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Regeneron Pharmaceuticals, Inc. v. Merus N.V.

United States Court of Appeals, Federal Circuit

July 27, 2017

REGENERON PHARMACEUTICALS, INC., Plaintiff-Appellant
v.
MERUS N.V., Defendant-Appellee

         Appeal from the United States District Court for the Southern District of New York in No. 1:14-cv-01650-KBF, Judge Katherine B. Forrest.

          Neal 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 York, NY.

          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.

          Kevin 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.,

          Before Prost, Chief Judge, Newman and Wallach, Circuit Judges.

          Prost, Chief Judge.

         Regeneron 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.

         I

         In 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.

         Merus 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 PTO.

         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).

         Following 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").[1] 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 unenforceable.

         Regeneron 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).

         A

         The '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.

         In 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.

         Antibodies 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 below:

         (Image Omitted)

         Appellant's 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.

         Mouse 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.

         (Image Omitted)

         Claim 1 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 antibodies.[2]

         B

         As 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.

         In July 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.

         In 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.

         In a 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.

         Following 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.

         Following 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.

         C

         Days 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 (1996) ("Brüggemann");
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").

         Dr. 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 References."[3]

         Given 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.

         Dr. 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.

         II

         "Inequitable 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]s 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. at 1291-92.

         A 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. Cir. 1997).

         In 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).

         Direct 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).

         On 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.

         "[W]e 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.

         Further, "[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. 2002).

         A

         The 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 1291-92.

         As with 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.

         1

         The 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).

         Both 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.

         Regeneron 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.

         Regeneron 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.

         Accordingly, 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.

         2

         Under 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 cumulative.

         During 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.

         First, 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.

         Second, 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.

         As 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.

         The 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 but-for material.

         Third, 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.

         As the 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 but-for material.

         Fourth, 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.

         As even 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 but-for material.

         In 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.

         Regeneron also argues that Brüggemann, Wood, and Taki are cumulative of references that the examiner considered during prosecution of the '018 patent.[4] 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.

         Kucherlapati relates generally to "the production of xenogeneic specific binding proteins in a viable mammalian host." Kucherlapati col. 1 ll. 20-21. ...


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