term “2mM or greater” means what it
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`says, with no limitation.
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`“It is the claims that define the metes and bounds of the patentee’s invention.
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`Phillips, 415 F.3d at 1313. The patentee is free to choose a broad term and expect to
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`obtain the full scope of its plain and ordinary meaning unless the patentee explicitly
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`redefines the term or disavows its full scope.” Thorner v. Sony Computer Entm’t Am.
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`LLC, 669 F.3d 1362, 1367 (Fed. Cir. 2012). “[O]ne purpose for examining the
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`specification is to determine if the patentee has limited the scope of the claims.”
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`Scimed Life Sys., Inc. v. Advanced Cardiovascular Sys., Inc., 242 F.3d 1337,1341 (Fed.
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`Cir. 2001) (quoting Watts v. XL Sys., Inc., 232 F.3d 877, 882 (Fed. Cir. 2000)). The
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`Court finds that the specification does, indeed, impose an upper limit of 100mM on the
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`thiol-pair buffer strength. The Court is particularly convinced by the fact that the
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`specification repeatedly sets forth a suggested range of redox buffer strengths, yet
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`each time specifically limits the possible ranges, “wherein the thiol-pair buffer strength is
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`effectively bounded at a maximum of 100mM.” Accordingly, the Court constructs the
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`claim term “”2mM or greater” to mean “2mM or greater, wherein the redox buffer
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`strength is effectively bounded at a maximum of 100mM.”
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`B.
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`The ’427 Patent
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`The parties identify two disputed claim terms in the ’427 Patent. They are
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`located in claims 1 and 4, which are set forth below:
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`1. A method of treating a disease requiring peripheral stem cell
`transplantation in a patient in need of such treatment,
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`comprising
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`administering to the patient a hematopoietic stem cell mobilizing-effective
`amount of G-CSF; and
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`thereafter administering to the patient a disease treating-effective amount
`of at least one chemotherapeutic agent.
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`4. The method of claim 1, wherein the at least one chemotherapeutic
`agent opens the enothelial barrier of the patient to render the endothelial
`barrier permeable for stem cells.
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`The first term in dispute in the ’427 Patent is “chemotherapeutic agent” as found
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`in claim 1. Amgen’s construction is: “Exogenous substance capable of damaging or
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`destroying microorganisms, parasites or tumor cells.” Apotex’s construction is:
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`“Therapeutic agents which open the endothelial barrier, rendering it permeable for stem
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`cells and/or exogenous substances suited and used to damage or destroy
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`microorganisms, parasites or tumor cells.” The Court concludes, based upon claim 1
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`and the dependent claim 4, as well as the use of the term “chemotherapeutic agent” in
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`the specification, that the term “chemotherapeutic agent” in claim 1 is not limited to
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`therapeutic agents which open the endothelial barrier. Accordingly, the Court
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`constructs the claim term “chemotherapeutic agent” to mean “Exogenous substance
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`capable of damaging or destroying microorganisms, parasites or tumor cells.”
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`The final term in dispute in the ’427 Patent is the phrase “disease treating-
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`effective amount.” Apotex argues that this term is indefinite, thus invalidating the
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`patent. Amgen’s construction is: “An amount sufficient to enhance the mobilization of
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`stem cells for recovery from the blood for subsequent peripheral transplantation.”
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`The specification explains that the treatment covered by the claim is for diseases
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`that require stem cell transplantation and that the treatment “depends on the
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`mobilization of the bone marrow stem cells . . . .” The specification also provides a
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`dosage range for the chemotherapeutic agent of “0.05 - 100 mg/kg/day.” Accordingly,
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`the Court agrees with Amgen that “[a] person of ordinary skill in the art would
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`understand that a dose of chemotherapeutic agent within this range, when administered
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`after G-CSF, would be the “disease treating-effective amount” needed to achieve the
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`goal of enhancing stem cell mobilization for recovery from blood and subsequent
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`transplantation.” DE [77], p.19. Thus, the Court constructs the term “disease treating-
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`effective amount” to mean “[a]n amount sufficient to enhance the mobilization of stem
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`cells for recovery from the blood for subsequent peripheral transplantation.”
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`It is so ORDERED.
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`DONE AND ORDERED in Chambers, Fort Lauderdale, Florida, this 7th day of
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`April, 2016.
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`Copies provided to:
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`Counsel of record via CM/ECF
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