Amgen Inc. et al v. Apotex Inc. et al

Filing 119

CLAIM CONSTRUCTION ORDER. See Order for details. Signed by Judge James I. Cohn on 4/7/2016. (sry)

UNITED STATES DISTRICT COURT
SOUTHERN DISTRICT OF FLORIDA
CASE NO. 15-61631-CIV-COHN/SELTZER

AMGEN, INC., and AMGEN
MANUFACTURING LIMITED,,
Plaintiffs,
v.
APOTEX INC. and APOTEX CORP.,
Defendants.
______________________________/
CLAIM CONSTRUCTION ORDER
THIS CAUSE has come before the Court upon the parties’ motions and briefs
(DE [76], [77], [82], [83], [89], and [90]) for the construction of certain claim language in
U.S. Patents Nos. 8,952,138 (the “’138 Patent”) and 6,162,427 (the “’427 Patent”).1
The ’138 patent is entitled “Refolding Proteins Using a Chemically Controlled Redox
State” and was issued on February 10, 2015. The ’427 patent is entitled “Combination
of G-SF with a Chemotherapeutic Agent for Stem Cell Mobilization” and was issued on
December 19, 2000. The patents are owned by Amgen, Inc., and Amgen
Manufacturing Limited (collectively “Amgen”).
Amgen develops, manufactures, and markets biologic therapy products
including Neulasta (a pegylated filgrastim product) and Neupogen (a filgrastim product).
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
considered in this Order.

of bacterial proteins that stimulate production of white blood cells in patients
undergoing chemotherapy and/or stem cell transplants. The ’138 patent is directed to
improved methods for refolding the proteins made in bacterial cells, allowing for
industrial scale protein production. The ’427 patent provides an improved means of
enhancing the mobilization of hematopoietic stem cells in patients undergoing stem cell
transplants. Amgen has asserted patent claims against Apotex Inc. and Apotex Corp.
(collectively “Apotex”) based upon Apotex’s filings with the U.S. Food & Drug
Administration seeking approval to market biosimilar versions of Amgen’s products.
The parties dispute the meaning of several claim terms in the ’138 and ’427
patents. The Court held a hearing on February 5, 2016, at which both parties
presented extensive argument. The parties agreed to rely upon the evidence and
affidavits in the record and, therefore, did not present any testimony.
I.

LEGAL STANDARD
The fundamental purpose of a patent is to give notice to others of the subject

matter as to which the inventor claims exclusive rights. See Oakley Inc. v. Sunglass
Hut Int’l, 316 F.3d 1331, 1340 (Fed. Cir. 2003). Thus, the focus of claim construction is
ascertaining how one of ordinary skill in the relevant art would have understood the
claim language at the time of the invention. See Phillips v. AWH Corp., 415 F.3d 1303,
1312-13 (Fed. Cir. 2005) (en banc).
With two exceptions not relevant here, the words used in a patent are evaluated
by determining their “ordinary and customary meaning.” Id. To ascertain that meaning,
the Court “looks to ‘those sources available to the public that show what a person of
skill in the art would have understood disputed claim language to mean.’” Id. at 1314
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(quoting Innova/Pure Water, Inc. v. Safari Water Filtration Sys., Inc., 381 F.3d 1111,
1116 (Fed. Cir. 2004)). Those sources include “the words of the claims themselves, the
remainder of the specification, the prosecution history, and extrinsic evidence
concerning relevant scientific principles, the meaning of technical terms, and the state
of the art.” Phillips, 415 F.3d at 1314 (quoting Innova, 381 F.3d at 1116).
The Court 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.
“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, 415 F.3d at
1312 (quoting Innova, 381 F.3d at 1115). Because the Court must examine the patent
as a whole, there is a presumption that claim terms normally will be used consistently
throughout a patent, such that “the usage of a term in one claim can often illuminate the
meaning of the same term in other claims.” Id. at 1314. Terms also must be construed
in light of the entirety of the patent, not just in the context of the particular claim(s) in
which they appear. Phillips, 415 F.3d at 1313. The claim language must be read in
conjunction with the description in the specification. “‘Usually, [the specification] is
dispositive; it is the single best guide to the meaning of a disputed term.’” Id. at 1315
(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
embodiment(s) into the claims. Phillips, 415 F.3d at 1319-20.
II.

ANALYSIS
A.

The ’138 Patent

The parties identified seven disputed claim terms in the ’138 Patent. The terms
appear in claim 1, which reads as follows:
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.
The first term at issue is “a protein . . . present in a volume at a concentration of
2.0g/L or greater. . . .” Amgen’s construction is: “A protein as it exists in a volume
before contacting the volume with a refold buffer. The protein concentration in the
volume is 2.0g/L or greater.” Apotex’s construction is: “a protein . . . present at a
concentration of 2.0g/L or greater after dilution in a refold buffer.” The sole point of
difference between the parties is whether the concentration of the protein is determined
before or after it is contacted with the refold buffer.
The Court agrees with Amgen that the concentration of the protein is determined
before it is contacted with the refold buffer. This construction is consistent with the
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
non-mammalian expression and present in a volume at a concentration of 2.0g/L or
greater. . . .” DE [77-1] ’138 Patent 2:52-54 (emphasis added). The specification
makes clear that the protein in a volume at a concentration of 2.0g/L or greater “is
contacted with a refold buffer . . . “ ’138 Patent 11:6-9. This is also consistent with the
Background of the Invention, which states that “[u]ntil the present disclosure, these
types of complex molecules could not be refolded at high concentrations, i.e.,
concentrations of 2.0g/L and higher, with any meaningful degree of efficiency on a
small scale, and notably not on an industrial scale.” DE [77-1], ’138 Patent 2:17-21.
Accordingly, the Court construes the claim term “a protein . . . present in a volume at a
concentration of 2.0g/L or greater. . . .” as “A protein as it existed in a volume before
contacting the volume with a refold buffer. The protein concentration in the volume is
2.0g/L or greater.”
The second disputed claim term is “refold buffer.” Amgen’s construction is: “A
preparation that supports the renaturation of 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 is: “A
preparation that supports the renaturation of protein to a biologically active form.”
Apotex argues that the components of the refold buffer are already expressly recited as
limitations within claim 1, and so their inclusion in the construction of “refold buffer” is
redundant and unnecessary.
The Court finds that Amgen’s construction of the claim term “refold buffer” is
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
does not contain the components required by the claim itself. This would be improper.
Gillette Co. v. Energizer Holdings, Inc., 405 F.3d 1367, 1372-74 (Fed. Cir. 2005) (the
word “comprising” indicates that the recited feature includes at least the listed
elements). For this reason, the Court construes the term “refold buffer” as “a
preparation that supports the renaturation of 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.”
The third disputed claim term is “redox component.” Amgen construes this term
to mean “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 2mM or
greater.” Apotex’s construction 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.”
Again, Apotex argues that Amgen’s construction is redundant, because it
contains terms already expressed in the claim itself. As stated above, the construction
offered by Amgen is consistent with the terms of the claim and reflects the express
claim language. Amgen’s construction does not render any other portion of the claim
superfluous. Accordingly, the Court construes the term “redox component” as “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
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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 2mM or greater.”
The fourth disputed claim term is “final thiol-pair ratio.” Amgen’s construction is:
“Defined by the following equation:
[reductant]2
[oxidant]
where the concentrations are the concentrations in the redox component.”
Apotex’s construction is: “The relationship of the reduced and oxidized redox species
used in the refold buffer as defined in Equation 1:
[reductant]2
[oxidant]
where the ratio is the ratio in the refold mixture.” The parties agree that the final thiolpair ratio is based on the concentrations of the reductant and the oxidant in a solution,
as defined by Equation 1 set forth at column 6, lines 23-28, but they disagree as to
whether the ratio applies to the redox component (Amgen) or the refold mixture
(Apotex).
Again, the plain language of the claim reveals that the redox component is
comprised of a final thiol-pair ratio and one or more listed elements, combined “to form
a refold mixture.” This indicates that the ratio applies to the redox component and not
to the refold mixture. The specification supports this conclusion as well, where it states:
“After the protein has been contacted with a redox component having the recited thiolpair ratio and redox buffer strength to form a refold mixture, the refold mixture is then
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
following equation:
[reductant]2
[oxidant]
where the concentrations are the concentrations in the redox component.”
The fifth disputed claim term is “redox buffer strength.” Amgen’s construction is:
“Also called ‘buffer thiol strength,’ ‘thiol-pair buffer strength,’ or ‘thiol-pair strength,’
defined by the following equation: 2[oxidant] + [reductant] where the concentrations are
the concentrations in the redox component.” Apotex’s construction is: “2[oxidant] +
[reductant] where the concentrations are the concentrations in the refold mixture.” The
parties agree on the equation for defining the redox buffer strength, but dispute which
solution (the redox component or the refold mixture) should be used as the basis for
calculating the redox buffer strength.
The Court finds that the plain language of claim 1 recites the redox buffer
strength of the redox component prior to the formation of the refold mixture; the claim
language is careful to say which value is measured at which stage. Adopting Apotex’s
proposed construction would require the Court to re-write the claim. Additionally,
Apotex’s proposed construction is contradicted by the teachings of the specification and
the rebuttal declaration of Richard C. Willson, Ph.D DE [83-1]. The values of the
concentrations of oxidants and reductants used in the equations in the specification are
based on the volume of the redox component, and not the refold mixture. Accordingly,
based upon the language of the claim and the specification, the Court construes the
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] +
[reductant] where the concentrations are the concentrations in the redox component.”
The sixth claim term in dispute is the term “refold mixture.” Amgen’s construction
is: “A mixture formed from contacting (1) the volume in which the concentration of
protein is 2.0g/L or greater with (2) the refold buffer. The refold mixture has a high
protein concentration, where “high protein concentration” is at or above about 1g/L
protein.” Apotex’s construction is: “A mixture formed from contacting the protein and
the refold buffer.” Apotex’s proposed construction of the term “refold mixture” derives
from its proposed construction that the term “a protein . . . present in a volume at a
concentration of 2.0g/L or greater. . . .” is “a protein . . . present at a concentration of
2.0g/L or greater after dilution in a refold buffer.” The Court has rejected that
construction and rejects Apotex’s construction of the term “refold mixture” as well. The
language of the claim, the specification and the state of the prior art support the
conclusion that the refold mixture of claim 1 of the ’138 Patent would be interpreted by
a person of ordinary skill in the art to have a minimum or “floor” concentration at or
above about 1g/L. Thus, the Court constructs the term “refold mixture” as “a mixture
formed from contacting (1) the volume in which the concentration of protein is 2.0g/L or
greater with (2) the refold buffer. The refold mixture has a high protein concentration,
where “high protein concentration” is at or above about 1g/L protein.”
The seventh, and last, disputed claim term of the ’138 Patent is the term “2mM
or greater.” Amgen’s construction is: “No construction necessary. The term should be
given its plain and ordinary meaning.” Apotex’s construction is: “2mM or greater,
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
is effectively bounded at a maximum of 100mM” and, therefore, “the specification
makes it abundantly clear to one skilled in the art that the patent is using the term ‘2mM
or greater’ to describe a redox buffer strength between 2mM and 100mM.” DE [76, p.
19]. To the contrary, Amgen argues that the maximum of 100mM referred to in the
specification is merely an embodiment, which does not impose a limitation on the
language of the claim. Thus, argues Amgen, the term “2mM or greater” means what it
says, with no limitation.
“It is the claims that define the metes and bounds of the patentee’s invention.
Phillips, 415 F.3d at 1313. The patentee is free to choose a broad term and expect to
obtain the full scope of its plain and ordinary meaning unless the patentee explicitly
redefines the term or disavows its full scope.” Thorner v. Sony Computer Entm’t Am.
LLC, 669 F.3d 1362, 1367 (Fed. Cir. 2012). “[O]ne purpose for examining the
specification is to determine if the patentee has limited the scope of the claims.”
Scimed Life Sys., Inc. v. Advanced Cardiovascular Sys., Inc., 242 F.3d 1337,1341 (Fed.
Cir. 2001) (quoting Watts v. XL Sys., Inc., 232 F.3d 877, 882 (Fed. Cir. 2000)). The
Court finds that the specification does, indeed, impose an upper limit of 100mM on the
thiol-pair buffer strength. The Court is particularly convinced by the fact that the
specification repeatedly sets forth a suggested range of redox buffer strengths, yet
each time specifically limits the possible ranges, “wherein the thiol-pair buffer strength is
effectively bounded at a maximum of 100mM.” Accordingly, the Court constructs the
claim term “”2mM or greater” to mean “2mM or greater, wherein the redox buffer
strength is effectively bounded at a maximum of 100mM.”
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B.

The ’427 Patent

The parties identify two disputed claim terms in the ’427 Patent. They are
located in claims 1 and 4, which are set forth below:
1. A method of treating a disease requiring peripheral stem cell
transplantation in a patient in need of such treatment,
comprising
administering to the patient a hematopoietic stem cell mobilizing-effective
amount of G-CSF; and
thereafter administering to the patient a disease treating-effective amount
of at least one chemotherapeutic agent.
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.
The first term in dispute in the ’427 Patent is “chemotherapeutic agent” as found
in claim 1. Amgen’s construction is: “Exogenous substance capable of damaging or
destroying microorganisms, parasites or tumor cells.” Apotex’s construction is:
“Therapeutic agents which open the endothelial barrier, rendering it permeable for stem
cells and/or exogenous substances suited and used to damage or destroy
microorganisms, parasites or tumor cells.” The Court concludes, based upon claim 1
and the dependent claim 4, as well as the use of the term “chemotherapeutic agent” in
the specification, that the term “chemotherapeutic agent” in claim 1 is not limited to
therapeutic agents which open the endothelial barrier. Accordingly, the Court
constructs the claim term “chemotherapeutic agent” to mean “Exogenous substance
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 treatingeffective amount.” Apotex argues that this term is indefinite, thus invalidating the
patent. Amgen’s construction is: “An amount sufficient to enhance the mobilization of
stem cells for recovery from the blood for subsequent peripheral transplantation.”
The specification explains that the treatment covered by the claim is for diseases
that require stem cell transplantation and that the treatment “depends on the
mobilization of the bone marrow stem cells . . . .” The specification also provides a
dosage range for the chemotherapeutic agent of “0.05 - 100 mg/kg/day.” Accordingly,
the Court agrees with Amgen that “[a] person of ordinary skill in the art would
understand that a dose of chemotherapeutic agent within this range, when administered
after G-CSF, would be the “disease treating-effective amount” needed to achieve the
goal of enhancing stem cell mobilization for recovery from blood and subsequent
transplantation.” DE [77], p.19. Thus, the Court constructs the term “disease treatingeffective amount” to mean “[a]n amount sufficient to enhance the mobilization of stem
cells for recovery from the blood for subsequent peripheral transplantation.”
It is so ORDERED.
DONE AND ORDERED in Chambers, Fort Lauderdale, Florida, this 7th day of
April, 2016.

Copies provided to:
Counsel of record via CM/ECF
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