Stemcells, Inc. et al v. Neuralstem, Inc.
Filing
251
MEMORANDUM OPINION. Signed by Judge Alexander Williams, Jr on 8/11/2011. (kns, Deputy Clerk)
IN THE UNITED STATES DISTRICT COURT
FOR THE DISTRICT OF MARYLAND
SOUTHERN DIVISION
STEMCELLS, INC. et al.
Plaintiffs,
v.
Action No. 08:06–CV–1877—AW
NEURALSTEM, INC.
Defendant.
MEMORANDUM OPINION
Plaintiffs StemCells, Inc. and Stemcells, California, Inc. (collectively, “StemCells”) filed
this action against Neuralstem, Inc., Karl Johe, and I. Richard Garr, on July 24, 2006, alleging
Neuralstem infringed several of StemCells’ patents in violation of 28 U.S.C. §§1, et seq. The
parties have requested that the Court construe several claim terms that are in dispute in this case.
A.
STANDARD OF REVIEW
Claim construction is decided by the court as a matter of law. Markman v. Westview
Instruments, Inc., 52 F.3d 967, 970-71 (Fed. Cir. 1995) (en banc), aff’d 517 U.S. 370 (1996).
“The duty of the trial judge is to determine the meaning of the claims at issue, and to instruct the
jury accordingly.” Exxon Chem. Patents, Inc. v. Lubrizoil Corp., 64 F.3d 1553, 1555 (Fed. Cir.
1995) (citations omitted), cert. denied, 518 U.S. 1020, 116 S. Ct. 2554, 135 L. Ed. 2d 1073
(1996). In order to determine the meaning of a claim term, the Court should first look to the
plain language of the claim and presume it carries its “ordinary and customary meaning.”
Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1324 (Fed. Cir. 2002); Vitronics Corp. v.
Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996). The ordinary and customary meaning
is defined as the meaning that the claim term would have to a person having ordinary skill in the
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art at the date the patent application in question was filed. Phillips v. AWH Corp., 415 F.3d 1303
(Fed. Cir. 2005) (en banc).
In order to ascertain the ordinary and customary meaning of a disputed claim term, the
claims themselves must be thoroughly examined. If a claim term is used more than once
throughout the patent, the “usage of a term in one claim can often illuminate the meaning of the
same term in other claims.” Markman, 52 F.3d at 978. “Differences among the claims can also
be a useful guide in understanding the meaning of particular claim terms.” Id. Further, the
language used to separate the preamble of a claim from the body of a claim can offer insight into
the claims’ meaning. See Gillette Co. v. Energizer Holdings, Inc., 405 F. 3d 1367, 1371 (Fed.
Cir. 2005). For example, “the word ‘comprising’ transitioning from the preamble to the body
signals that the entire claim is presumptively open-ended.” See id. (citing Crystal Semiconductor
Corp. v. TriTech Microelectronics Int'l, Inc., 246 F.3d 1336, 1347 (Fed. Cir. 2001)). Finally,
“the presence of a dependent claim that adds a particular limitation gives rise to a presumption
that the limitation in question is not present in the independent claim.” Phillips, 415 F.3d at
1315.
If there is ambiguity as to the ordinary and customary meaning, it is proper for the Court
to look to the specification in order to determine the “true intent and meaning of the language in
the claims.” Bates v. Coe, 98 U.S. 31, 38 (1878); see also Phillips, 415 F.3d at 1316. The
specification, in conjunction with the prosecution history and the prior art cited during the patent
prosecution serve as intrinsic evidence and can be used to ascertain the true meaning of the
disputed claim terms. Phillips, 415 F.3d at 1319-24. Preferred embodiments in the specification
should be used to assist in determining the claim scope since these embodiments reflect the
inventor’s desired use for his or her patent. However, if a proposed claim construction excludes
a preferred embodiment from the claim scope, this construction is rarely correct. Phillips, 415
F.3d at 1316; Anchro Wall Systems, Inc. v. Rockwood Retaining Walls, Inc., 340 F.3d 1298, 1308
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(Fed. Cir. 2003). On the other hand, it is improper to read limitations from the specification into
the claims unless the specification makes consistent and repeated statements leading to the
“inescapable conclusion” that a limitation stated only in the specification is part of the claimed
invention. Phillips, 415 F.3d at 1323. In order to add a limitation that excludes certain
embodiments of the invention to a claim, there must be some “express disclaimer or independent
lexicography in written description that would justify adding a negative limitation.” Omega
Eng’g, Inc. v. Raytek Corp., 334 F.3d 1314, 1322-23 (Fed. Cir. 2003).
In addition to the intrinsic evidence, dictionaries, expert testimony, and documents or
prior art not part of the prosecution history may be used to determine the true meaning of a claim
term, however, these documents are considered extrinsic evidence. Id. Although extrinsic
evidence may be used to assist the court in determining the meaning of the disputed claim terms,
intrinsic evidence will shed greater light onto what the term means to a person having ordinary
skill in the art, and thus carries more weight than extrinsic evidence. Id. It is not necessarily
important which order the Court consults these references in; what matters is that the Court gives
the consulted sources the appropriate weight. Id. at 1324 (citing Vitronics, 90 F.3d at 1582).
Because the Court must determine what the disputed claim terms would mean to a person having
ordinary skill in the art at the time of invention, it is most important to understand the claim term
in light of the invention’s scope, as determined by the claims themselves, the specification, the
prosecution history and the prior art. See id. at 1319-24.
B. CLAIM CONSTRUCTION OF DISPUTED TERMS
a. “multipotent” (Term No. 4)
Found in the following claims: 1, 2, 8, 21, 34, 36, 37, 39, 40, 41, 43, 44, 45, 47, 54,
55, 56, 60, 61, 67, 70, 72, 75, 79, and 80 of the ‘832 patent; 1, 7, and 24 of the ‘418
patent; 9 and 24 of the ‘505 patent; 1 and 10 of the ‘346 patent; 1 and 10 of the ‘709
patent; and 1, 8, 9, and 22 of the ‘872 patent.
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"multipotent"
Neuralstem's Proposed Construction
The progeny of a single neural stem cell have
multiple differentiative pathways such as
neurons, astrocytes (type 1 and type II), and
oligodendrocytes.
StemCells' Proposed Construction
When used in referring to a cell, means that
the progeny of the cell have multiple
differentiative pathways.
The parties’ proposed constructions of this term are substantively similar in that both
parties define the progeny of a multipotent cell to have “multiple differentiative pathways.” The
conflict between the two constructions arises because Neuralstem’s proposed construction
defines multipotent exclusively in terms of neural stem cells whereas StemCells prefers a
broader definition of multipotent that is applicable to stem cells of a non-neural lineage. By
referring only to neural stem cells, Neuralstem’s construction of “multipotent” correctly includes
the phrase, “such as neurons, astrocytes (type I and type II), and oligodendrocytes.” The
correctness of the examples is not in dispute as StemCells admits that Neuralstem’s
“construction is . . . applicable when the term ‘multipotent’ is used in conjunction with ‘neural
stem cells.’” Doc. No. 169, at 46. The prevailing issue is whether the term “multipotent” should
refer to all cells or just neural stem cells.
The Court needs to look no further than the specification to determine the proper scope
and thus proper construction of “multipotent.” The ‘832 patent clearly supports Neuralstem’s
definition of the claim term. The specification states, “[t]he progenitor cells generated from a
single multipotent neural stem cell are capable of differentiating into neurons, astrocytes (type I
and type II) and oligodendrocytes. Hence, the neural stem cell is ‘multipotent’ because its
progeny have multiple differentiative pathways.” U.S. Patent No. 5,851,832 col.12 ll.59-64
(filed Dec. 22, 1998). Both parties’ constructions are based on the specification; however,
StemCells’ definition of “multipotent” encompasses only a portion of the meaning given to the
claim term in the specification. Neuralstem’s construction of “multipotent” encompasses the
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entirety of the specification giving the term a definition which includes the specific
differentiative pathways of a multipotent neural stem cell’s progeny—neurons, astrocytes (type I
and type II), and oligodendrocytes. The “multiple differentiative pathways” referenced in the
specification and used in StemCells’ construction appear to simply summarize the specific types
of pathways previously mentioned in the specification. Thus, adopting StemCells’ construction
would require the Court to ignore the specific types of differentiative pathways that the
specification has explicitly mentioned to characterize multipotent neural stem cells in favor of a
summation of the pathways.
StemCells alleges that “multipotent” has “broader meanings and can be used to describe
stem cells of a non-neural lineage . . . . Neuralstem’s proposed definition of ‘multipotent’ would
therefore be completely at odds with the state of the art at the time of the filing.” Doc. No. 175,
at 58. Assuming StemCells’ premise to be true, the Court finds it irrelevant as the Court believes
that the patents-in-suit simply contemplate “progenitor cells generated from a single multipotent
neural stem cell,” not stem cells of a non-neural lineage. ‘832 Patent col.12 ll.59-60. StemCells,
in support of their premise, has cited an article from the Immunology and Cell Biology journal
proving that at the time of the filing, the term “multipotent” applied to stem cells of a non-neural
lineage, including “a multipotent hematopoietic (blood) cell.” Doc. No. 175, at 58. Yet, the
Court is not persuaded because Neuralstem’s construction is not meant to be a broad definition,
but rather only a definition applicable to the patents-in-suit. Further, the Court believes that the
patentee understood the term “multipotent” to only describe stem cells of a neural lineage. The
patent specification provides convincing evidence to support the Court’s conclusion that only
neural stem cells were considered. Therefore, the Court believes that the patents-in-suit only
describe neural stem cells, and thus the proper construction of the term “multipotent” does the
same.
Accordingly, the Court will adopt Neuralstem’s proposed construction of this claim term.
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b. “culture medium” (Term No. 21)
Found in the following claims: 1, 2, 3, 4, 8, 21, 22, 30, 31, 32, 33, 34, 35, 38, 40, 44,
45, 46, 47, 48, 49, 52, 53, 54, 58, 69, and 77 of the ‘832 patent; 1, 3, 7, and 9 of the
‘418 patent; 1, 2, 3, 13, 14, 18, 19, 20, 25, and 26 of the ‘505 patent; and 1, 3, 5, 8,
and 22 of the ‘872 patent.
"culture medium"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Liquid capable of supporting cell growth and
may contain serum or be serum-free.
A liquid or solid nutrient preparation capable
of supporting cell cultivation; culture medium
may contain serum or may be serum-free.
The parties agree that “culture medium” “support[s] cell growth and may contain serum
or be serum-free”. The parties dispute whether “culture medium” should be defined as a liquid
or both a liquid and “solid nutrient preparation.”
Neuralstem alleges that only a liquid form of “culture medium” should be included in the
term’s construction because only the liquid form of “culture medium” is described in the
specification. StemCells does not dispute Neuralstem’s contention that the specification fails to
mention a solid nutrient preparation of “culture medium” as “[n]eural cells are typically
cultivated in liquid culture media.” Doc. No. 169, at 49. However, StemCells believes that this
omission from the specification does not lead to the conclusion that solid nutrient preparation
should be excluded from the definition of “culture medium.”
On the contrary, StemCells argues that no precedential authority exists which mandates
that “the specification must describe or provide examples in order to include an art-known
embodiment into a claim term.” Doc. No. 175, at 54. StemCells claims “culture medium”
includes solid nutrient preparation in its “ordinary and customary meaning as understood by one
or [sic] ordinary skill in the art.” Doc. No. 169, at 48. StemCells cites the Concise Dictionary of
Biomedical and Molecular Biology, Id., and the journal article, Growth of Cells on Solid Culture
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Medium, for the proposition that “[t]he art had already known that culture medium, standing
alone, includes solid nutrient preparation.” Doc. No. 175, at 54. However, StemCells has
attached no excerpt or passage from the article to support their proposition.
Without any further support from the record, the Court will first look to the specification
for guidance as to the meaning of “culture medium” before consulting a dictionary. The
specification is not ambiguous as it mentions only the liquid form of “culture medium,” thus
clearly supporting Neuralstem’s proposed construction. StemCells does not dispute that the
specification mentions only the liquid form of “culture medium.” Therefore, the Court will
adopt Neuralstem’s proposed construction of this claim term.
c. “EGF-like ligands” (Term No. 25)
Found in the following claims: 5 of the ‘346 patent; and 5 of the ‘709 patent.
"EGF-like ligands"
Neuralstem's Proposed Construction
A compound structurally similar to EGF and
binds to the EGF receptor.
StemCells' Proposed Construction
A compound that is structurally similar to
EGF; EGF-like ligands include, e.g., EGF,
TGF-α, betacellulin, heparin-binding
epidermal growth factor, heregulin, cripto,
and/or amphiregulin.
Neuralstem’s proposed definition of the claim term requires the EGF-like ligands to bind
to the EGF receptor while StemCells’ proposed definition includes a list of examples of EGFlike ligands.
StemCells avers that the specification “clearly supports some of the EGF-like ligands
listed by StemCells,” citing claim 4 of the ‘832 patent as support. Doc. No. 175, at 55. Claim 4
of the ‘832 patent identifies EGF, TGF-α, and amphiregulin as EGF-like ligands. See ‘832
Patent col.69 ll.36-39. StemCells further supports the examples included in their proposed
construction by citing articles from Progress in Growth Factor Research, the Journal of
Mammary Gland Biology and Neoplasia, and Pharmacology & Therapeutics. See Doc. No. 175,
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at 56. While StemCells has supported the examples that are included in their proposed
construction, it is important to note that StemCells’ definition only “include[s]” certain
examples, meaning the list is not meant to be exclusive.
Neuralstem contends that by having the “EGF-like ligands bind to the EGF receptor
(their proposed construction) gives meaning to ‘ligand’ which in the field of biochemistry means
binding.” Doc. No. 171, at 42. Yet, StemCells opposes Neuralstem’s definition of this term on
the grounds that “not all EGF-like ligands bind to the EGF Receptor.” Doc. No. 175, at 56.
StemCells presents extrinsic evidence that clearly supports this notion in the form of a journal
article entitled Functional Selectivity of EGF Family Peptide Growth Factors: Implications for
Cancer. See Id. A figure from the article is presented below.
Kristy J. Wilson et al., Functional Selectivity of EGF Family Peptide Growth Factors:
Implications for Cancer, 122 Pharmacology & Therapeutics 1 (2009) (figure 2). As posited by
StemCells and demonstrated by the figure, “EGF-like ligands such as neuregulins do not bind to
the EGF receptor.” Doc. No. 175, at 56.
The Court will adopt StemCells’ proposed construction of this claim term because there
is ample support for all of the examples StemCells gave in their definition, the list of examples is
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not meant to be exhaustive, and Neuralstem’s proposed construction does not appear to be
scientifically accurate.
d. “neural stem cell(s)” (Term No. 37)
Found in the following claims: 1, 2, 8, 21, 34, 36, 37, 39, 40, 41, 43, 44, 45, 47, 54,
55, 56, 60, 61, 67, 70, 72, 75, 79, and 80 of U.S. Patent No. 5,851,832 (the ‘832
patent); 1 and 7 of U.S. Patent No. 7,115,418 (the ‘418 patent); 24 of U.S. Patent No.
7,361,505 (the ‘505 patent); 1 and 10 of U.S. Patent No. 6,294,346 (the ‘346 patent);
1 and 10 of U.S. Patent No. 7,101,709 (the ‘709 patent); and 1, 2, 3, 8, 9, 11, 12, 17,
22, 24, and 30 of U.S. Patent No. 6,497,872 (the ‘872 patent).
"neural stem cell(s)"
Neuralstem's Proposed Construction
A cell proliferated using the methods
described in Examples 1-4.
StemCells' Proposed Construction
An undifferentiated neural cell that (1) can be
induced to proliferate and is able to divide
essentially without limit; (2) is capable of
self-maintenance, meaning with each cell
division, at least one daughter cell will also be
a stem cell; and (3) its non-stem cell progeny
are progenitor cells capable of differentiating
into neurons, astrocytes and
oliogodendrocytes.
It is clear from the ‘832 patent that the patentee provided a special definition for “neural
stem cell(s).” Further, both parties agree that “[w]here, as here, a patentee sets out a special
definition that definition is controlling.” Doc. No. 171, at 13. However, both parties claim that
their proposed construction for “neural stem cell(s)” is the special definition provided by the
specification.
The ‘832 patent discusses “neural stem cell(s)” in the following manner:
The capability of a cell to divide without limit and produce
daughter cells which terminally differentiate into neurons and glia
are stem cell characteristics. Accordingly, as used herein, the cells
proliferated using the methods described in Examples 1-4 are
termed ‘neural stem cells’. [sic] A neural stem cell is an
undifferentiated neural cell that can be induced to proliferate using
the methods of the present invention. The neural stem cell is
capable of self-maintenance, meaning that with each cell division,
one daughter cell will also be a stem cell. The non-stem cell
progeny of a neural stem cell are termed progenitor cells. The
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progenitor cells generated from a single multipotent neural stem
cell are capable of differentiating into neurons, astrocytes (type I
and type II) and oligodendrocytes.
‘832 Patent col.12 ll.48-57. The examples to which the patent refers are:
Example 1
Dissociation of Embryonic Neural Tissue
14-day-old CD7 albino mouse embryos (Charles River) were decapitated and the brain and
striata were removed using sterile procedure. Tissue was mechanically dissociated with a firepolished Pasteur pipette into serum-free medium composed of a 1:1 mixture of Dulbecco's
modified Eagle’s medium (DMEM) and F-12 nutrient (Gibco). Dissociated cells were
centrifuged at 800 r.p.m. for 5 minutes, the supernatant aspirated, and the cells resuspended in
DMEM/F-12 medium for counting.
Example 2
Dissociation of Adult Neural Tissue
Brain tissue from juvenile and adult mouse brain tissue was removed and dissected into 500
µm sections and immediately transferred into low calcium oxygenated artificial cerebrospinal
fluid (low Ca2+ aCSF) containing 1.33 mg/ml trypsin, 0.67 mg/ml hyaluronidase, and 0.2
mg/ml kynurenic acid. Tissue was stirred in this solution for 90 minutes at 320° C.-35° C.
aCSF was poured off and replaced with fresh oxygenated aCSF for 5 minutes. Tissue was
transferred to DMEM/F-12/10% hormone solution containing 0.7 mg/ml ovomucoid and
triturated with a fire polished pasteur pipette. Cells were centrifuged at 400 rpm. for 5 minutes,
the supernatant aspirated and the pelleted cells resuspended in DMEM/F-12/10% hormone
mix.
Example 3
Proliferation of Neural Stem Cells on Substrates
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2500 cells/cm2 prepared as in Example 1 were plated on poly-L-ornithine-coated (15
µg/ml;Siqma) glass coverslips in 24 well Nunclon (0.5 ml/well) culture dishes. The culture
medium was a serum-free medium composed of DMEM/F-12 (1:1) including glucose (0.6%),
glutamine (2 µM), sodium bicarbonate (3 mM), and HEPES (4-[2hydroxyethyl]-1piperazineethanesulfonic acid) buffer (5 mM) (all from Sigma except glutamine [Gibco]). A
defined hormone mix and salt mixture (Sigma) that included insulin (25 µg/ml), transferrin
(100 µg/ml), progesterone (20 nM), putrescine (60 µM), and selenium chloride (30 nM) was
used in place of serum. Cultures contained the above medium, hereinafter referred to as
"Complete Medium" together with 16-20 ng/ml EGF (purified from mouse sub-maxillary,
Collaborative Research) or TGFα (human recombinant, Gibco). After 10-14 days in vitro,
media (DMEM only plus hormone mixture) and growth factors were replaced. This medium
change was repeated every two to four days. The number of surviving cells at 5 days in vitro
was determined by incubating the coverslips in 0.4% trypan blue (Gibco) for two minutes,
washing with phosphate buffered saline (PBS, pH 7.3) and counting the number of cells that
excluded dye with a Nikon Diaphot inverted microscope.
Example 4
Proliferation of Embryonic Mouse Neural Stem Cells in Suspension
Dissociated mouse brain cells prepared as in Examples 1 and 2 (at 1x105 cell/ml) were
suspended in Complete Medium with 20 ng/ml of EGF or TGFα. Cells were seeded in a T25
culture flask and housed in an incubator at 37° C., 100% humidity, 95% air/5% CO2. Cells
began to proliferate within 3-4 days and due to a lack of substrate lifted off the floor of the
flask and continued to proliferate in suspension forming clusters of undifferentiated cells,
referred to herein as “neurospheres”. After 6-7 days in vitro the proliferating clusters
(neurospheres) were fed every 2-4 days by gentle centrifugation and resuspension in DMEM
with the additives described above.
‘832 Patent col.34-35.
StemCells first argues that their proposed construction for “neural stem cell(s)” is a
special definition explicitly provided by the specification. StemCells urges that “the entire
specification, including specific examples, should be consulted rather than selected snippets.”
Doc. No. 175, at 20 (emphasis in original). By taking a holistic approach and reading the entire
intrinsic record, StemCells’ proposed construction comes from the entirety of the ‘832 patent
cited above. Similarly, Neuralstem posits that the patentee set forth a special definition for
“neural stem cell(s)” in the specification of the ‘832 patent which Neuralstem’s proposed
construction replicates. As support for their proposition, Neuralstem alleges that “the use of the
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words ‘accordingly,’ ‘as used herein,’ ‘are termed,’ and the deliberate use of quotation marks
around the term ‘neural stem cells’ all demonstrate that the patentee deliberately and precisely
set forth a special definition.” Doc. No. 171, at 13-14.
StemCells acknowledges that “the inventors have included in the specifications at least
four embodiments of the invention claim.” Doc. No. 169, at 18. However, StemCells also notes
that the “infringed claims are not methods claims restricted to these preferred embodiments[,]
and it would be error to read into these structural claims specific features of the method of
manufacturing these cells.” Id. The Court is convinced by the intrinsic record that “neural stem
cell(s)” is meant to be a claimed product rather than a method claim and should be read as such.
Yet, Neuralstem correctly cites Sinorgchem Co., v. International Trade Commission, 511
F.3d 1132 (Fed. Cir. 2007), for the proposition that when a term is “set off by quotation marks [it
is] often a strong indication that what follows is a definition.” 511 F.3d at 1136. Further,
Neuralstem provides numerous examples of language that often indicates a special definition is
forthcoming such as “the word ‘term[ed]’ or the phrases ‘herein as,’ ‘hereinafter referred to as,’
‘used herein,’ ‘as herein used,’ or its equivalent.” Doc. No. 178, at 4 (alteration in original). The
cited portion of the ‘832 patent itself uses the phrase “as used herein.” ‘832 Patent col.12 ll.51.
However, this method of claim construction is not absolute. The Court relies on precedent
supporting the proposition that the “court must construe the disputed claim in view of the entire
specification, including the drawings.” See Medtronic Sofamor Danek USA, Inc. v. Globus Med.,
Inc., No. 06-4248, 2008 WL 732022, at *23 (E.D. Pa. Mar. 18, 2008) (citing Markman v.
Westview Instruments, Inc., 52 F.3d 967, 979 (Fed. Cir. 1995). As several courts have observed,
“while examples disclosed in the preferred embodiment may aid in the proper interpretation of a
claim term, the scope of a claim is not necessarily limited by such examples.” E.g., STX, Inc. v.
Brine, Inc., 37 F. Supp. 2d 740, 766 (D. Md. 1999) (quoting Ekchian v. Home Depot, Inc., 104
F.3d 1299, 1303 (Fed. Cir. 1997).
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Viewing the specification in its entirety, it appears to the Court that the patentee’s
definition is more consistent with StemCells’ proposed construction. StemCells’ proposed
construction appears to adopt a definition which considers the entirety of the patent and the
properly claimed product, hence, not limiting this definition to the four embodiments cited.
Moreover, the prosecution history of this patent supports StemCells’ proposed construction as
the USPTO Board of Patent Appeals and Interferences held that “[n]eural stem cells are
undifferentiated cells that can ‘divide without limit and produce daughter cells which terminally
differentiate into neurons and glia.’” Ex Parte Weiss, No. 2006-0840, Doc No. 170-8, at 1-2
(B.P.A.I. May 9, 2006). Also, the Examiner’s definition of “neural stem cell(s)” being “an
undifferentiated neural cell that can be induced to proliferate, and is capable of self-maintenance
and multipotent” is more in agreement with StemCells’ definition than Neuralstem’s definition.
Doc. No. 175, at 22.
In conclusion, the intrinsic record and the the prosecution history of the ‘832 patent is
more consistent with StemCells’ proposed construction of this term. Therefore, the Court will
adopt StemCells’ proposed construction of this claim term.
e. “consisting of” (Term No. 38)
Found in the following claim: 80 of the ‘832 patent.
"consisting of the undifferentiated progeny of a single human multipotent neural stem
cell"
Neuralstem's Proposed Construction
All progeny of the single human multipotent
neural stem cell are undifferentiated.
StemCells' Proposed Construction
That the cluster does not contain cells other
than the undifferentiated progeny of a single
human multipotent neural stem cell, except
for impurities ordinarily associated with cell
culture prepared in vitro.
f. “consisting of” (Term No. 54)
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Found in the following claims: 1, 13, 14, and 25 of the ’505 patent.
"neurospheres consist of undifferentiated neural cells that are: nestin+ and; are glial
fibrillary acidic protein (GFAP)–; neurofilament (NF)–; and myelin basic protein
(MBP)–; and not nestin–"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Neurospheres contain all undifferentiated
neural cells. All of the undifferentiated neural
cells stain positive for Nestin, and none of the
undifferentiated neural cells stain positive for
neurofilament, glial fibrillary acidic protein,
or myelin basic protein.
The neurospheres do not include cells other
than undifferentiated neural cells, except for
impurities ordinarily associated with culturing
neurospheres, wherein the undifferentiated
neural cells are characterized by the
following:
(1) positive immunocytochemistry staining of
Nestin, and
(2) negative immunocytochemistry staining of
glial fibrillary acidic protein (GFAP),
neurofilament (NF), and myelin basic protein
(MBP), via standard immunocytochemistry
techniques;
"negative staining" means the signal of
immune-staining does not exceed background
level.
The preceding two claims are addressed together in the joint claim construction, and thus
the Court will address them accordingly. First, the parties dispute whether “consisting of” as
used in term number 38 can include “impurities ordinarily associated with cell culture prepared
in vitro.” StemCells alleges that “[a]lthough the term ‘consisting of’ signifies the exclusion of
unrecited steps or components, the exclusion is not absolute.” Doc. No. 175, at 12. StemCells
cites the USPTO Board of Patent Appeals and Interferences as supporting their claim that
“impurities ordinarily associated therewith” are not excluded from the term “consisting of.”
Doc. No. 175, at 37. Neuralstem counters StemCells by stating that “[t]he Federal Circuit has
held that ‘consisting of’ does not always include impurities.” Doc No. 178, at 24. However,
Neuralstem seemingly accepts that some impurities “such as sugars, amino acids, water, serum,
etc., would be acceptable” in the proposed construction. Id. at 25. The most important
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discrepancy between the parties’ proposed constructions is that Neuralstem believes “StemCells’
construction appears to leave open the illogical possibility that differentiated cells could be
within the scope of the ‘consisting of’ neurosphere claims.” Id. (emphasis in original).
Neuralstem argues that “to give proper meaning to the phrase ‘consisting of,’ all cells must be
undifferentiated.” Doc. No. 171, at 33.
The Court recognizes the Conoco, Inc. v. Energy & Environmental International, L.C.,
460 F.3d 1349 (Fed. Cir. 2006), holding that “consisting of” permits the presence of “impurities
that a person of ordinary skill in the relevant art would ordinarily associate with a component on
the ‘consisting of’ list.’” 460 F.3d at 1360. Neuralstem seemingly concurs with this finding by
accepting that some “common culture medium components . . . would be acceptable.” Doc No.
178, at 25. Neuralstem’s contention that differentiated cells should not be within the scope of the
“consisting of” list because the “specification does not describe differentiated cells as impurities
commonly associated with neurospheres” is not for a claim construction to determine. Doc No.
178, at 26. Neuralstem produces evidence that supports this notion; however, that evidence will
be judged by the fact-finder. Regardless of whether Neuralstem is correct in finding that
differentiated cells should not be considered an impurity, this Court is influenced by the
precedence which includes impurities within a “consisting of” list. Therefore, the Court will
adopt StemCells’ proposed construction of this claim term.
Secondly, there are three disputes between the parties’ proposed constructions for term
number 54. First, the parties agree that “neurospheres do not include cells other than
undifferentiated neural cells;” however, the parties again dispute whether the definition should
include an exception for impurities. The Court uses the same logic described for term number 38
above and once again decides that precedent dictates that the impurities exception should be
included within the “consists of” list. This determination favors StemCells’ proposed
construction.
Page 15 of 41
Further, the parties dispute “whether any cell in the neurosphere may stain positive for
neurofilament, glial fibrillary acidic protein, or myelin basic protein.” Doc. No. 224, at 6. The
Court surmises that Neuralstem is concerned with the phrase, “wherein the undifferentiated
neural cells are characterized by the following: … (2) negative immunocytochemistry staining of
glial fibrillary acidic protein (GFAP), neurofilament (NF), and myelin basic protein (MBP), via
standard immunocytochemistry techniques.” If differentiated cells are considered impurities and
thus are included within the “consisting of” list, then Neuralstem is concerned whether these
cells can test positive for neurofilament, glial fibrillary acidic protein, or myelin basic protein.
The Court, as first stated above for term number 38, does not think this is a matter for claim
construction. It is for the fact-finder to determine whether differentiated cells may be considered
impurities and thus “whether any cell in the neurosphere may stain positive for neurofilament,
glial fibrillary acidic protein, or myelin basic protein.” Id.
Finally, the parties dispute “whether the term ‘negative staining’ should be included.” Id.
There is no argument within the record by either party for or against the inclusion of the phrase
“negative staining.” The Court is persuaded by precedent that StemCells’ proposed construction
is the better definition in regards to the first two disputes. Therefore, the Court will adopt
StemCells’ proposed construction of this claim term.
g.
“neurosphere(s)” (Term No. 41)
Found in the following claims: 1, 13, 14, 18, 25, and 26 of the ‘505 patent; and 1
and 11 of the ‘346 patent.
"neurosphere(s)"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Page 16 of 41
A cluster of undifferentiated neural cells that
have lifted off the floor of the container and
continue to proliferate in suspension in the
continued presence of a proliferation-inducing
growth factor. Cells within a single
neurosphere are clonally derived.
A cluster of undifferentiated cells wherein (1)
the cells of a single neurosphere are clonal in
nature because they are the progeny of a
single neural stem cell and (2) in the
continued presence of a proliferation-inducing
growth factor precursor cells within the
neurosphere continue to divide resulting in
increase in the size of the neurosphere and the
number of undifferentiated cells.
The term “neurosphere(s)” is described in multiple locations of the specification and is
alluded to in numerous locations within the prosecution history of the patents-in-suit. The term
“neurosphere(s)” was not a known scientific term at the time of the filing and the patentee failed
to give one explicit definition for the term within the patents-in-suit. The parties’ proposed
constructions differ because of the ambiguity associated with “neurosphere(s).” Neuralstem
succinctly directs the Court to the differences in the parties’ proposed constructions of the term.1
The parties’ primary disagreement is whether the definition of “neurosphere(s)” should include
the “lifted off the floor” language. StemCells and Neuralstem both find support for their
respective proposed constructions in the specification, patent history, and extrinsic evidence.
Neuralstem’s proposed construction relies upon Example 4 of the ‘832 patent:
Cells began to proliferate within 3-4 days and due to a lack of
substrate lifted off the floor of the flask and continued to
proliferate in suspension forming clusters of undifferentiated cells,
referred to herein as “neurospheres”.
‘832 Patent col.35. StemCells’ proposed construction relies upon the specification of the ‘832
patent:
Within 3-4 days in the presence of a proliferation-inducing growth
factor, a multipotent neural stem cell begins to divide giving rise to
1
Neuralstem highlights that there are differences in the parties’ proposed definitions stating,
“[o]ne is that Neuralstem’s construction includes the concept that the cells must ‘lift[] off the
floor of the container and continue to proliferate in suspension.’ This limitation is absent from
StemCells’ construction. Another difference is that StemCells’ construction includes a limitation
that the cells are proliferated ‘in the continued presence of a proliferation-inducing growth
factor.’” Doc. No. 171, at 19.
Page 17 of 41
a cluster of undifferentiated cells referred to herein as a
“neurosphere”. The cells of a single neurosphere are clonal in
nature because they are the progeny of a single neural stem cell. In
the continued presence of a proliferation-inducing growth factor
such as EGF or the like, precursor cells within the neurosphere
continue to divide resulting in an increase in the size of the
neurosphere and the number of undifferentiated cells.
‘832 Patent col.17 ll.5-14. The specification seemingly supports both parties’ proposed
constructions. However, StemCells alleges that “Example 4 refers to ‘suspension’ culture [that]
‘due to a lack of substrate[]’ . . . the neurospheres would lift off the floor.” Doc No. 175, at 30.
The Court believes that a limitation found within an embodiment of the invention should not
limit the meaning of the term “neurosphere.”
Neuralstem supports the “lift off the floor” language by referring to extrinsic evidence
from the first named inventor of the patent, Samuel Weis. Weis explained that “he (and coinventor Brent Reynolds) ‘coined’ the term ‘neurosphere’ ‘to describe floating spheres of neural
cells.’” Doc. No. 178, at 13.2 Yet, Neuralstem seems to ignore the specification’s language that
“[p]roliferation and perpetuation of the neural stem cell progeny can be carried out either in
suspension cultures, or by allowing cells to adhere to a fixed substrate.” ‘832 Patent col.10 ll.6164. Moreover, Neuralstem’s proposed construction is flawed in light of the fact that in several
of the specification’s other provisions, the patentee explicitly defines a neural cell as one which
2
Neuralstem offers the following interview exchange between Weis and an interviewer:
Q. Sure. What is a neurosphere?
***
A. So “neurosphere” was a term coined by Brent Reynolds
and I think—I can't remember if it was Brent or I, one of
us, both—to describe floating spheres of neural cells.
***
Q. Sure. Well, what did you think the novel characteristics of
neurospheres were?
***
A. So neurospheres were—we coined the term “neurospheres”
as floating spheres of neural cells. Floating spheres of
neural cells. Does that answer your question?
Page 18 of 41
can proliferate in suspension or one which can adhere to a fixed structure. See id.; ‘832 Patent
col.12 ll.12-15.
The Court is not willing to read a limitation into the claim at the expense of excluding
other embodiments in the specification. Adopting Neuralstem’s proposed construction of the
term “neurospehere(s)” would lead to this result. Further, StemCells’ definition of
“neurosphere(s)” does not include any particular limitation and is more consistent with the
patent’s specification in this case. Therefore, the Court will adopt StemCells’ proposed
construction of this term.
h. “pure . . . consisting of” (Term No. 42)
Found in the following claims: 1, 13, 14, 18, 25, and 26 of the ’505 patent.
"pure in vitro cell culture composition . . . consisting of neurospheres and culture
medium, wherein said neurospheres consist of undifferentiated neural cells"
Neuralstem's Proposed Construction
The culture composition contains only
neurospheres and culture medium, and those
neurospheres contain only undifferentiated
neural cells.
StemCells' Proposed Construction
An in vitro culture that does not include
materials other than neurospheres and culture
medium, except for impurities ordinarily
associated with in vitro cell culture; and the
neurosphere does not include cells other than
undifferentiated neural cells, except for
impurities ordinarily associated with culturing
neurospheres.
The parties’ proposed definitions differ with respect to whether “pure” should include
impurities or alternatively a substance with no impurities. The term “pure . . . consisting of” is
not specifically defined in the patent. Thus, to determine the meaning of this term, the Court
must look to the plain language of the claim and presume that it carries its ordinary and
customary meaning. The ordinary and customary meaning is defined as the meaning that the
claim term would have to a person having ordinary skill in the art at the date the patent
Page 19 of 41
application in question was filed. See Phillips v. AWH Corp., 415 F.3d 1303 (Fed. Cir. 2005) (en
banc).
Neuralstem argues that logically “‘pure’ should [not] explicitly include ‘impurities.’”
Doc. No. 171, at 29 (emphasis in original). In support of their argument Neuralstem cites
Random House Webster’s College Dictionary for the proposition that “‘pure’ is something that is
‘free from adulterating or extraneous matter….’” Id.
StemCells, on the other hand, insists that “[t]he concept that a ‘pure’ culture is not 100%
pure is well understood in the art.” Doc. No. 175, at 46. StemCells cites many examples where
the term “pure” is used to connote 90%, 95%, 98%, and 99% purity within the scientific field.3
However, nothing in the briefs leads the Court to believe that this conclusion extends to all
scientific matter, or specifically, the technology at issue in this case. Because none of these
examples directly relates to neural stem cells, the Court is required to make an inference
regarding purity that the Court is not willing to make.
In further support of their proposed construction, StemCells cites Johns Hopkins
University v. Cellpro, Inc., 152 F.3d 1342 (Fed. Cir. 1998), for the proposition that the reality of
the technology at issue is that only a purity level of 85-90% can be reached. See 152 F.3d at
1355-56. The Court is not persuaded by StemCells’ argument as John Hopkins University was
debating the term “substantially free” and not “pure.” See id. at 1355. Further, the court in John
Hopkins University supported the inclusion of impurities largely because of the intrinsic record,
3
(1) StemCells offers the product brochure of Miltenyi Biotech to demonstrate that absolute
purity is scientifically unrealistic. Stemcells states, “In the Results and Discussions sections, the
actual purities of cell cultures were reported as >90% (page 8), 95% (page 22), or 98% (page
14).” Doc No. 175, at 46.
(2) StemCells references a journal article entitled A Pure Population of Lung Alveolar Epithelial
Type II Cells Derived from Human Embryonic Stem Cells where “the purity of the cell culture
was reported as >99%.” Id.
(3) StemCells references another journal article entitled Comprehensive Protocols to Isolate,
Characterize, and Culture pure-population of Multi-potent Stem Cell from Mouse Epidermis
where “the purity of the cell culture was reported as >90%.” Id.
Page 20 of 41
with the court noting that the “only disclosed embodiment of the claimed cell suspension[] is
highly indicative of the scope of the claims.” Id. Here, the Court finds no such support within
the intrinsic record for StemCells’ proposition that impurities should be included within the
definition of “pure.”
As such, the Court is convinced by the extrinsic evidence presented by Neuralstem that
“pure” should not include impurities. Therefore, the Court will adopt Neuralstem’s proposed
construction of this term.
i.
“consists essentially of” (Term No. 43)
Found in the following claims: 10 of the ’346 patent.
"neural cell population consists essentially of the progeny of a single multipotent neural
stem proliferated in vitro"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
The neural cell population is clonally-derived.
The neural cell population contain the
progeny of a single multipotent neural stem
cell that are proliferated in vitro, and do not
contain other types of cells that would
materially affect the basic characteristic of the
neural cell population.
The parties agree that this term is “a neural cell population that contains only the progeny
of a single multipotent neural stem cell population that is clonally-derived.” Doc No. 171, at 37.
From the briefings, it is apparent to the Court that the parties disagree over the inclusion of
impurities, a very similar disagreement to those had for term numbers 38, 54, and 42. The
contested language reads, “and do not contain other types of cells that would materially affect the
basic characteristic of the neural cell population.” Neuralstem alleges that this language imports
an improper legal standard into the claim, while Stemcells argues that this language is
appropriate because any other interpretation of the claim would require that “the neural cell
population contain clonally-derived cells only, and nothing else, i.e. that the cell population is
100% pure.” Doc. No. 175, at 42 (emphasis in original).
Page 21 of 41
StemCells’ proposes that the term “limit[s] the scope of a claim to the specified materials
or steps and those that do not materially affect the basic and novel characteristic(s) of the
claimed invention. Doc. No. 175, at 43. The court in AFG Industries, Inc. v. Cardinal IG Co.,
Inc., 239 F.3d 1239 (Fed. Cir. 2001), interpreted “consisting essentially of” to “‘exclude[]
ingredients that would materially affect the basic and novel characteristics of the claimed
composition’. The phrase is open to ‘unlisted ingredients that do not materially affect the basic
and novel properties of the invention.’” 239 F.3d at 1245 (citations omitted). In short, the case
law clearly supports StemCells’ proposed construction.
Neuralstem purports that the interpretation of “consisting essentially of” in AFG
Industries, Inc. “is an improper legal standard that has no place in claim construction” because
the court in AFG Industries, Inc. construed what “consisting essentially of” meant within the
context of the patents-in-suit. Doc. No. 171, at 37. The Court finds that AFG Industries, Inc.
applied the correct legal standard as many other courts have applied a similar definition of
“consisting essentially of” without placing the term within the context of the patents-in-suit. See
Kim v. ConAgra, Foods, Inc., 465 F.3d 1312 at 1319-20 (Fed. Cir. 2006); PPG Industries v.
Guardian Industries Corp., 156 F.3d 1351 at 1354 (Fed. Cir. 1998).
Neuralstem next argues that “StemCells’ construction falls short . . . as it does not recite
what the basic and novel characteristics of the claimed neural stem cell population might be.”
Doc. No. 178, at 29. This is so because the “patent applicant may . . . alter the typical meaning
of ‘consisting essentially of’ through disclaimers made during prosecution or statements in the
specification that define the basic and novel characteristics of the claimed invention” and
StemCells’ has failed to do so. Id. at 28. The Court finds no validity in this argument as
“patentee[s] can alter [the] typical meaning” of the term “consisting essentially of,” but of course
are never obliged to do so. Ecolab, Inc. v. FMC Corp., 569 F.3d 1335 at 1343-44 (Fed. Cir.
2009) (emphasis added).
Page 22 of 41
Finally, Neuralstem opposes StemCells’ proposed construction because it may include
non-clonally derived cells, and “[n]on-clonally derived cells would materially affect the basic
characteristics of a neural stem cell population of clonally derived cells.” Doc. No. 178, at 29. If
the Court chooses to accept StemCells’ proposed construction, then it is an issue for the factfinder to determine if non-clonally derived cells materially affect the basic characteristics of the
neural cell population. Thus, if Neuralstem’s contentions are true, then non-clonally derived
cells will not be included no matter which proposed construction is chosen.
The Court is persuaded by the prior case law that clearly supports StemCells’ proposed
construction of “consists essentially of.” Therefore, the Court will adopt StemCells’ proposed
construction of this term.
j.
“cluster” (Term No. 44)
Found in the following claims: 37, 38, and 80 of the ‘832 patent; and 1 of the ‘346
patent.
“cluster” or “cluster of cells” or “cluster of human cells” or “a cluster of proliferated
neural cells”
Neuralstem's Proposed Construction
StemCells' Proposed Construction
An aggregate of cells where cells are in
contact with one another.
An aggregate of cells wherein individual cells
are in contact with at least one other cell.
The parties agree that a “cluster” is an “aggregate of cells.” The parties differ as to the
scope of the physical contact element of cells in a cluster. Neuralstem’s proposed construction
requires that the cells in a cluster are “in contact with one another.” Contrarily, StemCells
alleges that the definition of cluster does not mandate that all cells in a cluster touch one another.
StemCells purports that “cluster” means “an aggregate of cells wherein individual cells are in
contact with at least one other cell.”
In short, Neuralstem believes a “cluster” of cells must be “in contact with one another”
while StemCells believes each cell must contact “at least one other cell.” StemCells’ definition
Page 23 of 41
is clear. A “cluster” is created when every cell is touching “at least one other cell” within the
cluster. Neuralstem opposes StemCells’ definition because it “leave[s] open the possibility that a
linear conformation of cells reads on the claim term.” Doc No. 227, at 12. Further, Neuralstem
alleges that “[a] line of cells—whereby each cell is in contact with two cells to form a chain—is
clearly not what was intended by the applicants during prosecution.” Id. Neuralstem supports
their argument by referencing an excerpt from Figure 1 of the ‘832 patent:
‘832 Patent fig. 1 (excerpt). The Court recognizes that this lone excerpt is not a “chain” as
described by Neuralstem and thus would run contrary to StemCells’ definition. However, the
Court refuses to limit the term “cluster” to exclude chains based solely on the single excerpt from
Figure 1 above. Neuralstem does not make any other arguments within the record to support the
claim that a chain should not be included within the definition of “cluster.”
Further, Neuralstem’s proposed construction featuring the language, “in contact with one
another,” is ambiguous. As StemCells correctly points out, Neuralstem insinuates that “‘contact
with one another’ would require physical contact so that each cell is touching all other cells in
the cluster . . . .” Doc. No. 175, at 60. Yet, Neuralstem clearly cannot be positing such a
definition as the excerpt above and Neuralstem’s own example below indicate.
Page 24 of 41
Doc No. 171, at 24. In both figures there are cells within each cluster that are not touching all
other cells within the cluster. In summation, Neuralstem’s argument for eliminating “chains”
indicates that their definition requires more contact within a cluster than a “chain” would
provide, which is essentially any cell contacting two other cells. Yet, Neuralstem’s illustration
and referenced excerpt indicate that their definition requires less contact within a cluster than the
contact of all cells with one another.
The Court believes that Stemcells’ proposed construction of the term “cluster” makes the
most sense in light of the ordinary meaning of the term. Therefore, the Court will adopt
StemCells’ proposed construction of this term.
k. “adherent” (Term No. 45)
Found in the following claims: 21 and 48 of the ‘832 patent; 6 and 12 of the ‘418
patent; 6, 12, and 23 of the ‘505 patent; and 1 of the ‘709 patent.
“adherent” or “adherent cell culture” or “adherent culture”
Neuralstem's Proposed Construction
Cells grown on and attached to a substrate
surface not maintained in an undifferentiated
state.
StemCells' Proposed Construction
A culture in which the cells are attached to the
surface of a substrate surface.
The parties’ only disagreement is in regards to the phrase, “not maintained in an
undifferentiated state.” Neuralstem argues that StemCells’ proposed construction would permit
neural stem cells to proliferate in an undifferentiated state. Neuralstem alleges StemCells’
proposed construction is flawed because the patent specification “includes no examples of
growing cells in an adherent culture and maintaining those cells in an undifferentiated state.”
Doc No. 171, at 26 (emphasis in original). Further, Neuralstem believes that the prosecution
history of the family of patents in dispute supports the inclusion of the phrase, “not maintained in
an undifferentiated state.”
Page 25 of 41
StemCells responds to Neuralstem’s objections by alleging that Neuralstem uses
improper means of inserting limitations into the term by using omissions to support their
proposed constructions and by “teaching away.” Doc. No. 175, at 68. StemCells alleges that the
specification demonstrates that neural stem cells and their undifferentiated progeny can be
proliferated as adherent culture. In Liebel-Flarsheim Co. v. Medrad, Inc., 358 F.3d 898, (Fed.
Cir. 2004), the court rejected the argument that “if a patent describes only a single embodiment,
the claims of the patent must be construed as being limited to that embodiment . . . . Even when
the specification describes only a single embodiment, the claims of the patent will not be read
restrictively unless the patentee has demonstrated a clear intention to limit the claim scope using
“words or expressions of manifest exclusion or restriction.” 358 F.3d at 906. Reviewing the
specification at issue in this case, the Court does not believe that the patentee demonstrated a
clear intention to limit the claim using “words or expressions of manifest exclusion.” Id.
Therefore, simply because the patent may not include examples of growing cells in an adherent
culture and maintaining those cells in an undifferentiated state, the Court is not willing to
interpret “adherent” as prohibiting cells from proliferating in this manner.
However, the Court does believe that the prosecution history of the patent supports
Neuralstem’s proposed construction. The purported sister application, Application Serial No.
10/199,830 (“the ‘830 application”), to the ‘832 patent had the exact specification as the patentsin-suit. The Examiner rejected the ‘830 application on the grounds that the specification
“fail[ed] to provide an enabling disclosure teaching how to proliferate the undifferentiated
multipotent neural stem cells on an adherent substrate in the presence of at least one
proliferation-inducing growth factor ‘without inducing differentiation.’” Doc. No. 171, at 27.
StemCells abandoned the ‘830 application after it was rejected on the above-mentioned basis.
Neuralstem treats this abandonment as a concession by the patentee that the Examiner’s
objections were true. Neuralstem uses this purported prosecution history to support their view
Page 26 of 41
that the ‘832 patent regards the term “adherent” to be “cells grown on and attached to a substrate
surface not maintained in an undifferentiated state.” Id. at 28. StemCells avers that “abandoning
a patent application is not an admission that the Examiner is right.” Doc. No. 175, at 66.
In Laitram Corp. v. Morehouse Industries, Inc., 143 F.3d 1456 (Fed. Cir. 1998), the court
articulated that “when two patents using the same claim term both stem from the same parent
patent application, the prosecution histories of both are relevant to an understanding of the term
in both patents.” 143 F.3d at 1460 n.2 (citing Jonsson v. Stanley Works, 903 F.2d 812, 818 (Fed.
Cir. 1990). The ‘830 application is a sister application of the ‘832 patent and thus the Court
believes that the prosecution history of the ‘830 application is persuasive. The examiner rejected
the ‘830 application because the application does not teach how to “proliferate neural stem cells
on an adherent substrate, as recited in the claims, while maintaining the cells in the
undifferentiated state.” Doc. No. 172-9, at 4. The Court is persuaded that Neuralstem’s
proposed construction is correct because of the prosecution history provided by the Examiner’s
rejection of the sister ‘830 application. The Court emphasizes that the patentee’s abandonment
of the ‘830 application is in no way a concession on the part of the patentee.
Therefore, the Court will adopt Neuralstem’s proposed construction of this term.
l. “purified” (Term No. 46)
Found in the following claims: 24 of the ‘505 patent; 1 of the ‘346 patent; and 1 of
the ‘709 patent.
“purified” or “the neural cell population is purified” or “a purified population of
multipotent neural stem cells”
Neuralstem's Proposed Construction
StemCells' Proposed Construction
All cells in culture are multipotent neural stem The cells are separated from at least some of
cells.
the cells with which they are naturally
associated; purified does not require the cell
population to be homogeneous.
Page 27 of 41
The parties disagree as to whether “purified” requires a homogenous neural stem cell
population. This is a similar disagreement to those had for term numbers 38, 54, 42, and 43.
Neuralstem’s proposed construction requires homogeneity while StemCells’ proposed
construction does not.
StemCells supports their proposed construction by referencing language from the
reexamination of the ‘346 patent and the USPTO Board of Patent Appeals and Interferences.
The patentee stated the following during the reexamination of the ‘346 patent:
The undifferentiated neural cell populations are “purified and
enriched in the number of multipotent neural stem cells compared
to primary human neural tissue” since these populations have a
greater proportion of multipotent neural stem cell in the culture
than primary human neural tissue.
Doc. No. 175, at 47. The patentee’s use of “purified” supports StemCells’ allowance for
heterogeneity, evidenced by the fact that two cell types are included in the definition of
“purified”—both neural stem cells and primary human neural tissue. Moreover, the prosecution
history supports StemCells’ proposed construction as the USPTO Board of Patent Appeals and
Interferences gave the following definition for “purified” during the prosecution of the ‘505
patent:
We interpret “purified” to mean cells are separated from at least
some of the cells with which they are naturally associated; purified
does not require the cell population to be homogeneous.
Doc. No. 169, at 29.
Neuralstem contends that the USPTO Board of Patent Appeals and Interferences’
interpretation of “purified” is not controlling because “the USPTO is required to use a different
standard for construing claims than that used by district courts.” Doc. No. 171, at 30. Further,
Neuralstem insists that the Court “must consult the specification, prosecution history, prior art,
and other claims to determine the proper construction of the claim language.” Id. The Court
agrees with Neuralstem that the USPTO Board of Patent Appeals and Interferences’
Page 28 of 41
interpretation is not controlling and that the Court must consult the intrinsic record to determine
the proper construction of “purified.” However, in Phillips v. AWH Corp., 415 F.3d 1303 (Fed.
Cir. 2005) (en banc), the court held that “the prosecution history, which [they] designated as part
of the ‘intrinsic evidence,’ consists of the complete record of the proceedings before the PTO and
includes the prior art cited during the examination of the patent. Like the specification, the
prosecution history provides evidence of how the PTO and the inventor understood the patent.”
415 F.3d at 1317 (citations omitted). Therefore, this Court will treat the USPTO Board of Patent
Appeals and Interferences’ interpretation of “purified” as intrinsic evidence. Further, the
patentee’s own understanding of “purified” as demonstrated during the reexamination of the ‘346
patent is additional intrinsic evidence supporting StemCells’ proposed construction.
Neuralstem argues that “to accept the view that purified somehow means unpurified
would be an illogical construction.” Doc. No. 171, at 31. Neuralstem cites Random House
Webster’s College Dictionary to prove “the ordinary meaning of purified is ‘to make pure; free
from pollutants or contaminants.’” Id. at 30. Neuralstem made a nearly identical argument for
their proposed construction of term number 42, “pure . . . consisting of.” The Court found in
favor of Neuralstem’s proposed construction of “pure . . . consisting of” because Neuralstem’s
extrinsic evidence was more persuasive than StemCells’ extrinsic evidence. Here, StemCells has
provided intrinsic evidence directly from the prosecution history which is more compelling than
extrinsic evidence in the Markman analysis. Therefore, the Court will adopt StemCells’
proposed construction of this term.
m. “Nestin(+)” (Term No. 47)
Found in the following claims: 1 and 7 of the ’418 patent; and 1, 13, 14, 18, 25, and
26 of the ‘505 patent.
"Nestin(+)” or “stain positive for nestin” or “Nestin(-)"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Page 29 of 41
Nestin(+) or “stain positive for nestin”:
positive staining by immunocytochemistry
using an antibody that binds Nestin, including
but not limited to the Rat 401 antibody;
Nestin(-): no specific staining by
immunocytochemistry using an antibody that
binds Nestin, including but not limited to the
Rat 401 antibody;
Nestin(+) or “stain positive for nestin”:
positive staining by immunocytochemistry
using an antibody that binds Nestin;
Nestin(-): no specific staining by
immunocytochemistry using an antibody that
binds Nestin;
“specific staining” means that the signal is
above background noise level.
“specific staining” means that the signal is
above background noise level.
The parties’ proposed constructions are almost identical. The parties dispute whether the
phrase, “including but not limited to the Rat 401 antibody,” should be included within the
definition. StemCells alleges that citing Rat 401 antibody as an example in this definition
“would mean that a cell that stains negative for Rat 401 antibody would be Nestin (-).” Doc. No.
175, at 52. However, the “Rat 401 is not a ‘universal’ antibody [because i]t does not bind to cat,
monkey, or human Nestin.” Id. Thus, StemCells argues that it is improper to include Rat 401
because if it is used to stain human neural stem cells the results will be negative, yet human
neural stem cells are Nestin(+).
Neuralstem correctly argues that the patent specification “clearly indicates that Rat401 is
an antibody available to identify nestin.” Doc. No. 171, at 49.4 StemCells does not dispute this
point as the specification is very clear. However, StemCells replies by arguing that “claim
construction does not require to read [sic] everything in the specification into the claims.” Doc.
No. 175, at 53. The Court will follow the specification which specifically states that Rat 401 is
an antibody that can be used to identify nestin. Moreover, Neuralstem is not reading a limitation
into the patent as StemCells contends. The language that Neuralstem uses, “including, but not
limited to,” clearly allows for other antibodies besides Rat 401 to be used in testing for nestin.
Therefore, the Court will adopt Neuralstem’s proposed construction of this term.
4
The specification for patent ‘832 explicitly states, “Antibodies are available to identify nestin,
including the rat antibody referred to as Rat401.” ‘832 Patent col.17 ll.21-22.
Page 30 of 41
n. “of . . . lack” (Term No. 52)
Found in the following claim: 7 of the ’418 patent.
"a culture of undifferentiated neural cells . . . said undifferentiated neural cells stain
positive for nestin and said undifferentiated neural cells lack differentiated neural cells
that do not stain positive for nestin and that stain positive for the differentiated neural
cell markers neurofilament, glial fibrillary acidic protein, neuron specific enolase, and
myelin basic protein"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Culture containing all undifferentiated neural
cells. All of the undifferentiated neural cells
stain positive for nestin, and none of the
undifferentiated neural cells stain positive for
neurofilament, glial fibrillary acidic protein,
or myelin basic protein.
(1) The culture that contains undifferentiated
neural cells, wherein the undifferentiated
neural cells are characterized by positive
immunocytochemistry staining of Nestin, and
(2) the culture does not contain detectable
level of differentiated neural cells, wherein
the differentiated neural cells are
characterized by negative staining of nestin,
and positive staining of neurofilament, glial
fibrillary acidic protein, neuron specific
enolase, and myelin basic protein via standard
immunocytochemistry techniques.
o. “of” (Term No. 55)
Found in the following claim: 1 of the ‘418 patent.
"a culture of undifferentiated neural cells . . . wherein said undifferentiated neural cells
are nestin+ and are glial fibrillary acidic protein (GFAP)–; neurofilament (NF)–; neuron
specific enolase (NSE)–; and myelin basic protein (MBP)"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Culture containing all undifferentiated neural
cells. All of the undifferentiated neural cells
stain positive for nestin, and none of the
undifferentiated neural cells stain positive for
neurofilament, glial fibrillary acidic protein,
neuron specific enolase, or myelin basic
protein.
The culture contains undifferentiated neural
cells, wherein the undifferentiated neural cells
are characterized by the following:
(1) positive immunocytochemistry staining of
Nestin, and
(2) negative immunocytochemistry staining of
glial fibrillary acidic protein (GFAP),
neurofilament (NF), and myelin basic protein
(MBP), via standard immunocytochemistry
Page 31 of 41
techniques;
“negative staining” means the signal of
immune-staining does not exceed background
level.
Term numbers 52 and 55 will be addressed together as these terms are addressed
simultaneously in the joint claim construction. Once again, Neuralstem and StemCells dispute
whether the constructions should be completely pure or include impurities. In this instance, the
dispute is whether any differentiated neural cells should be included within a culture.
Neuralstem argues that the constructions should reflect 100% purity by only including
undifferentiated cells.5 StemCells contends that “the term ‘of’ should be construed as being
open-ended” and thus allowing for “additional, unrecited elements.” Doc. No. 175, at 40.
StemCells avers that “of” is an open-ended rather than a closed-ended transitional phrase.
In support of this premise, StemCells argues that they are “unaware of any case law stating that if
a claim fails to mention element A, then it could only encompass element B.” Id. In addition,
StemCells correctly claims that “[a]lthough the ‘classical’ open-ended transitional phrase,
‘comprising,’ is not used, the Federal Circuit and the USPTO have allowed the use of other
transitional phrases.” Id. Yet, neither the Federal Circuit nor the USPTO have construed the
term “of” as an open-ended transitional phrase. Neuralstem argues that StemCells’ proposed
construction broadens the definition “to cover an invention that is nowhere described in the
patents-in-suit” and that the Court “cannot now rewrite the claims” to do just that. Doc. No. 171,
at 36. The Court is persuaded by the wording in claim 7 of the ‘418 patent which reads,
“undifferentiated neural cells lack differentiated neural cells . . . .” Doc. No. 171, at 35. The
Court believes this passage best shows the intended scope of the claim terms, a scope which does
not include differentiated cells.
5
Neuralstem alleges, “A plain reading of these claims leads one of the ordinary skill to conclude
that they are directed to proliferating a culture of undifferentiated neural cells for one simple
reason—the claims fail to mention ‘differentiated cells.’” Doc. No. 171, at 36.
Page 32 of 41
StemCells argues that “because the transitional phrase is not close-ended [sic], ‘lacking
differentiated cells’ is not the same as ‘undifferentiated cells only.’” Doc. No. 175, at 40. Thus,
the claim does not exclude “additional, unrecited elements.” Id. While the Court acknowledges
StemCell’s argument that “there are technological limitations to the purification techniques,” Id.
at 41, the Court has already held that without intrinsic evidence to prove otherwise, purity should
have its ordinary meaning, thus excluding elements not expressly called for in the claim.
Finally, Neuralstem’s proposed construction is nearly identical to the specification of the
‘418 patent which reads as follows:
[U]ndifferentiated neural cells lack differentiated neural cells that
do not stain positive for nestin and that stain positive for the
differentiated neural cell markers neurofilament, glial fibrillary
acidic protein, neuron specific enolase, and myelin basic protein . .
..
Doc. No. 171, at 35. Compare the ‘418 patent with Neuralstem’s proposed construction:
All of the undifferentiated neural cells stain positive for nestin, and
none of the undifferentiated neural cells stain positive for
neurofilament, glial fibrillary acidic protein, neuron specific
enolase, or myelin basic protein.
It is apparent to the Court that when the ‘418 patent describes the types of differentiated neural
cells that it lacks, Neuralstem imports this definition into their own constructions of the claim
terms.
The Court believes these claim terms were not intended to be open-ended and that
Neuralstem’s proposed constructions are the most consistent with the ‘418 patent. Therefore, the
Court will adopt Neuralstem’s proposed constructions of these terms.
p. “consist of . . . lack” (Term No. 53)
Found in the following claims: 18 and 26 of the ‘505 patent.
Page 33 of 41
"neurospheres consist of undifferentiated neural cells that stain positive for nestin and
said neurospheres lack differentiated neural cells that do not stain positive for nestin but
that stain positive for the differentiated neural cell markers, neurofilament, glial
fibrillary acidic protein and myelin basic protein"
Neuralstem's Proposed Construction
StemCells' Proposed Construction
Neurospheres contain all undifferentiated
neural cells. All of the undifferentiated neural
cells stain positive for nestin, and none of the
undifferentiated neural cells stain positive for
neurofilament, glial fibrillary acidic protein,
or myelin basic protein.
(1) The neurospheres do not include cells
other than undifferentiated neural cells, except
for impurities ordinarily associated with
culturing neurospheres, wherein the
undifferentiated neural cells are characterized
by positive immunocytochemistry staining of
Nestin; and
(2) The neurospheres do not contain
detectable level of differentiated neural cells,
wherein the differentiated neural cells are
characterized by negative staining of nestin,
and positive staining of neurofilament, glial
fibrillary acidic protein, neuron specific
enolase, and myelin basic protein via standard
immunocytochemistry techniques.
Neuralstem and StemCells “disagree on whether (1) the neurospheres must contain any
differentiated cells; (2) whether any cell in the neurosphere may stain positive for neurofilament,
glial fibrillary acidic protein, or myelin basic protein; (3) whether the phrase ‘negative staining’
should be included; and (4) whether phrase [sic] ‘detectable level’ should be included.” Doc.
No. 224, at 12. The Court has addressed the first three concerns above in its discussion of term
numbers 38 and 54, which are nearly identical to the present term “consist of . . . lack.” To
summarize, the Court is persuaded by the precedent provided by the Conoco v. Energy &
Environmental International court which permits the presence of certain impurities within a
“consisting of” list. See Conoco, Inc. v. Energy & Envtl. Int’l, L.C., 460 F.3d 1349, 1360 (Fed.
Cir. 2006). Therefore, the Court prefers StemCells’ proposed construction for the first three
disputes.
Page 34 of 41
Dispute number four is original to this term. Neuralstem opposes the phrase, “the
neurospheres do not contain detectable level of differentiated neural cells.” Neuralstem alleges
that the words “detectable level” are “nowhere found in the patents-in-suit.” Doc. No. 171, at
33. The Court feels that “detectable level” is to be defined by someone of ordinary skill in the
art, and as such, may go before the fact-finder. Therefore, the Court will adopt StemCells’
proposed construction of this term.
Neuralstem and StemCells “disagree on whether (1) the neurospheres must contain any
differentiated cells; (2) whether any cell in the neurosphere may stain positive for neurofilament,
glial fibrillary acidic protein, or myelin basic protein; (3) whether the phrase ‘negative staining’
should be included; and (4) whether phrase [sic] ‘detectable level’ should be included.” Doc.
No. 224, at 12. The Court has addressed the first three concerns above in its discussion of term
numbers 38 and 54, which are nearly identical to the present term “consist of . . . lack.” To
summarize, the Court is persuaded by the precedent provided by the Conoco v. Energy &
Environmental International court which permits the presence of certain impurities within a
“consisting of” list. See Conoco, Inc. v. Energy & Envtl. Int’l, L.C., 460 F.3d 1349, 1360 (Fed.
Cir. 2006). Therefore, the Court prefers StemCells’ proposed construction for the first three
disputes.
Dispute number four is original to this term. Neuralstem opposes the phrase, “the
neurospheres do not contain detectable level of differentiated neural cells.” Neuralstem alleges
that the words “detectable level” are “nowhere found in the patents-in-suit.” Doc. No. 171, at
33. The Court agrees with Neuralstem’s logic that “if a type of cell is not ‘detectable,’ then for
all practical purposes it does not exist.” Id. The phrase, “detectable level,” creates confusion
within the definition and the phrase requires a definition of its own. Therefore, the Court will
partially adopt StemCell’s proposed construction of this term. The definition will read as
follows:
Page 35 of 41
The neurospheres do not include cells other than undifferentiated
neural cells, except for impurities ordinarily associated with
culturing neurospheres, wherein the undifferentiated neural cells
are characterized by positive immunocytochemistry staining of
Nestin.
q. “transplant” (Term No. 56)
Found in the following claims: 1 and 22 of the ’872 patent.
"transplanting said multipotent neural stem cell progeny to said host” or “transplanting
said one or more cells to said host"
Neuralstem's Proposed Construction
Transferring multipotent neural stem cell
progeny to a host so that the transferred cells
survive, migrate to appropriate locations
within the host tissue, and form appropriate
neural connections with neighboring cells.
StemCells' Proposed Construction
Administering the multipotent neural stem
cell progeny to the host (e.g., injecting the
cells to a neural region of the host).
Each party has one distinct issue with the other’s proposed construction. Neuralstem
contends that “administer” is not synonymous with “transplant” and thus the two cannot be used
interchangeably. StemCells believes “a result that can be achieved does not mean that such
result must be achieved.” Doc. No. 175, at 70. As such, Neuralstem’s requirement that “the
transferred cells survive, migrate to appropriate locations within the host tissue, and form
appropriate neural connections with neighboring cells” only pertains to successful
transplantations, not all transplantations. Thus, StemCells believes that “Neuralstem’s proposed
construction improperly reads a limitation from a preferred embodiment into the claims.” Id.
First, the Court will address whether “administer” and “transplant” are synonymous.
StemCells references the ‘832 patent specification where they allege that the two words are being
used interchangeably. Specifically, they cite the following passage, bolding text to support their
arguments:
Transplantation can be done bilaterally, or, in the case of a
patient suffering from Parkinson’s Disease, contralateral to the
most affected side. Surgery is performed in a manner in which
Page 36 of 41
particular brain regions may be located, such as in relation to skull
sutures, particularly with a stereotaxic guide. Cells are delivered
throughout any affected neural area, in particular to the basal
ganglia, and preferably to the caudate and putamen, the nucleus
basalis or the substantia nigra. Cells are administered to the
particular region using any method which maintains the integrity
of surrounding areas of the brain, preferably by injection cannula.
Doc. No. 175, at 68-69 (emphasis in original). The Court does not believe this supports
StemCells’ argument that the two terms are synonymous. The synonymous relationship between
the terms appears attenuated at best.
According to Neuralstem, the specification does not use “transplant” and “administer”
interchangeably. Neuralstem cites the specification of the ‘832 patent to highlight the difference
between the two terms:
Neural stem cell progeny when administered to the particular
neural region preferably form a neural graft, wherein the neuronal
cells form normal neuronal or synaptic connections with
neighboring neurons, and maintain contact with transplanted or
existing glial cells which may form myelin sheaths around the
neurons’ axons and provide a trophic influence for the neurons.
As these transplanted cells form connections, they re-establish the
neuronal networks which have been damaged due to disease and
aging.
Doc. No. 171, at 39 (emphasis in original). Neuralstem contends that administered cells that “are
able to [form and maintain normal neuronal connections with neighboring neurons] are referred
to as ‘transplanted cells.’” Id. However, StemCells references this exact passage in support of
their argument that the two terms are synonymous. The Court agrees with StemCells in that the
passage seemingly supports the theory that the two terms are interchangeable. The Court is
persuaded by the phrase, “[a]s these transplanted cells form connections . . . .” Id. This infers
that the cells to which the specification refers have not yet formed the “normal neuronal
connections” that Neuralstem equates with transplanted cells. Id.
Neuralstem cites several other passages in support of their premise including another
portion of the specification:
Page 37 of 41
To date, treatment for CNS disorders has been primarily via the
administration of pharmaceutical compounds. Unfortunately,
this type of treatment has been fraught with many complications
including the limited ability to transport drugs across the bloodbrain barrier and the drug-tolerance which is acquired by patients
to whom these drugs are administered long-term . . . .
Recently, the concept of neurological tissue grafting has been
applied to the treatment of neurological disease such as
Parkinson’s Disease. Neural grafts may avert the need not only
for constant drug administration, but also for complicated drug
delivery systems which arise due to the blood-brain barrier.
However, there are limitations to this technique as well. First, cells
used for transplantation which carry cell surface molecules of a
differentiated cell from another host can induce an immune
reaction in the host. In addition, the cells must be at a stage of
development where they are able to form normal neural
connections with neighboring cells.
Doc. No. 227, at 7-8 (emphasis in original). This passage supports Neuralstem’s premise that
“transplant” and “administer” are not synonymous. Ultimately, the use of this term in the
specification is ambiguous, with different portions of the specification supporting both parties’
arguments. The Court is not persuaded by either parties’ argument.
Second, the Court will address whether “Neuralstem’s proposed construction improperly
reads a limitation from a preferred embodiment into the claims.” Doc. No. 175, at 70.
StemCells again references the specification in support of their argument:
Neural stem cell progeny when administered to the particular
neural region preferably form a neural graft, wherein the
neuronal cells form normal neuronal or synaptic connections with
neighboring neurons, and maintain contact with transplanted or
existing glial cells which may form myelin sheaths around the
neurons’ axons, and provide a trophic influence for the neurons.
As these transplanted cells form connections, they re-establish the
neuronal networks which have been damaged due to disease and
aging.
Id. at 69-70 (emphasis in original). This excerpt supports StemCells’ argument that the
requirements Neuralstem adopts as part of their proposed construction are actually requirements
for a preferred embodiment and not the claim itself.
Page 38 of 41
Neuralstem counters StemCells by referencing the ‘872 patent history. Neuralstem
contends that both the Examiner and patentee “understood the term ‘transplant’ to be distinct
from ‘administer.’” Doc. No. 171, at 39. The Examiner rejected all claims in an Office Action
that reads as follows:
The claims of the instant invention are broad in that they
encompass all neural stem cell progeny and it is not apparent from
the specification that any and all neural stem cell progeny can be
obtained and transplanted as claimed. Also, the claims are broad
in that they read on any transplantation site and it is not clear form
[sic] the specification that these cells could be transplanted to any
site within an organism.
Doc. No. 171, at 39. Neuralstem contends that “[i]f ‘transplant’ simply meant ‘administer,’ then
the Examiner’s enablement rejection would have been nonsensical” because cells can be
administered to any location within an organism. Id. Neuralstem then references the patentee’s
reply to the Examiner’s enablement rejection:
The Examiner’s § 112, 1st ¶ rejection is also based on the assertion
that “it is not apparent from the specification” that neural stem cell
progeny can be “transplanted as claimed.”
However, the
specification shows that neural stem cell progeny can be
successfully transplanted into animals, where they survive,
migrate to appropriate locations within the host tissue, and form
appropriate neural connections with neighboring cells.
Id. at 40 (emphasis added). Neuralstem believes this passage proves that the patentee understood
“transplant” to mean more than “administer.” StemCells recognizes the patentee’s preferred
embodiment which defines successfully transplanted cells as ones that survive and migrate to
appropriate tissues. However, Stemcells also avers that this is a preferred embodiment of the
invention, and that inserting limitations, as they claim Neuralstem does, would be improper.
StemCells alleges, “[s]uccesfully [sic] integration of the transplanted cells is the desired result,
and the Applicant demonstrated that such result can be achieved to meet the 112 enablement
rejection. However, a result that can be achieved does not mean that such result must be
achieved.” Doc. No. 175, at 05. The Court is persuaded by the overwhelming precedent in
Page 39 of 41
favor of StemCells’ position which is appropriately worded by the Kara Technology Inc. v.
Stamps.com Inc., 582 F.3d 1341 (Fed. Cir. 2009) courts finding that “the patentee is entitled to
the full scope of his claims, and we will not limit him to his preferred embodiment or import a
limitation from the specification into the claims.” 582 F.3d at 1348.
The Court believes that the requirements Neuralstem imposes on the term “transplanted”
are only found for successful transplantations with the Court believing successful
transplantations are a preferred embodiment. As such, the Court is not willing to limit the claim
to a preferred embodiment. Also, while the term “administer” may not be defined by the
specification, there is ample support for both parties’ positions. Because the Court is not willing
to create its own definition, the Court must choose between two imperfect choices. When
comparing the two proposed constructions, the Court is most uncomfortable with limiting a
claim to a preferred embodiment. Therefore, the Court will adopt StemCells’ proposed
construction of this term.
CONCLUSION
Having construed the individual claim terms, the Court refers the parties to the table
below for a quick reference to the claim terms which the Court has adopted. This litigation will
proceed pursuant to the most recent Scheduling Order issued in this case (Doc. No. 225).
Table of Definitions
Term Number
4
21
25
37
38
54
41
42
43
44
Term (as found in Doc. No. 224) Neuralstem StemCells
"multipotent"
X
"culture medium"
X
"EGF-like ligands"
X
"neural stem cell(s)"
X
"consisting of"
X
"consisting of"
X
"neurosphere(s)"
X
"pure . . . consisting of"
X
"consists essentially of"
X
"cluster"
X
Page 40 of 41
45
46
47
52
55
53
56
adherent
"purified"
"Nestin(+)"
"of . . . lack"
"of"
"consist of . . . lack"
"transplant"
X
X
X
X
X
X
X
/s/
Alexander Williams, Jr.
United States District Judge
August 11, 2011
Date
Page 41 of 41
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