AMAG PHARMACEUTICALS, INC. v. SANDOZ INC.

Filing 82

MEMORANDUM AND ORDER in re Markman Hearing. Signed by Judge Peter G. Sheridan on 7/19/2017. (mps)

UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF NEW JERSEY

AMAG PHARMACEUTICALS, INC.,
Plaintiff/Counterclaim-Defendant,
v.
SANDOZ, INC.,
Defendant/Counterclaim-Plaintiff.

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Civil Action No:
16-cv-1508 (PGS)(LHG)

MEMORANDUM
AND
ORDER

SHERIDAN, U.S.D.J.
This matter comes before the Court on Joint Claim Construction submitted by Amag
Pharmaceuticals, Inc. (“AMAG” or “Plaintiffs”) and Sandoz, Inc. (“Sandoz” or “Defendant”)
pursuant to L. Pat. R. 4.3 (see D.I. 38).
In order to market and sell pharmaceutical drug Feraheme®, AMAG has listed the
following U.S. Patents—6,599,498 (the “’498 patent); 7,553,479 (the “’479 patent); 7,871,597 (the
“’597 patent”); 8,591,864 (the “’864 patent”); and 8,926,947 (the “’947 patent”) (collectively
“Patents-in-Suit”)—in Food and Drug Association’s (“FDA”) Approved Drug Products with
Therapeutic Equivalence Applications, commonly known as the Orange Book. See 21 U.S.C. §
355(B)(1). Feraheme® is used to treat iron deficiencies in people with chronic kidney disease.
Thereafter, Sandoz filed an Abbreviated New Drug Application (“ANDA”) with the FDA
in order to seek approval to market a generic version of Feraheme®. See 21 U.S.C. § 355(j)(1).
Accordingly, pursuant to 21 U.S.C. § 355(j)(5)(B)(iii), AMAG initiated this suit against Sandoz
because Sandoz’s request to market the generic version of Feraheme® was done prior to the
expiration of the Patents-in-Suit.

On April 26-27, 2017, pursuant to L. Pat. R. 4.6, a Markman hearing was conducted before
the Court for multiple claim terms recited in the Patents-in-Suit. These terms are construed below.
BACKGROUND
Feraheme® (ferumoxytol) is an FDA approved pharmaceutical drug approved for the use
of treating iron deficiencies in people with chronic kidney disease (“CKD”). Feraheme® is
administered either as a bolus or as an intravenous solution. (See the ’498 patent, col. 3, ll. 17-19
and 29).
I.

THE PATENT FAMILY
Amongst the Patents-in-Suit, the ’498 patent is the parent patent as it issued from the first-

filed patent application. The ’479 and ’597 patents claim priority to the ’498 patent as their
respective patent applications are continuation-in-part patent applications of the ’498 patent.1 As
such, the disclosure of the ’479 and ’597 patents include additional subject matter that is not
disclosed in the ’498 matter.
Further, the patent application of the ’864 patent is a continuation application2 of the U.S.
Patent 8,501,158, whose patent application is a divisional application3 of the ’597 patent. As such,
the disclosure of the ’864 patent is the same as the disclosure of the ’597 patent because no new

See Manual of Patent Examining Procedure (“MPEP”) 201.08 (“A continuation-in-part application is an
application filed during the lifetime of an earlier nonprovisional application, repeating some substantial
portion or all of the earlier nonprovisional application and adding matter not disclosed in the earlier
nonprovisional application.”).
1

See MPEP 201.07 (“A continuation application is an application for the invention(s) disclosed in a priorfiled co-pending non-provisional application […]. The disclosure presented in the continuation must not
include any subject matter which would constitute new matter if submitted as an amendment to the parent
application.”).
2

See MPEP 201.07. (“A later application for an independent or distinct invention, carved out of a
nonprovisional application […] is known as a divisional application.”).
3

2

matter is added to the ’864 patent. Likewise, the ’947 patent shares the same disclosure as the ’864
and ’597 patent because it is a continuation application of the ’864 patent.
In short, the three patents with three distinct, non-overlapping, disclosures are—the ’498
patent, the ’479 patent, and the ’597 patent. The disclosures of the ’864 and ’947 patents are the
same as the ’597 patent.
II.

THE ’498 PATENT
A. Disclosure of the ’498 Patent
The ’498 patent is directed towards pharmaceutical compositions that are used for

providing enhanced magnetic resonance imaging (“MRI”) of a patient’s internal organs, such as
liver, spleen, or lymph nodes, during an MRI scan. The compositions are imaging agents that
comprise carboxyalklayed reduced polysaccharides coated ultra-small superparamagnetic iron
oxides. (See Abstract of the ’498 patent).
The ’498 patent identifies that the conventional contrast agents are distributed into two
classes of imaging agents—namely, low molecular weight gadolinium complexes such as
Magnevist® and colloidal iron oxides. The conventional contrast agents face the following
problems—expense, inefficiency, loss of coating of sterilized agent by autoclaving, narrow range
of organ uptake for purposes of imaging. (Id. at col. 1, ll. 25-35). During the autoclaving process,
for example, the polymer coating becomes dissociated from the iron oxide cores due to exposure
to heat. The polymer dissociation results in functional consequences, such as, physical changes in
the material (i.e., clumping), bio-distribution changes (i.e., changes in plasma half-life), and
changes in toxicity profile (i.e., potential increases in adverse events). (Id. at col. 7, ll. 60-65).
In order to mitigate dissociation of the coating from the iron oxide when the material is
subject to heat stress, the ’498 patent discloses a method for the synthesis of a colloid of an iron

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oxide that is associated with a water soluble polysaccharide coating. (Id. at col. 10, ll. 30-35). The
term “heat stress” being defined as “heating the colloid to approximately 121°C or higher for about
30 minutes at neutral pH […] that are well known in the art to autoclave (or terminally sterilize)
an injectable drug.” (Id. at col. 10, ll. 35-40).
In an example embodiment, the ’498 patent discloses that a coated colloid may be prepared
by adding a polysaccharide to an iron oxide sol (a colloidal dispersion in a liquid). Wherein the
term “colloid” includes “any macromolecule or particle having a size less than about 250 nm
[(nanometer)]”. The iron oxide polysaccharide colloids of the invention have improved physical
characteristics and manufacturability such as ability to withstand heat stress and show less
evidence of polysaccharide dissociation under stress. (Id. at col. 11, ll. 5-20).
The colloids of the ’498 patent can be used as contrast agents for MRI scanning or in other
applications such as magnetic fraction of cells, immunoassays, magnetically targeted drug
delivery, and as therapeutic injectable iron supplements. (Id. at col. 11, ll. 40-45). In particular, the
colloids are suited for parenteral administration because the final sterilization is autoclaving.
Autoclaving being a preferred method because it eliminates viability of all cellular life forms
including bacterial spores and viruses. (Id. at col. 11, ll. 45-50).
Accordingly, the improvements provided in these colloids that can be used as contrast
agents over the prior art include—(i) heat sterilization by autoclaving that optimizes long-term
storage at ambient temperatures; (ii) being non-toxic to mammals, including humans, at higher
doses; and (iii) ability to obtain additional images during a single clinical visit and use of the
imaging apparatus due to successive doses being administered after a brief interval after
administration of a first dosage. (Id. at col. 11, ll. 60-67—col. 12, ll. 1-5).

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According to the various example embodiments, the ’498 patent discloses that a reduced
polysaccharide iron oxide complex or a derivatized reduced polysaccharide iron oxide complex,
which is a reduced polymer of glucose, is produced by sterilizing the same by autoclaving. An
example of a reduced polymer of glucose is a reduced dextran. (Id. at col. 2, ll. 1-15). In another
example embodiment, the ’498 patent discloses that a complex such as a reduced derivatized
polysaccharide iron oxide complex may be stable at a temperature of at least approximately 100°C
or 121°C. (Id. at col. 5-20).
The ’498 patent includes a total of 26 claims, wherein claims 1, 13, 23 and 25 are
independent claims. Claims 1 and 23 being method claims and claims 13 and 25 being product
claims.
B. Prosecution History of the ’498 Patent
i.

Applicant’s Arguments/Remarks filed October 9, 2001.

In its response to the July 5, 2001 non-final Office action, the Applicant responded by
arguing that none of the cited references disclosed a “reduced polysaccharides” or
“carboxyalkylated polysaccharides” such as reduced carboxymethylated dextran as required in
then pending claims 1-13, 18-29-35-36, 39-52 and 57-66. (See Image File Wrapper4 of the ’498
Patent; Applicant’s Arguments/Remarks at 6-7, filed October 9, 2001). Additionally, with respect
to a particular reference cited against the claimed invention, Applicant argued that there was no
disclosure of autoclavability of the MRI contrast agents. (Id. at 8). With respect to then claims 1820 and 29, the Applicant argued that the methods and compositions are “stable after autoclaving,
with respect to certain physical and chemical properties (e.g., stability at particular elevated

See Manual of Patent Examining Procedure (“MPEP”), Section 719 (“The electronic file record in which the U.S.
Patent and Trademark Office maintains the application papers is referred to as an image file wrapper. The electronic
file record is the official record of the [patent] application.”); available at https://portal.uspto.gov/pair/PublicPair.
4

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temperatures, or stability of colloidal suspensions without aggregation),” which were not disclosed
by any of the prior art references. (Id. at 9).
Further, in the same response, in order to distinguish the claimed invention over the cited
art, the Applicant equates the term “complex” to “polysaccharide,” by arguing that “Golman et al.
neither teaches nor suggests autoclaving, either of a polysaccharide or of a complex.” (Id. at 11).
ii.

Applicant’s Arguments/Remarks filed April 25, 2002.

Next, in response statements made on April 25, 2002, the Applicant noted that preamble
“for administration to a mammalian subjection,” would be understood by one of ordinary skill in
the art to mean that “the iron oxide complex must have an acceptable profile with respect to
stability and risk of adverse reaction, and if the mammal is a human, must typically be approved
by a regulatory authority such as the Food and Drug administration.” (See Applicant’s
Arguments/Remarks at 4, filed April 25, 2002). Further, in order to distinguish over the cited art,
the Applicant primarily relies on an affidavit of one of the co-inventors of the ’498 patent.
Pursuant to 37 C.F.R. § 1.132, in support of its response, the Applicant submitted an
affidavit of Dr. Jerome Lewis. Dr. Lewis is a co-inventor of polysaccharide superparamagnetic
iron oxide complexes and related materials and methods. (Id. at Declaration of Jerome Lewis
(“Decl. of Lewis”) at ¶ 1). Dr. Lewis noted that from a regulatory and commercial perspective, to
have a “polysaccharide superparamagnetic iron oxide complex as a pharmaceutical that when
terminally sterilized (autoclaved) does not form particulates and that has minimal edematous
response.” (Id. at ¶ 3). Terminal sterilization (autoclaving) being favored over filter sterilization
because—(i) terminal sterilization provides a much higher level of sterility assurance; and (ii) their
opaque nature prevents ordinary visual inspection by the physician during administering the drug,
thereby making terminal sterilization more desirable. (Id. at ¶¶ 4-5 (internal citations omitted)).

6

In his declaration, Dr. Lewis provides a background on the development of these types of
pharmaceutical drugs. In particular, he notes that the drug disclosed in the present application is a
third generation drug. The two previous generation drugs had issues. The first generation drug was
Feridex® disclosed in U.S. Patent 4,827,945. The material used in Feridex® had issues such as
particulate formulation and adverse reactions such as edematous response (i.e., accumulation of
an excessive amount of watery fluid in cells, tissues, or body cavities). (Id. at ¶ 7). The second
generation drug being Combidex®, a complex of ultra-small particles. This drug is filtered by a
process of filtration, instead of terminal sterilization, at the time it is administered to the patient.
The risks with this drug being—edematous response, administration of the material only after
dilution, and slow administration.
Unlike the first and second generation drugs, this third generation drug, which is a complex
of ultra-small particles and has a favorable bio-distribution, has sufficiently small risk of
particulate formulation such that no filtration is required during administration. (Id. at ¶¶ 7-9).
And, because of low risk of adverse reaction, the drug disclosed in the ’498 patent can be
administered more rapidly and without dilution. (Id. at ¶ 10). In short, Dr. Lewis notes that the
new material disclosed in the ’498 patent is sterilized using the autoclaving method. And, unlike
the conventional drugs, Combidex® and Feridex®, the new material does not require filtration
during administration, no dilution, no slow administration, and no edematous response.
Accordingly, noting that such properties are commercially and medically desirable in an iron based
colloidal MRI contrast agent. (Id. at ¶ 11).
In distinguishing the third generation agent disclosed in the ’498 patent from the
conventional drugs, Dr. Lewis states that “autoclaving normally requires temperatures of at least
121 degrees [C] (see, for example, Exhibit C), and in any event at least 115 degrees C.” (Id. at ¶

7

15). Dr. Lewis notes that the material disclosed in the prior art references, noted in the Office
action dated November 2, 2001, namely, Lewis and Groman references, are autoclaved in the
presence of citrate. Doing so has a risk of particulate formulation requiring administration through
a filter, and an adverse reaction risk requiring dilution and slow administration. (Id. at ¶ 15). In
other words, the cited references fail to teach anything about creating a material without
degradation or decreased risk of adverse reactions. (Id.)
Under the section titled “Consideration of Certain Terms in the Patent Application,” Dr.
Lewis notes, “[i]n the present invention, the reduced polysaccharide is a poly alcohol compound;
thus, it contains multiple OH groups. All the OH groups are functional groups and thus potential
reactive sites to form derivatives of the original compound.” (Id. at ¶ 16). With respect to
“ultrasmall” term, Dr. Lewis relied on a publication to define this term as a new class of contrast
agents “small enough to migrate across the capillary wall, a prerequisite in the design of targetable
particulate pharmaceuticals.” (Id. at ¶ 19 (internal citations omitted)).
In support of Dr. Lewis’ declaration, Applicant submits multiple exhibits to the Patent
Office. One of these exhibits, Exhibit D, is entitled “European Pharmacopoeia, 3rd Edition, 1997.”
Exhibit D states, “[s]terility is the absence of viable micro-organisms […] [which] is assured by
the application of a suitably validated production process.” As such, failure to follow a
meticulously validated process involves the risk of a non-sterile product or of a deteriorated
product. Wherever possible, “a process in which the product is sterilized in its final container
(terminal sterilization) is chosen.” For terminal sterilization, it is essential to take into account the
non-uniformity of the physical and chemical conditions within the sterilizing chamber. By
establishing a terminal sterilization process, knowledge of its performance in routine use is gained

8

wherever possible, by monitoring and suitably recording the physical and chemical conditions
achieved within the load in the chamber throughout each sterilizing cycle.
Additionally, attached Exhibits H and I, note that ultrasmall superparamagnetic iron oxide
(USPIO) are small enough to migrate across the capillary wall, a prerequisite in the design of
targetable particulate pharmaceuticals. As such, the applications of USPIO being—(i) used as an
intravenous contrast agent for the lymphatic system, (ii) a bone marrow contrast agent, (iii) a longhalf-life perfusion agent for brain and heart, and (iv) the magnetic moiety in organ-targeted
superparamagnetic contrast agents for magnetic resonance imaging. (Id. at Exhibit I, “Radiology”).
iii.

Applicant’s Arguments/Remarks filed June 4 2002, October 8, 2002 and November
13, 2002.

With respect to the remarks filed June 4, 2002, no significant comments were made by the
Applicant.
However, with respect to the remarks filed October 8, 2002, the Applicant noted “[t]he
change in claims such as 53 and 54 from ‘colloid’ to ‘complex’ is intended to be a broadening
amendment; similar language already appeared in numerous claims.” (See Applicant’s
Arguments/Remarks at 6, filed October 8, 2002). Additionally, Dr. Lewis’ attached declaration
notes that the material in the patent application of the ’498 patent employs a synthetic method that
“does not require a reflux step or centrifugation. And the resulting material falls apart upon
autoclaving – i.e., heating at 121°C for 30 min. does not result in an increase in particulate
formulation.” (Decl. of Lewis at ¶ 11, dated September 25, 2002). In addition, Dr. Lewis notes that
his experimental data indicates that such “autoclaved materials are stable (as measured by no
increase in particulate level per mL of material) for up to 3 years.” (Id. at ¶ 12).

9

Whereas, in the remarks filed November 13, 2002, Applicant again noted that the changing
of claim terms from “colloid” to “complex” is intended to be a broadening amendment.
iv.

Notice of Allowance mailed on January 22, 2003.

Under the reasons for allowance, the Examiner noted that the claimed subject matter was
novel and nonobvious because the prior art references did not disclose—(i) a reduced
carboxyalkylated polysaccharide iron oxide complex wherein the complex is stable at a
temperature of about 121°C; and (ii) a method of providing an iron oxide complex for
administration to a mammalian subject consisting of producing a carboxyalkylated reduced
polysaccharide iron oxide complex and sterilizing the complex by autoclaving. The Examiner
further noted that the declaration filed by Dr. Lewis on October 8, 2002, was sufficient and
persuasive to overcome the prior art references because the material disclosed in the prior art was
“not stable upon autoclaving (heating at 121 C for 30 minutes),” unlike the material of the patent
application of the ’498 patent.
III.

THE ’479 PATENT
A. Disclosure of the ’479 Patent
The Court notes that the patent application for the ’479 patent is a continuation-in-part

patent application for the patent application for the ’498 patent. As such, a substantial portion of
the disclosure in the ’479 patent is recited in the ’498 patent. (See supra fn. 1).
Based on a review of the disclosure of the ’479 patent, additional disclosure regarding the
colloid particles is made in the ’479 patent. The ’479 patent explains that unlike the conventional
drugs, Combidex® and Feridex®, the colloid particles disclosed in this patent application show less
evidence of polysaccharide dissociation under stress, and exhibiting no appreciable change in size.
The ’479 patent identifies the shortcomings with the conventional drugs such as loss of dextran

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coating when subjected to heat stress, increase in particle diameter size, and clumping of material.
(See the ’479 patent, col. 11, ll. 5-20).
The ’479 patent discloses an improved method of administration, which comprises
injection of an autoclaved reduced polysaccharide iron oxide complex in a volume of 15 mL or
less. In another aspect of the embodiment the injected volume is injected as a bolus. (See the ’479
patent, col. 3, ll. 20-25).
The ’479 patent includes two (2) claims wherein claim 1 is in independent form, and is
directed to a pharmaceutical composition in a vial. Claim 1 of the ’479 patent, unlike the claims
of the ’498 patent, recites carboxymethylated dextran iron oxide complex, which comprises at least
750 micromole and less than 1500 micromole of carboxyl groups per gram of dextran. (See the
’479 patent, col. 38, ll. 25-30).
B. Prosecution History of the ’479 Patent
i.

Applicant’s Arguments/Remarks filed December 14, 2006.

In responding to the rejections set forth in the outstanding Office action issued by the patent
examiner, the Applicant argued, “[w]hether a composition, or in this case a complex, is terminally
sterilizable – i.e. autoclavable – depends on the chemical composition of the disclosed complex, it
does not describe a purpose or intended use.” (See Applicant’s Arguments/Remarks at 9, filed
December 14, 2006). The Applicant further states that “[a]utoclavability is a physical property that
reflects a chemical property and thus chemical composition.” (Id. at 10).
The Applicant further notes that the term “terminally sterilizable” also “adds patentable
weight to the claimed iron oxide composition, because not all reduced carboxyalkylated
polysaccharide iron oxide complexes are terminally sterilizable and stable at temperatures of at
least 100°C.” As such, the term “terminally sterilizable” imparts essential chemical structure via

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this physical property because a composition that is “terminally sterilizable” is chemically
different from one that is not. (Id. at 10). The Applicant argued that they have developed
“unexpectedly and surprisingly” developed a process that prepares reduced carboxyalkylated
polysaccharide iron oxide complexes that can be autoclaved without precipitating or degrading.
In support of its arguments, the Applicant submitted a declaration by one of the inventors’,
Dr. Jerome Lewis. Generally, the declaration of Dr. Lewis submitted with the Applicant’s remarks
was substantially similar to the declaration by Dr. Lewis in the ’498 patent.
ii.

Applicant’s Arguments/Remarks filed February 23, 2007.

In its remarks, the Applicant addressed indefiniteness rejections under 35 U.S.C. § 112,
first paragraph by making certain amendments. Next, the Applicant addressed obviousness
rejection by asserting that the cited art failed to disclose “an injectable complex in a vial that is
stable at a temperature of about 100°C, or an injectable complex in a vial that is terminally
sterilizable (autoclavable) within the vial.” (See Applicant’s Arguments/Remarks at 4, filed
February 23, 2007).
iii.

Applicant’s Arguments/Remarks filed May 4, 2007.

In its remarks, relying on the declaration by Dr. Lewis and Dr. Timothy Frigo, the
Applicant argued that unlike the conventional drugs, PCU-USPIO iron oxide complex, showed an
insignificant change in size upon autoclaving. (See Applicant’s Arguments/Remarks at 5, filed
May 4, 2007). Dr. Timothy Frigo is an assignee of the ’479 patent and one of the senior scientists
who prepared and analyzed the substances disclosed in this patent. Dr. Frigo’s declaration indicates
that the size of PCU-USPIO after autoclaving did not change drastically, as it did for the
conventional drugs. (See Declaration of Dr. Frigo (“Decl. of Frigo) at ¶¶ 10-11, filed May 4, 2007).

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iv.

Notice of Allowance mailed on April 10, 2009.

In its reasons for allowance, the Examiner indicated that the claimed subject matter is
patentable over the cited art because the compositions disclosed in the references are not stable
when subjected to autoclaving. As such, the compositions in the claimed subject matter do “not
form into a gel or form substantial particulates and remains clear and can be micro-filtered.” (See
Notice of Allowance at 3, mailed on April 10, 2009).
IV.

THE ’597 PATENT
A. Disclosure of the ’597 Patent
The ’597 patent is directed towards administrating an effective amount of a

pharmacological composition that uses an iron oxide complex with a polyol or polyether. The
complex is formulated in a biocompatible liquid that provides minimal detectable free iron in a
subject and minimal incidence of anaphylaxis (i.e., allergic reaction). (See the ’479 patent, col. 2,
ll. 5-10). The ’479 patent notes that unlike the existing iron oxide complexes, polyol or polyether
iron oxide complexes disclosed herein, when administered parenterally to a patient for use as a
pharmacological agent, provides minimal detectable free iron and anaphylaxis in a patient. (Id. at
col. 11, ll. 15-20).
Accordingly, the improvement comprising that of parenteral administration to a
mammalian subject of an effective dose of the complex formulated in a biocompatible liquid
delivered at a rate substantially greater than 1 mL/min. (Id. at col. 3, ll. 40-45). The method of
administration comprising—injection of an autoclaved reduced polysaccharide iron oxide
complex in a volume of 15 mL or less. (Id. at col. 6, ll. 60-67).
Further, this patent notes that four of the conventional types of iron oxide compounds used
as MRI contrast agents and/or hematinic agents (i.e., agents for increasing the amount of

13

hemoglobin in the blood) have serious drawbacks. (Id. at col. 15, ll. 45-65 and col. 16, ll. 1-25).
Accordingly, the embodiments of the ’597 patent are directed to polyol or polyether iron oxide
complex, when administered to a patient, provides both minimal detectable free iron in a subject
and minimal anaphylaxis in a patient. For example, as discussed in examples 6 and 7 and examples
8 and 9 of the ’597 patent. (Id. at col. 19, ll. 45-50). The polyol or polyether iron oxide complex
of the ’597 patent are administered parenterally by bolus injection at a dosage of from about 1 mg
to about 4 mg of iron/kg of body weight. (Id. at col. 26, ll. 30-35).
The ’597 patent identifies autoclave or terminally sterilize as synonyms. (Id. at col. 10, ll.
65-67). “Terminal sterilization (autoclaving) is a preferred method of sterilizing drugs for
injection.” (Id. at col. 13, ll. 4-5).

“These colloids are particularly suited to parenteral

administration, because the final sterilization typically is autoclaving, a preferred method since it
eliminates viability of all cellular life forms including bacterial spores, and viruses.” (Id. at col.
18, 35-40).
In example 62, the ’597 patent discloses that following autoclaving for 30 minutes at 121°C,
USPIO coated with reduced dextran maintained its small size. Whereas, USPIO coated with native
dextran increased in size 28-fold following autoclaving. (Id. at col. 45, ll. 35-45). Additionally, a
second type of increased stability was achieved by use of reduced dextran to coat USPIO is the
property of pH of the bulk solvent. (Id. at col. 45, ll. 50-55). The data in both Tables 12 and 13
show that the particles coated with reduced dextran had significantly improved pH stability upon
autoclaving, compared to those coated with native dextran. As such, the effect of autoclaving on
pH, size, and bound polysaccharide of colloids coated with native and reduced dextran was
observed. (Id. at col. 45, ll. 55—col. 46, ll. 1-30).

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An example embodiment disclosed in the ’597 patent is that of a method that comprises
mixing the polyol, reduced polysaccharide, or polyether with iron salts in an acidic solution
selected from the group comprising ferric salts, ferrous salts, or a mixture of ferrous and ferric
salts, cooling the solution, neutralizing the solution with a base, and recovering the coated iron
oxide colloid. (Id. at col. 17, ll. 30-35). Cooling the solution to 5°C as noted in example 5 or cooled
to a room temperature as noted in example 36. (Id. at col. 25, ll. 40-45; col. 37, ll. 25-35).
B. Prosecution History of the ’597 Patent
i.

Applicant’s Arguments/Remarks filed July 3, 2006.

In responding to the rejections set forth in the outstanding Office action, the Applicant
argued that the claimed subject matter is directed to ‘pharmacological compositions,’ which
requires a composition that will be acceptable for use in humans. That is, the aforementioned term
informs a person of ordinary skill in the art that the iron oxide complex must have an acceptable
profile with respect to stability and risk of adverse reaction in humans. (See Applicant’s
Arguments/Remarks at 7, filed July 3, 2006). Applicant further goes onto indicate that those skilled
in the art recognize that in the art of contrast agents, use of terminal sterilization (autoclaving) over
filter sterilization is preferred because terminal sterilization provides a much higher level of
sterility assurance. (Id. at 7). As such, being desirable to have polyol/polyether superparamagnetic
iron oxide complex as pharmacological composition that is capable of being autoclaved and that
can be administered after autoclaving to provide minimal detectable free iron and minimal
incidence of anaphylaxis. (Id. at 8).
The Applicant further identifies that the drug disclosed in the patent application is better
than the conventional drugs, Combidex® and Feridex®, because it has a sufficiently small risk of
particulate formulation after autoclaving that no filtration is required during administration of the

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drug. Thereby, providing minimal free iron to the subject upon administration. And, the risk of
adverse reaction is lower compared to the conventional drugs, which results in more rapid
administration of this new drug without dilution. (Id. at 9).
Next, the Applicant argues that the prior art cited did not disclose a pharmacological
composition that is “capable of being parenterally administered (composition), or actually
administered (method), at a rate substantially greater than 1mL/min.” (Id. at 11). Further, the
Applicant argues that the reduced carboxyalkylated polysaccharide iron oxide complexes claimed
in the instant application can be autoclaved, and the claims require that they be autoclaved or
autoclavable. (Id. at 14).
ii.

Applicant’s Arguments/Remarks filed January 29, 2007.

In support of its remarks, Applicant submitted a declaration of Dr. Lewis, one of the
inventors of this patent. In order to distinguish over the cited art, the Applicant amended the claims
to include claim term “autoclavable” in the body of the claim in order to give patentable weight to
this claim term. The Applicant asserted that “[a]utoclavability is a physical property that reflects a
chemical

property

and

thus

limits

the

chemical

composition.”

(See

Applicant’s

Arguments/Remarks at 8, filed January 29, 2007). And, because not all reduced carboxyalkylated
polysaccharide iron oxide complexes are autoclaved and thus stable, the term “autoclavable” adds
patentable weight. (Id. at 9). Dr. Lewis points out that that the “distinguishing property of the
complexes of the present application compared to the previous generation complexes Feridex and
Combidex, and the [reference] Maruno EP compound, is autoclavability.” (Id. at 10).
iii.

Applicant’s Arguments/Remarks filed May 18, 2007.

In support of its remarks, Applicant submitted a declaration of Dr. Timothy Frigo, an
assignee and one of the senior scientists who prepares and analyzes the substances disclosed in the

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this patent. Dr. Frigo noted that PSC-USPIO proprietary iron oxide complex showed an
insignificant change in size upon autoclaving. (See Applicant’s Arguments/Remarks at 7-8, filed
May 18, 2007).
iv.

Applicant’s Arguments/Remarks filed December 4, 2007.

In support of its remarks, the Applicant submitted a declaration of Dr. Frigo. In
differentiating the claimed invention over the cited art, the Applicant asserted that the disclosure
of “free flowing” with regard to complexes A and B in prior art reference Maruno, is not proof of
autoclaving. The Applicant cites to paragraph 13 of Dr. Frigo’s declaration and argues that the use
of filter sterilization in Maruno confirms that complexes in the cited art cannot be autoclaved. (See
Applicant’s Arguments/Remarks at 7-8, filed December 4, 2007).
In short, the Applicant, relying upon the declaration of Dr. Frigo, essentially argued that
the complexes disclosed in the prior art references do not anticipate the claimed invention because
the complexes disclosed deteriorate before autoclaving. As such, one of ordinary skill in the art
would not rely on the complexes disclosed in the cited art to be autoclavable. (Id. at 9-10).
v.

Applicant’s Arguments/Remarks filed September 26, 2008.

In its remarks, the Applicant, in differentiating over the cited art, argued, “[o]f particular
interest, the claim for that patent covered a composition very similar to Applicants’ own
compositions – namely, a complex of dextran with an iron compound. […] A composition
comprising a substantially nonionic complex of ferric hydroxide with a dextran having an average
intrinsic viscosity […].” (See Applicant’s Arguments/Remarks at 8, filed September 26, 2008).
vi.

Applicant’s Arguments/Remarks filed August 14, 2009.

In responding to the outstanding Office action, the Applicant argued that the cited art of
Maruno EP “gives no information about how to make a complex that is autoclavable […]. The

17

declaration of Dr. Timothy Frigo, filed herein on December 4, 2007, reports specifically on his
synthesis of the foregoing complexes 3, 5, and 7, and reports that none of them are stable [for]
autoclaving.” (See Applicant’s Arguments/Remarks at 7-8, filed August 14, 2009; citing Decl. of
Frigo at ¶ 4). In paragraph 4 of Dr. Frigo’s declaration, he notes that “[o]f these six complexes, the
only ones disclosed as stable at 80°C by Maruno are the three shown in Maruno EP, Table 7
(complexes 3, 5 and 7) […].” And, the Maruno EP reference, EP 0450092, discloses, in-part, as
follows—
“Processes for preparing complexes of the invention from the foregoing
polysaccharide carboxyalkyl ethers and magnetic metal oxides can roughly be
classified into the following two processes. Namely, the first process is a process
which comprises first preparing an aqueous sol or suspension containing magnetic
metal oxide particles which will be the core of the complex, and subjecting it to
reaction with a carboxyalkyl ether of a polysaccharide. The second process is a
process which comprises mixing a divalent metal salt, a trivalent metal salt and a
base with stirring in an aqueous system in the presence of a polysaccharide
carboxyalkyl ether to progress reaction.”

(See Maruno EP at p. 4, ll. 41-46). Accordingly, the Applicant asserted that the cited art does not
disclose complexes that are autoclavable or are stable to autoclaving.
vii.

Notice of Allowance mailed on September 10, 2010.

Under its reasons for allowance, the Examiner noted that Maruno EP is the closest prior art
reference to the claimed invention. Further, the Examiner explained that the claimed invention is
patentable over the cited art because “Applicants have shown that their compositions as claimed
are stable to autoclaving, meaning that it does not form into a gel or form substantial particulates
and remains clear and can be micro-filtered. On the other hand, the complexes of Maruno [EP]
showed degredation, an increase in the number and size of particulates and could not be microfiltered after autoclaving thus proving that Applicants complexes are different from Maruno’s [EP]
complexes.” (See Notice of Allowance at 3, mailed on September 10, 2010).
18

LEGAL STANDARD
“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) (en banc) (quoting Innova/Pure Water Inc. v. Safari Water Filtration Sys., Inc.,
381 F.3d 1111, 1115 (Fed. Cir. 2004)). Claim construction determines the correct claim scope,
and is a determination exclusively for the court as a matter of law. Markman v. Westview
Instruments, Inc., 52 F.3d 967, 978-79 (Fed. Cir. 1995) (en banc), aff’d, 517 U.S. 370 (1996). The
focus in construing disputed terms in claim language “is on the objective test of what one of
ordinary skill in the art at the time of the invention would have understood the term[s] to mean.”
Id. at 986.
To determine the meaning of the claims, courts start by considering the intrinsic evidence.
Phillips, 415 F.3d at 1313; C.R. Bard, Inc. v. U.S. Surgical Corp., 388 F.3d 858, 861 (Fed. Cir.
2004); Bell Atl. Network Servs., Inc. v. Covad Comms. Group, Inc., 262 F.3d 1258, 1267 (Fed. Cir.
2001).

The intrinsic evidence includes the claims themselves, the specification, and the

prosecution history. Phillips, 415 F.3d at 1314; C.R. Bard, Inc., 388 F.3d at 861.
The claims themselves provide substantial guidance in determining the meaning of
particular claim terms. Phillips, 415 F.3d at 1314. First, the context in which a term is used in the
asserted claim can be very instructive. Id. Other asserted or non-asserted claims can aid in
determining the claim’s meaning because claim terms are normally used consistently throughout
a patent. Id. Differences among claims can also assist in understanding a term’s meaning. Id.
For example, when a dependent claim adds a limitation, there is a presumption that the independent
claim does not include that limitation. Id. at 1314-15.

19

“[C]laims ‘must be read in view of the specification of which they are a part.’” Id. at 1315
(quoting Markman, 52 F.3d at 979). “[T]he specification ‘is always highly relevant to the claim
construction analysis. Usually, it is dispositive; it is the single best guide to the meaning of a
disputed term.’” Id. (quoting Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir.
1996)). This is true because a patentee may define his own terms, give a claim term a different
meaning than the term would otherwise possess, or disclaim or disavow the claim scope. Id. at
1316. In these circumstances, the inventor’s lexicography governs. Id. The specification may
also resolve the meaning of ambiguous claim terms “where the ordinary and accustomed meaning
of the words used in the claims lack sufficient clarity to permit the scope of the claim to be
ascertained from the words alone.” Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1325
(Fed. Cir. 2002). But, “[a]lthough the specification may aid the court in interpreting the meaning
of disputed claim language, particular embodiments and examples appearing in the specification
will not generally be read into the claims.” Comark Commc’ns, Inc. v. Harris Corp., 156 F.3d
1182, 1187 (Fed. Cir. 1998) (quoting Constant v. Advanced Micro-Devices, Inc., 848 F.2d 1560,
1571 (Fed. Cir. 1988)); also see Phillips, 415 F.3d at 1323 (“although the specification often
describes very specific embodiments of the invention, we have repeatedly warned against
confining the claims to those embodiments.”).
The prosecution history is another tool to supply the proper context for claim construction.
It “can often inform the meaning of the claim language by demonstrating how the inventor
understood the invention and whether the inventor limited the invention in the course of
prosecution, making the claim scope narrower that it would otherwise be.” Phillips, 415 F.3d at
1317.

20

“Extrinsic evidence consists of all evidence external to the patent and prosecution history,
including expert and inventor testimony, dictionaries, and learned treatises.” Markman, 52 F.3d
at 980. Although extrinsic evidence can be useful, it is “less significant than the intrinsic record
in determining ‘the legally operative meaning of claim language.’” Phillips, 415 F.3d at 1317
(quoting C.R. Bard, Inc., 388 F.3d at 862).
Dictionaries and treatises may aid a court in understanding the underlying technology and
the manner in which one skilled in the art might use claim terms, but dictionaries and treatises may
provide definitions that are too broad or may not be indicative of how the term is used in the patent.
Id. at 1318.

Similarly, expert testimony may aid a court in understanding the underlying

technology and determining the particular meaning of a term in the pertinent field, but an expert’s
conclusory, unsupported assertions as to a term’s definition are entirely unhelpful to a court. Id.
Generally, extrinsic evidence is “less reliable than the patent and its prosecution history in
determining how to read claim terms.” Id. The Supreme Court recently explained the role of
extrinsic evidence in claim construction:
In some cases, however, the district court will need to look beyond
the patent’s intrinsic evidence and to consult extrinsic evidence in
order to understand, for example, the background science or the
meaning of a term in the relevant art during the relevant time period.
. . . In cases where those subsidiary facts are in dispute, courts will
need to make subsidiary factual findings about that extrinsic
evidence. These are the “evidentiary underpinnings” of claim
construction that we discussed in Markman, and this subsidiary fact
finding must be reviewed for clear error on appeal.
Teva Pharm. USA, Inc. v. Sandoz, Inc., 135 S.Ct. 831, 841 (2015).
Overall, in construing the claims, “[t]he judge’s task is not to decide which of the
adversaries is correct. Instead, the judge must independently assess the claims, the specification,
and if necessary the prosecution history […], and declare the meaning of the claims.” Exxon
Chem. Patents, Inc. v. Lubrizol Corp., 64 F.3d 1553, 1556 (Fed. Cir. 1995).
21

ANALYSIS
Now, the Court will construe the claim terms listed in the Patents-in-Suit.
A. “COMPLEX”
AMAG’s Proposed Construction
Plain and ordinary meaning:
“substance formed by the association
of two or more substances.”

Sandoz’s Proposed Construction
“a macromolecule or particle having indeterminable
chemical structure made through specific synthetic
parameters and having particular physiochemical
properties, which include:
(i) it is autoclavable without the addition of
excipients such as citrate and low-molecular weight
sugars (e.g., mannitol),
(ii) the desired particle size is achieved at outset
during synthesis, without any filtration,
centrifugation, or other reduction step,
(iii) it may be safely administered as a bolus or IV
push, and
(iv) it provides an acceptable profile with respect to
risk of adverse reaction upon administration,
including minimal incidence of anaphylaxis and
minimal incidence of free iron”

Representative claim 1 of the ’498 patent recites,
1. A method of providing an iron oxide complex for administration to a mammalian
subject, the method consisting of:
producing a carboxyalkylated reduced polysaccharide iron oxide complex;
and
sterilizing the complex by autoclaving.
AMAG asserts that “complex” should be construed to mean a “substance formed by the
association of multiple substances,” because such definition is supported by intrinsic evidence and
it is a common chemistry term with a well-understood meaning. (See Pl.’s Br. at 9; D.I. 48).
AMAG cites to col. 4, ll.35-43 of the ’498 patent to assert that when “viewed in context of the
whole specification, a person of ordinary skill would understand the term ‘complex’ refers to a
substance (the disclosed iron oxide complex) formed by association of multiple substances (iron
22

oxide and a polysaccharide).” (Id. at 10); also see Markman Hearing Transcript, April 26, 2017
(“Trans.”) at 30:6-11).
Further, AMAG asserts that Sandoz’s proposed construction should be rejected because it
imports numerous limitations about the specific synthetic parameters that are used to make the
iron oxide complex identified in the specification and the prosecution history. Thereby improperly
importing specific preferred embodiments into the claims. (Id. at 10-11; citing Kara Tech. Inc. v.
Stamps.com Inc., 582 F.3d 1341, 1347-48 (Fed. Cir. 2009) (“The claims, not specification
embodiments define the scope of patent protection.”)). In addition, AMAG argues that Sandoz’s
disavowal argument, discussed below, should be not considered because the statements made by
Dr. Lewis during the prosecution of the Patents-in-Suit describe the unexpected results of the
claimed iron oxide “complex,” and not define the full scope of the term “complex.” (Id. at 14).
Because the Applicants never argued that the term “complex” be limited to something with those
particular properties or results, the term “complex” should not be limited with those particular
properties or results, as proposed by Sandoz. (Id.).
During the Markman hearing, AMAG’s counsel pointed out that Sandoz’s proposed
construction should not be adopted because the features recited in their proposed construction are
already recited in claim 1 of the ’597 patent. (See Trans. at 31:7-14 (“And our position simply is
if all of these are separately called out in the claim, why would you read them into the word
complex.”).
In contrast, Sandoz sets forth a detailed argument as to why each of its proposed limitations
should be incorporated into the definition of “complex.” With respect to the limitation—“a
macromolecule or particle having indeterminable chemical structure made through specific
synthetic parameters and having particular physiochemical properties”—Sandoz relies on the

23

Applicant’s statements made during the prosecution of the Patents-in-Suit in order to differentiate
over the cited art, Maruno reference (EP 0450092). Sandoz indicates that the Applicants, on behalf
of AMAG, repeatedly made statements differentiating their claimed complex from the complex
disclosed in Maruno based on—(i) different and specific synthetic parameters, (ii) different
resulting properties, and (iii) different chemical structures resulting in different chemical
compositions. (See Def.’s Br. at 6-8; D.I. 46). As such, Sandoz holds the position that the
aforementioned limitation should be incorporated in defining the term “complex.”
Next, with respect to the limitation—“autoclavable without the addition of excipients such
as citrate and low-molecular weight sugars (e.g., mannitol)”—Sandoz again relies on the
statements made by the Applicants during the prosecution history, in which the Applicants argued
that the “presence of excipients during autoclaving frequently leads to changes in the nature of the
complex, which increases the risk of adverse reaction.” (Id. at 9 (internal citations omitted)). In
addition, the Applicants described the claimed complex being able to heat sterilized without using
excipients like mannitol and citrate as part of autoclaving or subsequent storage processes. (Id.).
As such, based on the intrinsic evidence, Sandoz holds the position that the aforementioned
limitation directed to the autoclaving should be incorporated in defining the term “complex.”
Next, with respect to the limitation—“the desired particle size is achieved at outset during
synthesis, without any filtration, centrifugation, or other reduction step”—Sandoz again relies on
the statements made by the Applicants during the prosecution history of the ’498 patent. During
prosecution of the ’498 patent, the Applicants indicated the following—
“In contrast [to Maruno], the presently claimed material (see in particular Example
31, p. 36 of the Application) can be prepared without any filtration or centrifugation
step at all. Our disclosed synthetic method produces a very narrow size range of
ultrasmall particles having the desired particle size from the outset without any
filtration or need to limit the particle size below a specific diameter. Our synthetic
method does not require a reflux step or centrifugation.”
24

(Id. at 10 (internal citations omitted)). Sandoz asserts that the aforementioned argument made by
the Applicants is evidence that the specific example embodiments (example 31), relied upon to
differentiate the claimed invention over the cited art, are to be incorporated when defining
“complex.” As such, based on the intrinsic evidence, Sandoz argues that the aforementioned
limitation directed to the process steps should be incorporated in defining the term “complex.”
Next, with respect to the limitation—“may be safely administered as a bolus or IV push”—
Sandoz relies on the disclosure of the Patents-in-Suit and the prosecution history to assert that the
aforementioned limitation should be incorporated into the term “complex.” In particular, Sandoz
cites to the following statement made by the Applicants, on behalf of AMAG—
“[T]he claims require that the pharmacological composition must be capable of
being parenterally administered (composition), or actually administered
(method), at a rate substantially greater than 1 mL/min (with dependent claims
requiring a rate of about 1 mL/sec).”
(Id. at 10 (internal citations omitted)). Sandoz asserts that based on the intrinsic evidence, a skilled
artisan would understand that a complex that could not be safely administered as a rapid bolus is
chemically different from AMAG’s complex, and as such was disclaimed by AMAG. (Id. at 11).
Lastly, with respect to the limitation—“provides an acceptable profile with respect to risk
of adverse reaction upon administration, including minimal incidence of anaphylaxis and minimal
incidence of free iron”—Sandoz relies on the intrinsic evidence to assert that the aforementioned
limitation should be incorporated in defining the term “complex.” Sandoz relies on the following
statement made during prosecution of the Patents-in-Suit—
“In contrast [to the complexes of Maruno], the presently claimed pharmacological
compositions are a brilliant and nonobvious improvement over Maruno because
they are autoclavable, can be safely administered to provide minimal detectable
free iron and minimal incidence of anaphylaxis, at a fast rate of substantially
greater than 1 mL/min, and as fast as even 1 mL/sec.”

25

(Id. at 12 (internal citations omitted)). Sandoz asserts that recitation of “minimal incidence of
anaphylaxis” and “free iron” are structural properties of the claimed complex; and as such should
be incorporated into the claim term “complex.”
During the Markman hearing, Sandoz’s counsel essentially argued with respect to the claim
term “complex” that the statements made by AMAG during the prosecution history are AMAG’s
own representations, which AMAG should be held accountable for. (See Trans. at 56 at 19-23
(“And all we’re asking the Court again is to hold them to their own representation.”)).
The Court notes that the prosecution history is relevant intrinsic evidence, but the Court’s
2005 en banc Phillips opinion reduced the importance to be given to the file history, as it represents
an “ongoing negotiation” between the Applicant and the Patent & Trademark Office (“PTO”)
rather than a final product. Phillips, 415 F.3d at 1317. The Federal Circuit cases broadly state that
an Applicant’s statements to the PTO characterizing its invention may give rise to a prosecution
disclaimer. Hockerson-Halberstadt, Inc. v. Avia Group Int’l, Inc., 222 F.3d 951, 957 (Fed. Cir.
2000). For a prosecution disclaimer inquiry, “we examine the entire prosecution history.”
Seachange Int’l, Inc. v. C-COR Inc., 413 F.3d 1361, 1372 (Fed. Cir. 2005).
“Regardless of the examiner’s motives, arguments made during prosecution shed light on
what the applicant meant by its various terms.” E.I. du Pont de Nemours & Co. v. Phillips
Petroleum Co., 849 F.2d 1430, 1438 (Fed. Cir. 1988). In Uship Intellectual Properties, LLC, the
Court noted that the “applicant’s argument persuaded the examiner, who noted in the ensuing
Office Action that the restriction requirement was overcome. From this exchange, a competitor
would reasonably conclude that the applicant clearly and unmistakably limited all of the method
claim steps to performance by an automated shipping machine […].” Uship Intellectual
Properties, LLC v. U.S., 714 F.3d 1311, 1316.

26

The definition of a claim term can be affected through “repeated and definitive remarks.”
Computer Docking Station Corp. v. Dell, Inc., 519 F.3d 1366, 1374 (Fed. Cir. 2008). For example,
in InTouch Technologies, Inc., the Court ruled that repeatedly explaining a “call back mechanism”
during the prosecution made it clear as to what was meant by this term. InTouch Technologies,
Inc. v. VGO Communications, Inc., 751 F.3d 1327, 1341-42 (“The prosecution history of the ‘357
patent removes any remaining doubt that the call back mechanism requires a message to a specific
user that requested and was denied access.”). Similarly in Saffran, the Court found the claimed
invention to be limited in scope based on the statements made by the patentee to distinguish the
claimed invention over a prior art reference. Saffran v. Johnson & Johnson, 712 F.3d 549, 559
(Fed. Cir. 2013).
Based on the case law, and the intrinsic evidence brought before the Court, the Court does
not find AMAG’s proposed construction to suffice the true meaning of “complex.” In light of the
statements made by the Applicants, on behalf of AMAG, one skilled in the art, such as a
competitor, would not define the term “complex” to mean a “substance formed by the association
of two or more substances.” As such, the Court rejects AMAG’s proposed construction.
Now, the Court considers Sandoz’s proposed construction for this term. As correctly
pointed out by AMAG, Sandoz’s proposed construction does have issues, and as such should not
be adopted in its entirety. For example, the term “indeterminable chemical structure,” as recited in
Sandoz’s proposed construction is ambiguous and vague. By defining “complex” to mean an
“indeterminable” structure would not only be unclear to one skilled in the art, but would also run
counter to the intrinsic evidence as the intrinsic evidence appears to indicate the particle size and
the chemical structure of the iron oxide complex.

27

Further, the Court takes issue of certain process steps introduced into Sandoz’s proposed
claim construction, such as—“specific synthetic parameters,” “autoclavable,” and “without any
filtration, centrifugation, or other reduction step.”
The Court recognizes that during the prosecution of the Patents-in-Suit, the Applicant
repeatedly made assertions that the “complex” recited in the claimed invention was different from
the complex recited in the Maruno reference because the claimed “complex” was—(i)
autoclavable, (ii) had different and specific synthetic parameters, (iii) had different resulting
properties, and (iv) had different chemical structures and compositions. (See Def.’s Br. at 9-10;
D.I. 46). The Court agrees with AMAG’s assertion that introduction of these features in defining
“complex” introduces process steps in defining a product. (See Pl.’s Br. at 12; D.I. 47). “Even
though product-by-process claims are limited by and defined by the process, determination of
patentability is based on the product itself. In addition, statements made regarding specific example
embodiments from the specification (example 31) during prosecution are generally not introduced
into the claim language itself. Augme Technologies, Inc. v. Yahoo! Inc., 755 F.3d 1326, 1340 (Fed.
Cir. 2014) (“Yahoo!'s discussion of an embodiment did not amount to lexicography or
disavowal”).
In addition, Sandoz’s proposed construction with respect to “safely administered as a bolus
or IV push,” is directed to an intended use, which are generally not given patentable weight. (See
MPEP 2111; In re Sinex, 309 F.2d 488, 492 (CCPA 1962) (statement of intended use in an
apparatus claim did not distinguish over the prior art apparatus)).
Lastly, with respect to the recitation of “provides an acceptable profile with respect to risk
of adverse reaction upon administration,” is directed to a resultant effect, and does not define the
structure of the “complex” itself.

28

The Court does note that the prosecution of the Patents-in-Suit contain repeated and
definitive remarks regarding “complex,” and as such affect the scope of this claim term. Based on
the intrinsic evidence presented, the Court determines that one skilled in the art would define the
term “complex” to mean—“a macromolecule or particle configured to be autoclavable without the
addition of excipients such as citrate.” The Court finds support for this construction in the
prosecution history of the ’498 patent, where Dr. Lewis argued that autoclaving in the presence of
citrate, as done in the prior art references Lewis and Groman, resulted in a risk of particulate
formulation. (See the ’498 patent, Applicant’s Arguments/Remarks filed April 25, 2002).
Accordingly, the claim term “complex” is defined—“a macromolecule or particle
configured to be autoclavable without the addition of excipients such as citrate.”

B. “COLLOID”
AMAG’s Proposed Construction

Sandoz’s Proposed Construction

“Any macromolecule or particle
having a size less than about 250 nm.”

“a mixture comprising any macromolecule or particle
of the complex of the present invention having a size
less than about 250 nanometers dispersed through a
second substance”

Representative claim 4 of the ’864 patent recites,
4.

A pharmacological composition comprising:
an autoclaved colloid comprising particles of a superparamagnetic iron
oxide coated with a carboxymethylated reduced dextran, the reduced dextran
having an average molecular weight of about 10 kDa; and
a biocompatible liquid, wherein the particles in the autoclaved colloid
having a diameter between about 10 nm and about 50 nm.

29

The Court notes that the ’864 patent is a continuation of the ’597 patent, and as such the ’864
patent shares the same disclosure as the ’597 patent. And, wherein the ’597 patent is a continuationin-part of the ’498 patent. (See supra fn. 2, 3).
AMAG asserts that its proposed definition should be adopted because it is consistent with
the definition provided in the specification of the ’864 patent. As its own lexicographer, the
inventor defined “colloid” to mean “any macromolecule or particle having a size less than about
250 nm [nanometer].” (See Pl.’s Br. at 16, fn. 22; D.I. 47, (citing the ’864 patent at 11:15-17
(‘“Colloid’ […] shall include any macromolecule or particle having a size less than about 250 nm
[nanometer].”)).
AMAG asserts that Sandoz’s proposed construction should not be adopted because the
specification never describes “colloid” as a mixture comprising of a macromolecule and a particle,
and that it is contrary to the definition recited in the specification. (See Pl.’s Br. at 17).
In contrast, Sandoz asserts that in reading the specification of the ’864 patent, one skilled
in the art would understand that “macromolecule or particle having a size less than about 250 nm”
is a reference to the complex of the alleged invention, which is dispersed through a second
substance or phase. (See Def.’s Br. at 23; D.I. 46). During the Markman hearing, Sandoz’s counsel
added that when interpreting the term “colloid” in claim 4, we look at the claim itself, which recites
“an autoclaved colloid comprising two things […] and a biocompatible liquid.” Sandoz’s counsel
further noted that because claim 4 is directed to a mixture of particle of the complex, which is
dispersed through a second substance. (See Trans. 84: 6-13).
Here, the Court finds Sandoz’s position persuasive in-part. Sandoz is correct in noting that
in interpreting “colloid,” we look at the claim itself. Here, claim 4 is directed to a pharmacological
composition, which comprises of two things—(i) an autoclaved colloid, and (ii) a biocompatible

30

liquid. The structure of the autoclaved colloid is further limited or defined by “particles of a
superparamagnetic iron oxide coated with a carboxymethylated reduced dextran.”
In other words, “colloid” comprises of superparamagnetic iron oxide particles that are
coated with a carboxymethylated reduced dextran. As such, based on a plain and ordinary reading
of claim 4, it would be apparent to one of ordinary skilled in the art that “colloid” does not include
a mixture as argued by Sandoz. Instead, the “colloid” simply consists of a single particle or
macromolecule.
The Court recognizes that “colloid” is defined in the specification of the ’864 patent to
mean, “any macromolecule or particle having a size less than about 250 nm [(nanometer)]”. (See
the ’864 patent at 11:15-17).
However, incorporating a limitation from the specification into a claim is improper. SciMed
Life Sys. Inc. v. Advanced Cardiovascular Sys. Inc., 242 F.3d 1337, 1340 (Fed.Cir.2001) (reading
a limitation from the specification into a claim is “one of the cardinal sins of patent law.”). As
such, the Court does not construe “colloid” to mean “having a size less than about 250 nm.”
Instead, based on a reading of the claims and intrinsic evidence, the Court defines “colloid” to
mean—“a macromolecule or a particle.”
C. “STABLE”
AMAG’s Proposed Construction
“does not form into a gel or form
substantial particulates and remains
clear and can be micro-filtered”

Sandoz’s Proposed Construction

Indefinite.
Alternatively: “retaining the same chemical,
physical, microbiological, therapeutic, and
toxicological properties and characteristics”

31

Representative claim 12 of the ’498 patent recites,
12. A reduced polysaccharide iron oxide complex produced according to the
method of claim 1, wherein the produced complex is stable at a temperature of at
least 100° C.
Sandoz asserts that the claim term “stable” as recited in the claims of the Patents-in-Suit is
indefinite because it is not precise enough to afford a skilled artisan of what properties define
stability. That is, a carbohydrate chemist may understand this term to mean physical and chemical
properties of a complex’s polymer coating, whereas a nephrologist may understand this term to
mean therapeutic and toxicological properties of the complex upon administration. (See Def.’s
Opening Br. at 21 (internal citations omitted); D.I. 46). As such, because this term is not capable
of informing those skilled in the art about the scope of the invention with reasonable certainty, the
term “stable” is definite. (Id.)
Generally, “a patent is invalid for indefiniteness if its claims, read in light of the
specification delineating the patent, and the prosecution history, fail to inform, with reasonable
certainty, those skilled in the art about the scope of the invention.” Nautilus, Inc. v. Biosig
Instruments, Inc., 572 U.S. 134 S.Ct. 2120, 2124 (2014).
Here, Sandoz, along with AMAG, has tabled the indefiniteness argument for a later
proceeding—after the Court construes the term “stable.” (See Trans. at 108:4-9 (“[T]he parties
have agreed that we’re going to push indefiniteness down to either the summary judgment phase
of the case or at trial.”).
“To determine whether [a] claim at issue is indefinite, we look at the patent record […] to
ascertain if they convey to one of skill in the art with reasonable certainty the scope of the invention
claimed.” Teva Pharmaceuticals USA, Inc. v. Sandoz, Inc., 789 F.3d 1335, 1341 (Fed. Cir. 2015).
“The purpose of claim construction is to ‘determin[e] the meaning and scope of the patent claims

32

asserted to be infringed.’” O2 Micro Intern. Ltd. v. Beyond Innovation Technology Co., Ltd., 521
F.3d 1351, 1359 (Fed. Cir. 2008) (citing Markman, 52 F.3d at 976).
Granted, submission of a proposed construction for a claim term does not amount to a
waiver of a later indefiniteness challenge. Leader Technologies, Inc. v. Facebook, Inc., 770
F.Supp.2d 686, 706 (D. Del. 2011) (internal citations omitted). However, construing the term
“stable” at the present time is futile because the Court would be delving into the same inquiry at a
later proceeding. Undertaking claim construction of this term is apt for a later time, after the Court
has reviewed and considered the indefiniteness arguments by the parties.
Accordingly, at the present time, the Court does not construe the term “stable” recited in
the Patents-in-Suit.
D. “AUTOCLAVING” AND “TERMINALLY STERILIZING”
i.

“Autoclaving”; “Autoclaved” and “Autoclavable”

AMAG’s Proposed Construction

Plain and ordinary meaning, which is
“heating or sterilizing under pressure and
steam for a period sufficient to eliminate
the viability of all microorganisms”
Plain and ordinary meaning, which is,
“able to withstand autoclaving.”
Plain and ordinary meaning, which is
“having undergone autoclaving.”

Sandoz’s Proposed Construction
“autoclaving”: “employing an autoclave
sterilization process, such that the postautoclaved
material:
(i) does not form substantial particulates (size or
quantity),
(ii) does not form a gel,
(iii) remains clear,
(iv) can be micro-filtered, and
(v) maintains therapeutic efficacy and adequate
safety with respect to risk of adverse reaction
(including minimal incidence of anaphylaxis) for
its intended purpose or administration”
“autoclavable”: “able to withstand autoclaving”
“autoclaved”: “having undergone autoclaving”

33

The representative claim for the patent term “autoclaving,” is claim 1 of the ’498 patent,
which recites:
1. A method of providing an iron oxide complex for administration to a mammalian
subject, the method consisting of:
producing a carboxyalkylated reduced polysaccharide iron oxide complex; and
sterilizing the complex by autoclaving.

ii.

“TERMINALLY STERILIZING” AND “TERMINALLY STERILIZABLE”

AMAG’s Proposed Construction

Plain and ordinary meaning, which is
“sterilizing a substance in its final
container”
“terminally sterilizable”: “able to
withstand terminally sterilizing”

Sandoz’s Proposed Construction
“terminally sterilizing”: “employing an autoclave
sterilization process of a material in its final, sealed
container which results in a composition that is
capable of administration”
“terminally sterilizable”: “able to withstand
terminally sterilizing”

The representative claim for the patent term “terminally sterilizing,” is claim 23 of the
’498 patent recites, which recites:
23.
A method of providing a hematinic agent for treating a subject deficient in
iron, consisting of the steps of:
formulating a composition which is a carboxymethylated reduced
ultrasmall iron oxide complex; and
terminally sterilizing the composition by autoclaving.
AMAG and Sandoz agree that the derivative terms “autoclaved” and “autoclavable” should
be construed to mean “having undergone autoclaving” and “able to withstand [or capable of
withstanding] autoclaving,” respectively. (See Pl.’s Opening Br. at 20, fn. 30; D.I. 47, citing Joint
Claim Construction and Prehearing Statement; D.I. 38 at 28—29; also see Trans. 90:14-18).
Similarly, the parties agree that “terminally sterilizing” and the derivative term “terminally
sterilizable” should be construed as “able to withstand terminally sterilizing.” (See Pl.’s Opening
34

Br. at 23, fn. 36; D.I. 47, citing Joint Claim Construction and Prehearing Statement; D.I. 38 at 39;
also see Trans. 125:10-11 (“And the parties largely agree as to the definition of terminally
sterilizable”)).
The parties agree that “autoclaving” or autoclave sterilization process involves—“heating
or sterilizing under pressure and steam for a period sufficient to eliminate the viability of all
microorganisms.” (See Pl.’s Opening Br. at 21, fn. 32 (citing Sandoz’s Invalidity Contentions at
29—32); also see Def.’s Opening Br. at 15; D.I. 46); also see Trans. 90:25—91:1-4 (“There’s not
a dispute that what autoclaving is to heat something up in a wet high pressure temperature, and
that’s the way as Mr. Razoczy [Sandoz’s counsel] said previously you kill the microorganisms.
There’s not a dispute [] that’s the common meaning of autoclave.”); also see Trans. 92:17-20
(“There’s agreement that Sandoz agrees with AMAG that an autoclave sterilization process
involves “heating or sterilizing under pressure and steam for a period sufficient to eliminate the
viability of all microorganisms.’”).
However, Sandoz argues that based on the intrinsic evidence, “a skilled artisan would
understand the post-autoclaved material (i.e., the complex) to possess [certain] characteristics.”
(See Def.’s Opening Br. at 15; D.I. 46; also see Trans. 98:21-23 (“the process of autoclaving and
it changes the material [complex]”); Trans. 100:12-15 (“property of autoclavability”)). These
characteristics of the post-autoclaved material being—(i) not forming substantial particulates (size
or quantity); (ii) not forming a gel; (iii) remaining clear; (iv) able to be micro-filtered; (v) able to
maintain therapeutic efficacy and adequate safety with respect to anaphylaxis. (See Def.’s Opening
Br. at 15-16).
Sandoz asserts that one skilled in the art would construe the term “autoclaving” to mean
these aforementioned characteristics because in the prosecution history of the Patents-in-Suit,

35

AMAG differentiated the post-autoclaved material from the cited art based on the material’s
characteristics (i.e., size, quantity, efficacy, etc.). (Id. at 16; citing prosecution history of the ’498
patent, the ’479 patent, and the ’597 patent). As such, one skilled in the art would understand the
term “autoclaved” to include the aforementioned characteristics.
In contrast, AMAG argues that Sandoz’s proposed construction seeks to import structural
characteristics with regards to the material—the iron oxide complex—which are unrelated to the
term “autoclaving” itself. (See Pl.’s Reply Br. at 20; D.I. 53). As such, AMAG maintains that the
term “autoclaving” should be given its plain and ordinary meaning, and additional limitations
proposed by Sandoz should not be incorporated into this term.
The ’498 patent discloses that the final sterilization process for the colloids of the ’498
patent is autoclaving, which is a preferred method because it eliminates viability of all cellular life
forms including bacterial spores and viruses. (See the ’498 patent, col. 11, ll. 45-47). The agents
that are embodiments of the present invention are heat sterilized by autoclaving, and thus
optimized for long-term storage at ambient temperatures. Thereby, these agents, inter alia,
maintain stability during the sterilization or storage process, and are non-toxic to mammals at
higher doses. (See Id. at col. 11, ll. 60—col. 12, ll. 5). The “heat stress” being defined as heating
the colloid to approximately 121°C, or higher for about 30 minutes at neutral pH, or other
combinations of time, temperature, and pH that are known in the art to autoclave an injectable
drug. (Id. at col. 10, ll. 35-40).
During prosecution of the ’498 patent, in response to an Office action, the Applicant
provided a declaration from Dr. Jerome Lewis, a co-inventor on the ’498 patent. In his declaration,
Dr. Lewis stated that “autoclaving normally requires temperatures of at least 121 degrees [C] (see,
for example, Exhibit C), and in any event at least 115 degrees C.” (See the ’498 patent, Applicant’s

36

Arguments/Remarks at 4, filed April 25, 2002). In the notice of allowance, the patent examiner
noted that Dr. Lewis’s Declaration was sufficient and persuasive to overcome the prior art because
the material in the prior art was “not stable upon autoclaving (heating at 121°C for 30 minutes),”
unlike the material in the ’498 patent. (See the ’498 patent, Notice of Allowance mailed on January
22, 2003).
Based on the intrinsic evidence, the Court does not find Sandoz’s proposed claim
construction persuasive. The additional characteristics provided in Sandoz’s proposed
construction—i.e., size and quantity of the particulates; lack of gel formation; maintaining
therapeutic efficacy and adequate safety, etc.—pertain to the material of the iron oxide complex.
Not to the process of autoclaving.
These characteristics cannot pertain to “autoclaving” because autoclaving requires taking
a series of actions or steps in order to achieve a particular end. Granted, during prosecution the
Applicant made remarks pertaining to the physical and chemical properties of the material, and
how it is stable after autoclaving. (See the ’498 Patent; Applicant’s Arguments/Remarks at 6-7,
filed October 9, 2001). However, these characteristics do not pertain to a series of actions or steps.
Instead, these characteristics pertain to the end product of the material that has been subjected to
autoclaving.
As such, the Court does not find Sandoz’s proposed construction persuasive as it
incorporates limitations from the prosecution history that pertain to the material, the iron oxide
complex, and not the process of autoclaving.
Absent incorporation of the aforementioned characteristics, the Court adopts in-part the
agreed upon definition between the parties. The agreed upon definition between the parties
includes characteristics of time and temperature to achieve the desired result—the elimination of

37

the viability of all microorganisms. This language of the proposed construction is consistent with
the intrinsic evidence. (See the ’498 patent, col. 10, ll. 35-40 (“heating the colloid to approximately
121°C, or higher for about 30 minutes at neutral pH, or other combinations of time, temperature,
and pH that are known in the art to autoclave an injectable drug”); also see the ’498 patent,
Applicant’s Arguments/Remarks at 4, filed April 25, 2002 (“autoclaving normally requires
temperatures of at least 121 degrees [C] (see, for example, Exhibit C), and in any event at least
115 degrees C.”)).
However, in addition to the proposed definition of “autoclaving,” the Court finds that the
definition of “autoclaving” should also include “a material in a final container.” This language is
adopted in-part from the proposed construction of the term “terminally sterilizing” or “terminally
sterilizable.” (See Trans. 126:12-15 (“Also the prosecution history, in Dr. Lewis' declaration
submitted on January 27th, 2007, in paragraph 7 states that terminal sterilization in the final
container is preferred.”)).
The Court relies on the proposed construction of the aforementioned terms because the
intrinsic evidence dictates that the terms “autoclaving” and “terminally sterilizing” are synonyms.
((See the ’498 patent, col. 10, ll. 40-41 (“autoclave (or terminally sterilize) an injectable drug”);
also see the ’498 patent, Applicant’s Arguments/Remarks filed April 25, 2002 (“Terminal
sterilization (autoclaving) being favored over filter sterilization.”); also see the ’597 patent, col.
13, ll. 4-5 (“Terminal sterilization (autoclaving) is a preferred method of sterilizing drugs for
injection.”); also see the ’597 patent, Applicant’s Arguments/Remarks at 7, filed July 3, 2006 (“use
of terminal sterilization (autoclaving) over filter sterilization is preferred because terminal
sterilization provides a much higher level of sterility assurance”); also see Trans. 126:1-6 (“And
the intrinsic record makes clear that sterilization takes place or terminal sterilization takes place in

38

the final container. For instance in the '498 patent at column 7, lines 53 through 54, the patent
states: Terminal sterilization (autoclaving) is a preferred method of sterilizing drugs for
injection.”)).
Throughout the prosecution history and specification of the Patents-in-Suit, AMAG used
the terms autoclave and terminal sterilization interchangeably. Often denoting and referring them
to mean the same. By reciting these terms as “autoclave (or terminally sterilize)” or “terminal
sterilization (autoclaving),” without providing further distinguishing characteristics or features
between the two terms, the Court finds the terms “autoclaving” and “terminally sterilizing” to have
the same scope and meaning. In other words, these terms are construed to be synonyms. (See Trans.
127:23—128:1 (“if the autoclaving or autoclavable was already in the claim[,] there is no need to
include it in the construction in the term terminally sterilizing.”). By reciting these terms
interchangeably, it is evident that any “autoclaving” being done to the material is being done when
the material is in a final container, which is capable of being injected into a subject.
The Court notes that Sandoz’s claim construction recites “final, sealed container” as
opposed to AMAG’s construction, which simply recites “final container.” The ’498 patent does
disclose a 5ml glass vial being sealed. (See the ’498 patent, col. 25, ll. 1-3 and ll. 28-29). However,
the Court does not incorporate the term “sealed” in construing the aforementioned terms for two
reasons.
First, “sealed” container is only one example disclosed in examples 30 and 31. (See the
’498 patent, col. 24, ll.50—col. 25, ll. 30). By incorporating the same in the claims, the Court
would be excluding the other disclosed examples in the specification. See Phillips, 415 F.3d at
1323 (recognizing that the embodiments in a patent often are examples meant to teach a person of

39

ordinary skill in the art how to make and use the invention, but should not be construed to limit
the invention only to a specific embodiment).
Second, including the term “sealed” into the claim language would require importing
limitations from the specification into the claim, which is one of the cardinal sins of patent law.
SciMed Life Sys. Inc. v. Advanced Cardiovascular Sys. Inc., 242 F.3d 1337, 1340 (Fed.Cir.2001)
(reading a limitation from the specification into a claim is “one of the cardinal sins of patent law.”).
As such, the Court does not incorporate the term “sealed,” as proposed by Sandoz, into the claim
language.
Accordingly, the Court defines the terms “autoclaving” and “terminally sterilizing” to
mean the same, which is— “heating or sterilizing a material in a final container under pressure and
steam for a period sufficient to eliminate the viability of all microorganisms in the material.”

E. “Injectable”; “Intended for administration by injection”
AMAG’s Proposed Construction

Sandoz’s Proposed Construction

Plain and ordinary meaning, which is
“capable of being injected into a
patient.”

“injectable”: “capable of injection from the vial
directly into a mammalian subject without further
sample preparation”;
“intended for administration by injection”:
“injectable,” as defined above

Representative claim 1 of the ’479 patent,
1. A pharmaceutical composition in a vial comprising an injectable reduced
carboxymethylated dextran iron oxide complex, wherein the carboxymethylated
reduced dextran comprises at least 750 micromole and less than 1500 micromole
of carboxyl groups per gram of dextran and wherein said complex is stable at a
temperature of at least about 100°C.

40

Initially, the Court notes that that the claim term “injectable,” recited in claim 1 of the ’479
patent, and the claim term “intended for administration by injection,” recited in claim 1 of the ’947
patent, essentially mean the same. (See Trans. 152:10-14 (“There doesn't seem to be a dispute that
intended for administration by injection is the same as injectable, so we're construing these claims
together.”)). In other words, construing the term “injectable” would in effect the construe the term
“intended for administration by injection.” As such, now, the Court will define the term
“injectable.”
AMAG argues that the claim term “injectable” should not be construed to mean additional
terms such as “from the vial directly into a mammalian subject without further sample
preparation,” as proposed by Sandoz, because such construction is contrary to the plain and
ordinary meaning. Moreover, AMAG asserts that Sandoz’s reliance on Dr. Frigo’s statements
during prosecution of the Patents-in-Suit is improper because Dr. Frigo’s statements were limited
to distinguishing the complexes of the present invention from those disclosed in the prior art
references. That is, Dr. Frigo’s statements centered around complexes of prior art not being stable
when autoclaved, unlike complexes of the present invention. (See Pl.’s Br. at 26, D.I. 47).
In contrast, Sandoz asserts that claim 1 of the ’479 expressly recites, inter alia, “[a]
pharmaceutical composition in a vial comprising an injectable reduced carboxmethylated dextran
iron oxide complex […].” The pharmaceutical composition “in a vial” being “injectable,” thereby
requiring direct injection from a vial with further preparation. (See Def.’s Br. at 27; D.I. 46). In
support, Sandoz asserts that during prosecution, AMAG repeatedly confirmed that direct injection
from a vial without further sample preparation is a unique attribute to the invention, which allows
for “superior administration profiles,” compared to prior art complexes. As such, asserting that

41

one skilled in the art would understand “injectable” to mean “capable of injection from the vial
directly into a mammalian subject without further sample preparation.” (Id. at 28).
When reading claim 1 of the ’479 patent, the Court determines that claim 1 is essentially
directed to a pharmaceutical composition in a vial. Wherein the pharmaceutical composition
comprises a reduced carboxymethylated dextran iron oxide complex. This complex being
“injectable” from the vial. For example, the injected volume of the complex being injected as a
bolus. (See the ’479 patent, col. 3, ll. 25-26). The ’479 patent notes that advantages of multiple
bolus injections, within a single examination, being that any deficiencies in an imaging can be
corrected. (Id. at col. 36, ll. 32-35).
The Court notes that Sandoz’s proposed construction has two issues. First, the term
“directly,” proposed by Sandoz, is not recited in the ’479 patent with reference to the injection of
the complex from the vial. The only recitation of “directly” in the ’479 patent is with respect to a
mixture that is used “directly in the preparation of USPIO [Ultrasmall superparamagnetic iron
oxide].” As such, the Court notes that Sandoz’s proposed construction of “directly” in construing
“injectable” is improper and is not supported by intrinsic evidence.
Second, and lastly, “without further sample preparation,” recites a negative limitation that
is also unsupported by the specification. Generally, for a negative limitation to be recited in a claim
language, the specification should expressly recite the negative limitation. (See MPEP 2173.05(i)
“Negative Limitation” (Any negative limitation or exclusionary proviso must have basis in the
original disclosure.”)). Here, the ’479 patent does not expressly recite or have basis for such a
negative claim limitation. As such, incorporating such a limitation can lead to indefinite issues
under 35 U.S.C. 112, second paragraph.

42

The term “injectable,” which modifies the complex recited in claim 1 of the ’479 patent,
should be given its plain and ordinary meaning. However, the Court does note that recitation of
terms “patient” or “mammalian” to define “injectable” are not required because recitation of whom
the pharmaceutical composition is administered is directed to intended use, which generally is not
given patentable weight. (See MPEP 2111; In re Sinex, 309 F.2d 488, 492 (CCPA 1962) (statement
of intended use in an apparatus claim did not distinguish over the prior art apparatus)).
Accordingly, the terms “injectable” and “intended for administration by injection,” are
construed to mean—“capable of being injected.”
F. “ADMINISTRATION” & “ADMINISTERING PARENTERALLY”
i.

“Administration”

AMAG’s Proposed Construction

Plain and ordinary meaning, which is
“giving of a pharmacological agent”

Sandoz’s Proposed Construction
Plain and ordinary meaning, “to deliver into a
subject”

With respect to the claim term “Administration,” the representative claim is claim 1 of
the ’597 patent, which recites—
1. A unit dosage of a pharmacological composition comprising a terminally
sterilizable autoclavable reduced carboxymethylated dextran iron oxide complex
composition which is stable at 121 C and is prepared,
in a total volume of biocompatible liquid from about 1 mL to about 15 mL
and for a total single dose from about 50 mg to about 600 mg, the pharmacological
composition capable of being parenterally administered to a subject at a rate
substantially greater than 1 mL/min and wherein the unit dosage provides upon
administration:
minimal detectable free iron in the subject; and
minimal incidence of anaphylaxis.

43

ii.

“Administering Parenterally”; “Parenterally Administered”

AMAG’s Proposed Construction

Plain and ordinary meaning, which is
“giving of a pharmaceutical agent by a
means other than through the
alimentary canal”

Sandoz’s Proposed Construction
Plain and Ordinary meaning
“administering parenterally”: “delivering into a
subject’s body by a means other than through the
alimentary canal”
“parenterally administered”: “delivered into a
subject’s body by a means other than through the
alimentary canal”

With respect to the claim term “Administering Parenterally” and “Parenterally
Administered,” the representative claim is claim 1 of the ’597 patent, which recites—
1. A unit dosage of a pharmacological composition comprising a terminally
sterilizable autoclavable reduced carboxymethylated dextran iron oxide complex
composition which is stable at 121 C and is prepared,
in a total volume of biocompatible liquid from about 1 mL to about 15 mL
and for a total single dose from about 50 mg to about 600 mg, the pharmacological
composition capable of being parenterally administered to a subject at a rate
substantially greater than 1 mL/min and wherein the unit dosage provides upon
administration:
minimal detectable free iron in the subject; and
minimal incidence of anaphylaxis.

With respect to the aforementioned patent claim terms, the parties agree that they dispute
only as to the term “administration.” (See Trans. 136:18—137:1 (“the parties agree that the
construction or the meaning of the term parenterally in the dispute for that related term is […] the
parties have nothing additional to talk about with respect to parenterally administering other than,
you know, the definition of administration.”); also see Trans. 137:19-21 (“There’s really only just
one dispute here, it’s whether the term administration requires delivery into a subject.”)). As such,

44

based on the agreement between the parties as to the disputed issue, the Court is going to limit its
claim construction to the term “administration.”
AMAG argues that “administration” should be construed to mean “giving a
pharmacological agent” because claims and specification of the ’498 recites the aforementioned
term to provide a composition containing the disclosed iron oxide complex to a mammalian
subject. (See AMAG’s Br. at 27-28; Dkt. No. 47; citing the ’498 patent at col. 1:66—2:1, 3:23-59,
36:44—46; also see Trans. 136:9-17).
In contrast, Sandoz asserts that the aforementioned term should be interpreted to mean “to
deliver into a subject” because an administration can only occur by actual delivery into a subject
as there is detection of free iron in the subject and incidence of anaphylaxis, as required by the
claim language. (See Trans. 138:7-10 (“the only way that administration can occur […] if it’s
delivered into a subject.”). During the Markman hearing, Sandoz’s counsel cited AstraZeneca,
wherein the Court stated that “a person of ordinary skill in the art would understand the term
administration to refer to the means of delivering the medication to an individual.” AstraZeneca
AB v. Hanmi USA, Inc., 2012 WL 6203602, at *5-6 (D.N.J. Dec. 12, 2012) (Trans. 138:14-18).
The Court finds Sandoz’s argument persuasive that the aforementioned deals with
administration to a subject because the claim language recites, “pharmacological composition
capable of being parenterally administered to a subject,” and “the unit dosage provides upon
administration: minimal detectable free iron in the subject; and minimal incidence of anaphylaxis.”
(See claim 1 of the ’597 patent). That is, before and after the term “administration” in claim 1 of
the ’597 patent, the subject is being provided the pharmacological composition, which results in
detecting free iron in the subject and incidence of anaphylaxis. (See Trans. 138:21-24 (“You
wouldn’t have [administration of minimal detectable free iron in the subject] unless something is

45

actually delivered into the subject.”)). Moreover, the specification of the parent patent ’498 recites
that the pharmaceutical drug is administered either as a bolus or as an intravenous solution. (See
the ’498 patent, col. 3, ll. 17-19 and 29).
The Court further notes that the term “administration” in claim 1 of the ’597 patent likely
relates back to the “paternally administered” step as recited in the claim. As such, instead of
reciting “paternally administering” in the claim, the Applicant wrote the short hand version of
“administration.”
Accordingly, the Court construes the term “administration” to mean—“giving a
pharmacological composition to a subject.”
G. “Cooling the Resulting Solution”
AMAG’s Proposed Construction

Sandoz’s Proposed Construction

“cooling the solution containing the
mixture of carboxymethylated reduced
dextran, ferric and ferrous salts.”

“cooling the solution formed by contacting the
carboxymethylated reduced dextran with a mixture of
ferric and ferrous salts”

Representative claim 1 of the ’947 patent recites,
1. A method of making an autoclavable carboxymethylated reduced dextran iron
oxide complex intended for administration by injection to a mammalian subject,
the method comprising the steps of:
(i) reacting a dextran with a borohydride salt, or hydrogen in the presence
of a hydrogenation catalyst, to produce a reduced dextran;
(ii) carboxymethylating the reduced dextran to produce a
carboxymethylated reduced dextran;
(iii) complexing the carboxymethylated reduced dextran with an iron salt to
produce a carboxymethylated reduced dextran iron oxide complex; and
(iv) sterilizing the carboxymethylated reduced dextran iron oxide complex
by autoclaving;
the complexing comprising contacting the carboxymethylated reduced
dextran with a mixture of ferric and ferrous salts, cooling the resulting solution
and adding ammonium hydroxide to neutralize the solution and recovering the
carboxymethylated reduced dextran iron oxide complex; such complex being stable
46

at a temperature of at least about 121° C. for a period effective to sterilize the
complex;
wherein the reduced dextran has an average molecular weight of about 10
kDa and a particle size of 10 nm to 50 nm; and
the carboxymethylated reduced dextran comprises at least about 1100
micromoles of carboxyl groups per gram and less than about 1500 micromoles of
carboxyl groups per gram.

The aforementioned claim term was not argued during the Markman hearing. Instead, the
parties stipulated to their papers in support of their argument. (See Trans. 157:19-24). In its opening
brief, AMAG argues that this claim term appears only in the claims of the ’947 patent. (See Pl.’s
Br. at 29, fn. 42; D.I. 47). The Court notes that the disclosure of the ’947 patent relates back to the
disclosure of the parent patent ’597 patent because the ’947 patent is essentially a continuation of
the ’597 patent. (See supra fn. 2).
In support of its position, AMAG asserts that the common meaning of the claim merely
requires cooling a solution that contains three components—the carboxymethylated reduced
dextran, the ferric salts and the ferrous salts. In other words, it is the solution which contains all
three components that is cooled. As such, the claim does not require that the solution be formed in
a particular way, as proposed by Sandoz. (See Pl.’s Br. at 29-30).
In contrast, Sandoz asserts that its construction of the aforementioned term is based on the
claim language itself. That is, as recited in claim 1 of the ’947 patent, the complexing includes
“contacting the carboxymethylated reduced dextran with a mixture of ferric and ferrous salts.”
And, because this is the only solution that would have antecedent basis for the term resulting, and
one that is consistent with the chemical reactions involved, this interpretation should be
maintained. (See Def.’s Br. at 29; D.I. 46).
Here, the Court finds Sandoz’s claim construction persuasive. When reviewing claim 1 of
the ’947 patent, it is important to note that it is a method or a process claim. We know that claim
47

1 is a method claim because of its—(i) preamble (“A method of making […]”), and (ii) the body
of the claim. It is important to remember that the elements, or the body, of a method claim are
method steps, which should usually be verbal (gerundial) phrase, introduced by a gerund or verbal
noun (the “-ing” form of a verb).5 The body of claim 1 recites method steps that are introduced by
gerund or verbal phrases, for example, “reacting;” “carboxymethylating;” “complexing;” and
“sterilizing.” From the body of claim 1, it appears that four (4) steps are recited. However, upon a
closer review, it appears that claim 1 recites a fifth step of “cooling.”
Line 12 of claim 1 starts as “the complexing comprising contacting the carboxymethylated
reduced dextran with a mixture of ferric and ferrous salts, cooling the resulting solution and adding
[…].” It is clear that “the complexing” in this phrase is referring back to the third step of claim 1
in order to ensure proper antecedent basis under pre-AIA (America Invents Act) 35 U.S.C. § 112,
second paragraph. In line 12 of claim 1, the inventor further defined the complexing step to
“compris[e] [of] contacting the carboxymethylated reduced dextran with a mixture of ferric and
ferrous salts.” As such, a reasonable person of ordinary skill in the art would interpret the third
step of claim 1 to recite, ‘complexing comprising contacting the carboxymethylated reduced
dextran with a mixture of ferric and ferrous salts to produce a carboxymethylated reduced dextran
iron oxide complex.’
After performing the fourth step of sterilizing, the last step to follow is “cooling” of the
resulting solution, wherein the ‘resulting solution’ is what was synthesized in the fourth step. And
by reading the entire claim 1, it is apparent to one of ordinary skill in the art that the ‘resulting
solution,’

includes

the

autoclaved

carboxymethylated

5

reduced

dextran

iron

oxide

See Chapter 4: Method or Process Claims. § 4:2 Elements of Method Claims, available at
http://www.pli.edu/public/booksamples/16966_sample4.pdf, (last visited July 15, 2017).

48

complex. Wherein, the carboxymethylated reduced dextran iron oxide complex is formed by
contacting the carboxymethylated reduced dextran with a mixture of ferric and ferrous salts.
Accordingly, the Court interprets the claim term “cooling the resulting solution” to mean—
“cooling the solution formed by contacting the carboxymethylated reduced dextran with a mixture
of ferric and ferrous salts.”
ORDER
IT IS on this 19th day of July, 2017,
ORDERED that “complex” is defined as—“a macromolecule or particle configured to be
autoclavable without the addition of excipients such as citrate”;
ORDERED that “colloid” is defined as—“a macromolecule or a particle”;
ORDERED that “autoclaving” and “terminally sterilizing” are defined as— “heating or
sterilizing a material in a final container under pressure and steam for a period sufficient to
eliminate the viability of all microorganisms in the material”;
ORDERED that “injectable” and “intended for administration by injection” are defined
as—“capable of being injected”;
ORDERED that “administration,” “administering parenterally,” and “parenterally
administered” are defined as—“giving a pharmacological composition to a subject”; and it is
further
ORDERED that “cooling the resulting solution” are defined as—“cooling the solution
formed by contacting the carboxymethylated reduced dextran with a mixture of ferric and ferrous
salts.”

s/Peter G. Sheridan
PETER G. SHERIDAN, U.S.D.J.
49