from the United States District Court for the Southern
District of New York in No. 1:14-cv-01650-KBF, Judge
Katherine B. Forrest.
Kumar Katyal, Hogan Lovells U.S. LLP, Washington, DC, argued
for plaintiff-appellant. Also represented by Christopher P.
Borello, Michael Enzo Furrow, Brendan M. O'Malley, Robert
Seth Schwartz, Fitzpat-rick, Cella, Harper & Scinto, New
Patricia A. Carson, Kirkland & Ellis LLP, New York, NY,
argued for defendant-appellee. Also represented by Saunak
Desai, Aaron D. Resetarits; John C. O'Quinn, Washington,
DC; Peter B. Silverman, Merus US, Inc., Cambridge, MA.
Edward Noonan, McDonnell, Boehnen, Hul-bert & Berghoff,
LLP, Chicago, IL, for Amicus Curiae Seven Chicago Patent
Lawyers. Also represented by Jeffrey Palmer Armstrong, Aaron
Vincent Gin, James Lee Lovsin, Jeremy E. Noe, Andrew W.
Williams, Donald Louis Zuhn, Jr.,
Prost, Chief Judge, Newman and Wallach, Circuit Judges.
Pharmaceuticals, Inc. ("Regeneron") appeals from a
final judgment of the district court holding U.S. Patent No.
8, 502, 018 ("'018 patent") unenforceable
because of Regeneron's inequitable conduct during
prosecution. Regeneron also appeals the district court's
construction of several claim terms and determination of
indefiniteness. Because we conclude that Regeneron engaged in
inequitable conduct during prosecution of the '018
patent, we affirm.
March 2014, Regeneron filed suit in the Southern District of
New York accusing Merus B.V. ("Merus") of
infringing the '018 patent. The district court heard
argument and expert testimony on claim construction and
issued an opinion construing various terms. See
Regener-on Pharm., Inc. v. Merus B.V., No. 14-cv-1650,
2014 WL 6611510 (S.D.N.Y. Nov. 21, 2014). The court also
declared one term indefinite. Id. at *23-24.
asserted a counterclaim of unenforceability due to
inequitable conduct. It argued that Regeneron's patent
prosecutors withheld four references (the "Withheld
References") from the U.S. Patent and Trademark Office
("PTO") during prosecution of the '018 patent.
According to Merus, these references were cited in a
third-party submission in related U.S. patent prosecution and
in European opposition briefs, were but-for material, and
were withheld by Regeneron with the specific intent to
deceive the PTO. There was no dispute that Regeneron knew of
the Withheld References during prosecution of the '018
patent. Regeneron argues, however, that the references were
not but-for material, that they were cumulative of references
the PTO actually relied on during prosecution, and that
Regeneron did not have any specific intent to deceive the
district court scheduled a bench trial on Regener-on's
inequitable conduct, but bifurcated the trials based on the
two elements of inequitable conduct: a first bench trial on
the materiality of the Withheld References, and a second
bench trial regarding the specific intent to deceive the PTO.
See Therasense, Inc. v. Becton, Dickinson & Co.,
649 F.3d 1276, 1287 (Fed. Cir. 2011) (en banc).
the first trial, the district court issued a lengthy opinion
detailing the materiality of the Withheld References.
Regeneron Pharm., Inc. v. Merus B.V., 144 F.Supp.3d
530 (S.D.N.Y. 2015) ("Regeneron
I"). The district court, however, never held
the scheduled second trial on Regeneron's specific intent
to deceive the PTO. In- stead, in its opinion following the
first bench trial, the court exhaustively detailed
Regeneron's discovery misconduct throughout litigation
and sanctioned Regeneron by drawing an adverse inference of
specific intent to deceive the PTO. In particular, the
district court discussed Regeneron's repeated violations
of the district court's discovery orders and improper
secreting of relevant and non-privileged documents. Based on
this misconduct, the district court drew an adverse inference
that Regeneron's agents failed to disclose the Withheld
References to the PTO with the specific intent to deceive the
PTO. Having determined the but-for materiality of the
Withheld References and drawn an adverse inference of
Regeneron's specific intent to deceive the PTO, the
district court concluded that Regeneron had committed
inequitable conduct and held the '018 patent
timely appealed the district court's claim construction
order and final judgment of inequitable conduct. We have
jurisdiction under 28 U.S.C. § 1295(a)(1).
'018 patent emerged from a family of applications that
originated in December 2000. In February 2001, Regeneron
filed a continuation-in-part from that original application,
which ultimately issued as U.S. Patent No. 6, 596, 541
("'541 patent"). Regeneron then filed a
divisional of the '541 patent, and from that divisional
filed several continuations including U.S. Application No.
13/164, 176 ("'176 application") entitled
"Method of Modifying Eukaryotic Cells." That
continuation application issued as the '018 patent on
August 6, 2013, to inventors Drs. Andrew J. Murphy and George
D. Yancopoulos, who assigned it to Regeneron.
general, the '018 patent relates to using large DNA
vectors to target and modify endogenous genes and chromosomal
loci in eukaryotic cells. '018 patent col. 1 ll. 17-33.
One practical use of this technology is that users may target
and modify specific genes in mice so that the mice develop
antibodies that can be used by humans.
are proteins that the body uses to counteract specific
pathogens such as bacteria, viruses, and other foreign
substances in the blood. Antibodies are typically represented
by a "Y" shape consisting of four chains of amino
acids: two longer "heavy" chains, and two shorter
"light" chains. Each of the chains, in turn,
consists of two regions: a "variable" region toward
the top of the "Y, " and a "constant"
region toward the bottom. One such antibody is illustrated
Br. 5 (stripes added). In this antibody, the light chains are
striped and the heavy chains are solid. Further, the constant
regions are represented in lighter shades, and the variable
regions in darker shades.
DNA coding for antibodies can be modified using human DNA in
various different ways. For example, mouse DNA can be
manipulated to create chimeric antibodies that have mouse
variable region DNA and human constant region DNA. Similarly,
mice can be used to create humanized antibodies that have
some mouse variable region DNA, some human variable region
DNA, and human constant region DNA. Further, genetically
modified mice can be used to create antibodies that have
fully human DNA. Finally, mice can also be modified to create
reverse chimeric antibodies that have mouse constant region
DNA and human variable region DNA. This spectrum of modified
antibodies is illustrated below.
of the '018 patent, the only claim at issue here,
recites, in its entirety, "[a] genetically modified
mouse, comprising in its germline human unrearranged variable
region gene segments inserted at an endogenous mouse
immunoglobulin locus." '018 patent col. 29 11.
24-26. As discussed in greater detail below, Regeneron
contends that under the broadest reasonable construction,
this claim is limited to mice that produce reverse chimeric
antibodies. Merus, on the other hand, argues that under the
broadest reasonable construction, claim 1 includes mice that
can produce humanized, fully human, or reverse chimeric
originally filed, claim 1 of the '176 application recited
"[a] genetically modified mouse, comprising in its
germline human unrearranged variable gene region segments
inserted at a mouse immunoglobulin locus." J.A. 450. In
January 2012, the PTO issued a Non-Final Office Action
rejecting claims 1-19 of the '176 application as being
anticipated by a U.S. Application No. 11/009, 873 to Nils
Lonberg and Robert Kay ("Lonberg"). J.A. 376-88.
2012, Regeneron's Dr. Smeland, in-house counsel
responsible for prosecuting the '176 application and
others in the same family in the United States and Europe,
replied to this Office Action. He argued that unlike the
recited claims of the '176 application, Lonberg teaches
random and not targeted insertion. In particular, Dr. Smeland
argued that Lonberg did not teach inserting "human
unrearranged variable region gene segments" in the mouse
immunoglobulin ("Ig") locus. Instead, according to
Dr. Smeland, Lonberg teaches genes that are "randomly
inserted at (unknown) loci." J.A. 408-09.
October 2012, the PTO mailed a Final Office Action, rejecting
the pending claims of the '176 application, maintaining
the rejection of claims 1-19 as anticipated by Lonberg.
January 2013 Reply to the Final Office Action, Regeneron
amended claim 1 to include the additional limitation that the
human unrearranged variable region gene segments would be
inserted at "an endogenous" mouse immunoglobulin
locus. Regeneron also sent a presentation to the PTO with the
Reply. In that presentation, Regeneron asserted that it had
developed a commercial embodiment of the claimed mouse with
surprising results. It is undisputed that that assertion was
false. J.A. 7563. Regeneron had not developed any such mouse
at the time.
receipt of Dr. Smeland's Reply and presentation, the PTO
issued an Advisory Action maintaining the rejection of claims
1-19 as anticipated by Lonberg, and claim 20 remained
rejected in view of Lonberg and other references. Shortly
thereafter, in February 2013, Regeneron retained Brendan
Jones, Ph.D., to assist with prosecution. Drs. Jones and
Smeland together planned an in-person meeting with the
Examiner during which they relied on the misleading
presentation asserting that Regeneron had developed a
commercial embodiment of the claimed mouse. That meeting
occurred in March 2013.
that meeting, in April 2013, the PTO issued a Notice of
Allowance for the '176 application. In the statement of
reasons for allowance, the Examiner stated that "[t]he
prior art does not teach or suggest a genetically modified
mouse comprising, in its germline cells, human unrearranged
variable region gene segments inserted at an endogenous mouse
immunoglobulin locus." J.A. 531. The applicant
transmitted the fee in June 2013, and the '018 patent
issued on August 6, 2013.
before the PTO issued its notice of allowance for the
'176 application, which would become the '018 patent,
a third-party filed a submission in the parent application of
the '018 patent, describing three references:
1. Marianne Brüggemann & Michael S. Neu-berger,
"Strategies for Expressing Human Antibody Repertoires in
Transgenic Mice, " 17(8) Review Immunology Today 391
2. Shinsuke Taki et al., "Targeted Insertion of a
Variable Region Gene into the Immunoglobu-lin Heavy Chain
Locus, " 262 Science 1268 (1993) ("Taki"); and
3. Yong-Rui Zou et al, "Cre-loxP-mediated Gene
Replacement: A Mouse Strain Producing Humanized Antibodies,
" 4(12) Current Biology 1099 (1994) ("Zou").
Rajewsky co-authored both the Taki and Zou refer- ences.
Further, Dr. Alt, another inventor, co-invented WIPO Patent
Publication No. WO 91/00906 entitled "Chimeric and
Transgenic Animals Capable of Producing Human Antibodies,
" credited to Clive Wood et al. ("Wood").
Collectively, the Brüggemann, Taki, Zou, and Wood
references are the "Withheld
their prior work, Regeneron recruited Drs. Alt and Rajewsky
to its scientific advisory board to work on the claimed mouse
before Regeneron filed the '018 patent. During
prosecution, these individuals corresponded with Dr. Murphy,
an '018 patent inventor, expressing concerns about his
characterizations of the prior art in related publications.
Smeland knew of the third party submission as well as all
four Withheld References during prosecution, yet withheld
them from the '018 patent's examiner. Although
Regeneron did not disclose the Withheld References during
prosecution of the '018 patent, once the '018 patent
had been allowed, Regeneron disclosed the Withheld References
to the PTO in every related application having the same
specification and similar claims. Merus contends that
Regeneron's failure to disclose the Withheld References
constituted inequitable conduct. Regeneron responds that Dr.
Smeland was under no obligation to disclose these references
because they were not but-for material.
conduct is an equitable defense to patent infringement that,
if proved, bars enforcement of a patent."
Therasense, 649 F.3d at 1285. Unlike validity
defenses, which are claim specific, inequitable conduct
regarding a single claim renders the entire patent
unenforceable. Id. at 1288. Inequitable conduct has
two separate requirements: materiality and intent.
Id. at 1290.
a general matter, the materiality required to establish
inequitable conduct is but-for materiality."
Id. at 1291. A prior art reference is "but-for
material if the PTO would not have allowed a claim had it
been aware of the undisclosed prior art." Id.
In determining the materiality of a reference, the court
applies the preponderance of the evidence standard and gives
claims their broadest reasonable construction. Id.
reference is not but-for material, however, if it is merely
cumulative. See Dig. Control Inc. v. Charles Mach.
Works, 437 F.3d 1309, 1319 (Fed. Cir. 2006)
("However, a withheld otherwise material prior art
reference is not material for the purposes of
inequitable conduct if it is merely cumulative to that
information considered by the examiner."). A reference
is cumulative when it "teaches no more than what a
reasonable examiner would consider to be taught by the prior
art already before the PTO." Regents of the Univ. of
Calif. v. Eli Lilly & Co., 119 F.3d 1559, 1575 (Fed.
addition to proving the materiality of withheld references,
"the accused infringer must prove that the patentee
acted with the specific intent to deceive the PTO."
Therasense, 649 F.3d at 1290. "[A] court must
weigh the evidence of intent to deceive independent of its
analysis of materiality. Proving that the applicant knew of a
reference, should have known of its materiality, and decided
not to submit it to the PTO does not prove specific intent to
deceive." Id. (citing Star Sci., Inc. v.
R.J. Reynolds Tobacco Co., 537 F.3d 1357, 1366 (Fed.
Cir. 2008)). "In a case involving nondisclosure of
information, clear and convincing evidence must show that the
applicant made a deliberate decision to withhold a
known material reference." Id.
(quoting Molins PLC v. Textron, Inc., 48 F.3d 1172,
1181 (Fed. Cir. 1995)) (internal quotation marks omitted).
evidence of intent is not, however, required. A court may
infer intent from circumstantial evidence. Id. An
inference of intent to deceive is appropriate where the
applicant engages in "a pattern of lack of candor,
" including where the applicant repeatedly makes factual
representations "contrary to the true information he had
in his possession." Apotex Inc. v. UCB, Inc.,
763 F.3d 1354, 1362 (Fed. Cir. 2014).
appeal, Merus asserts that Drs. Smeland and Murphy violated
their duty of candor and engaged in inequitable conduct.
Regeneron does not contest that both of these individuals had
a duty of candor to the PTO. Regeneron, however, argues that
the duty was not violated because none of the Withheld
References were but-for material and because the district
court improperly concluded that the applicants possessed the
necessary specific intent to deceive the PTO.
review the district court's findings of materiality and
intent for clear error." Am. Calcar, Inc. v. Am.
Honda Motor Co., 768 F.3d 1185, 1189 (Fed. Cir. 2014). A
finding of inequitable conduct based on those facts is
reviewed for an abuse of discretion. Id.
"[w]hen reviewing the imposition of sanctions under a
district court's inherent powers, we apply the law of the
regional circuit in which the district court sits, "
here the Second Circuit. Monsanto Co. v. E.I. Du Pont de
Nemours & Co., 748 F.3d 1189, 1196 (Fed. Cir. 2014).
The Second Circuit reviews a district court's imposition
of sanctions and an adverse inference for litigation
misconduct for abuse of discretion. Residential Funding
Corp. v. DeGeorge Fin. Corp., 306 F.3d 99, 107 (2d Cir.
first step in an inequitable conduct inquiry is determining
whether the patentee failed to disclose but-for material
information to the PTO. Determining but-for materiality
requires that the court place itself in the shoes of a patent
examiner and determine whether, had the reference(s) been
before the examiner at the time, the claims of the patent
would have still issued. Therasense, 649 F.3d at
an invalidity analysis, the first step in determining but-for
materiality of a reference is determining the scope of the
claims at issue. Thus, the court must first determine the
broadest reasonable construction of the claims that the PTO
would have applied during prosecution. Next, based on the
broadest reasonable construction, the court must determine
whether a reasonable patent examiner would have allowed the
claims had she known of the Withheld References. See Am.
Honda Motor, 768 F.3d at 1189.
broadest reasonable construction of a claim term is one that
is consistent with "the specification and the record
evidence" and is "consistent with the one that
those skilled in the art would reach." Microsoft
Corp. v. Proxy-conn, Inc., 789 F.3d 1292, 1298 (Fed.
Cir. 2015). But "[a] construction that is unreasonably
broad and which does not reasonably reflect the plain
language and disclosure will not pass muster."
Id. (internal quotation marks omitted).
Regeneron and Merus agree that the claimed mouse has, as
recited in claim 1, "human unrearranged variable region
gene segments." But Regeneron argues that under the
broadest reasonable construction of claim 1, the non-variable
(constant) region of the claimed mouse's modified gene
segments exclusively contains mouse genes. In other words,
Regeneron argues that claim 1 is limited to a reverse
chimeric mouse. Appellant's Br. 32-35. Merus, on the
other hand, argues that the constant region of the gene
segments in the claimed mouse may contain mouse genes or
human genes, and may, therefore, be reverse chimeric,
humanized, or fully human. Appellee's Br. 51.
first relies on the claim language to support its position.
As noted above, claim 1 recites "[a] genetically
modified mouse, comprising in its germline human unrearranged
variable region gene segments inserted at an endogenous mouse
immunoglobulin locus." According to Regeneron, because
claim 1 only recites modifying the mouse by inserting
"human unrearranged variable region gene segments,
" it implies leaving the remainder of the mouse's
DNA unmodified. This, however, is inaccurate. Because
"comprise" is inclusive or open-ended, the use of
the term does not exclude unrecited elements. See
Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501 (Fed.
Cir. 1997) ("'Comprising' is a term of art used
in claim language which means that the named elements are
essential, but other elements may be added and still form a
construct within the scope of the claim.");
accord MPEP § 2111.03 ("The transitional
term 'comprising, ' which is synonymous with
'including, ' 'containing, ' or
'characterized by, ' is inclusive or open-ended and
does not exclude additional, unrecited elements or method
steps."). A germline that "comprises" human
variable region gene segments may very well also include
human constant gene segments. Thus, the "customary and
ordinary" meaning of the language in claim 1 is not
limited to a reverse chimeric mouse.
further argues that the specification purportedly limits the
claim to mice that produce "hybrid antibodies containing
human variable regions and mouse constant regions."
Appellant's Br. 33 (citing '018 patent col. 20 ll.
37-39). The patent, however, clearly teaches producing
antibodies that "compris[e] a human constant
region." '018 patent col. 7 ll. 19-23 (emphasis
added). Regeneron argues that this disclosure is limited to
reverse chimeric antibodies that are later modified to insert
a human constant region. But Regeneron points to no portion
of the specification to support its argument. In context, it
is clear that the endogenously produced antibodies may
comprise a human constant region. The specification thus does
not limit the claims to mice with human variable regions and
mouse constant regions.
we disagree with Regeneron and conclude that under the
broadest reasonable construction, the district court
correctly found that the claims are not limited to mice that
solely comprise mouse constant region gene segments.
this broadest reasonable construction, the court next
determines if the district court clearly erred in finding the
Withheld References but-for material and not cumulative of
prior art that the PTO considered during prosecution. We
conclude that the district court properly found that the
Withheld References were but-for material and were not
prosecution, Drs. Smeland and Murphy knew of the Withheld
References and did not disclose them to the PTO. Merus
argues, and the district court found, that each of these
references was but-for material, i.e., the "PTO would
not have allowed [the] claim had it been aware of" these
references. Therasense, 649 F.3d at 1291. Regeneron
disagrees. As noted above, the four Withheld References were
Brüggemann, Wood, Taki, and Zou.
Regeneron argues that the district court improperly found
Brüggemann to be but-for material. Brüggemann is a
review paper that teaches the use of transgenic mice to
express human antibodies. In particular, Brüggemann
teaches that "[a]n attractive alternative [to the random
integration of human genes into mouse genes] would be to
replace the mouse Ig loci with the human Ig loci." J.A.
3917. Brüggemann further expands that in doing so,
"much of the DNA of the mouse Ig loci" might be
replaced with human DNA. J.A. 3918. Regen-eron only contests
Brüggemann's materiality because Brüggemann
purportedly does not disclose a reverse-chimeric mouse.
See Appellant's Br. 37-38
("[Brügge-mann] does not specify that the mouse
constant region should be retained, or that any portion of
the mouse locus should be retained at all."). As
discussed above, however, claim 1 is not limited to
reverse-chimeric mice. Claim 1 encompasses humanized, fully
human, and reverse chi-meric mice as well. We therefore are
not persuaded by the distinction drawn by Regeneron and
conclude that the district court did not clearly err in
finding Brüggemann but-for material.
Regeneron argues that the district court improperly found
Wood to be but-for material. According to Regeneron, Wood
does not teach inserting a human variable gene into a mouse
by targeting the mouse Ig locus. Instead, Regeneron contends
that Wood teaches "randomly integrating human
transgenes" into a mouse genome with no such targeting.
Appellant's Br. 40.
Merus's expert Dr. Geoff Davis explained, however, Wood
does disclose specific targeting of the mouse's Ig locus.
For example, Wood teaches that "[t]he present invention
relates generally to immunoglobulin rearrangement in
chimeric and transgenic animals, and more specifically to a
mouse containing in its germline . . . the ability to
generate immunoglobulins . . . ." Wood at 1:4-9
(emphasis added); J.A. 2125-26. Wood further teaches that
when human DNA is combined with mouse DNA, the "constant
region, " i.e., the constant region of the DNA in the Ig
locus, "is of exogenous or endogenous species
origin" and that this constant region may be "from
the animal itself." Wood at 6:17-20, 10:3-5 (emphasis
added); J.A. 2126-28. Skilled artisans are therefore taught
to specifically target the endogenous Ig locus when inserting
human DNA into the mouse. The district court did not err in
finding Wood but-for material.
dissent argues that Wood is not material because it only
teaches a "DNA fragment construct" but
does not describe "any targeted insertion method
described elsewhere in the prior art . . . ." Dissent at
17. As an initial matter, neither party argues this position
and the district court did not make this factual finding.
See 3M Co. v. Avery Dennison Corp., 673 F.3d 1372,
1378 (Fed. Cir. 2012) ("[I]t is improper for us to
determine factual issues in the first instance on appeal . .
. finding those facts in the first instance would overstep
our bounds as a reviewing court and we cannot resolve the
parties' factual disputes on appeal."). Regardless,
the dissent's argument is unavailing because the claim at
issue does not recite a particular method of inserting DNA
into a mouse. The claim simply recites a genetically modified
mouse that comprises "human unrearranged variable region
gene segments inserted at an endogenous mouse immunoglobu-lin
locus." Wood teaches that "[t]he animals of this
invention are designed by the integration into their
germlines of DNA carrying unrearranged or only partially
rearranged exogenous Ig gene segments." J.A. 2127. Wood
thus teaches the elements of the claim at issue and is
Regeneron argues that the district court improperly found
Taki to be but-for material. According to Regeneron, Taki
only teaches inserting rearranged variable region DNA from
one mouse into the genome of another mouse. Claim 1,
on the other hand, recites inserting unrearranged
human variable region DNA into a mouse genome.
district court correctly noted, Taki teaches insertion of
exogenous (i.e., foreign) "rearranged mouse variable
region [DNA] into the Ig locus" to produce a transgenic
mouse with good B-cell development and antibodies.
Regeneron I, 144 F.Supp.3d at 573. The development
of a transgenic mouse with good B-cell development and
antibodies is also an intended goal of the '018 patent.
'018 patent col. 20 ll. 63-65 ("These interactions
are important for a strong and specific immune response, for
the proliferation and maturation of B cells, and for the
affinity maturation of antibodies."). The fact that Taki
teaches using exogenous mouse DNA instead of exogenous human
DNA does not detract from the motivation Taki provides to
target the mouse Ig locus with exogenous DNA, including human
DNA. As the district court correctly found,
Taki teaches targeting at the specific locus-the Ig
locus-with operable linkage . . . taking advantage of the
mouse regulatory and constant regions. Taki, in short,
provides the motivation to target human variable region DNA
into the mouse Ig locus.
Regeneron I, 144 F.Supp.3d at 574. The district
court did not err by finding Taki's disclosure of
targeting insertion of exogenous variable region DNA to be
Regeneron argues that the district court improperly found Zou
to be but-for material. Regeneron contends that Zou only
teaches modifying a mouse's constant region whereas the
'018 patent teaches modifying a mouse's variable
region. According to Regeneron, "the '018 Patent
discloses the insertion of human variable regions; Zou does
not. Zou discloses the insertion of human constant regions;
the '018 Patent does not." Appellant's Br. 44.
Regeneron admits, Zou teaches specifically inserting human Ig
DNA into the mouse Ig locus, preserving part of the mouse
constant region, and discloses producing antibodies at the
"same level and efficiency as wild-type mice." J.A.
2414-17. The district court properly found that Zou's
teaching of inserting portions of human constant, rather than
variable, DNA did not detract from its motivation to insert
human variable regions in the mouse Ig locus. In fact, as
Merus's expert Dr. Davis noted, Brüggemann cited Zou
for this precise disclosure a few years later. J.A. 2123-24.
Thus, the district court properly concluded that Zou was also
addition to arguing that the Withheld References are not
but-for material individually, Regeneron also argues that the
Withheld References are not but-for material in combination.
We disagree. As noted above, the references both individually
and in combination teach one of skill in the art to
genetically modify mice by inserting exogenous, including
human, variable region gene segments endogenously into a
mouse immunoglobulin locus. The references, in particular
Taki and Zou, also provide the motivation to combine these
references to develop the genetically modified mouse.
also argues that Brüggemann, Wood, and Taki are
cumulative of references that the examiner considered during
prosecution of the '018 patent. In particular, Regeneron
contends that Brüggemann is cumulative of U.S. Patent
No. 6, 114, 598 issued to Raju Kucherlapati et al. on June 5,
1995 ("Kucherlapati"), Wood is cumulative of
Lonberg, and Taki is cumulative of Kucherlapati and Lonberg.
There is no dispute that the PTO considered both Lonberg and
Kucherlapati during prosecution.
relates generally to "the production of xenogeneic
specific binding proteins in a viable mammalian host."
Kucherlapati col. 1 ll. 20-21. ...