375 F.3d 1126
TI GROUP AUTOMOTIVE SYSTEMS (NORTH AMERICA), INC. (now known as TI Group Automotive Systems, L.L.C.) Plaintiff-Appellant,v.VDO NORTH AMERICA, L.L.C., Mannesmann VDO AG, Siemens VDO Automotive Corp., and Siemens VDO Automotive AG, Defendants-Cross Appellants.
No. 02-1630.
No. 03-1482.
United States Court of Appeals, Federal Circuit.
DECIDED: June 30, 2004.
Rehearing and Rehearing En Banc Denied August 24, 2004.

COPYRIGHT MATERIAL OMITTED COPYRIGHT MATERIAL OMITTED William J. Schramm, Reising, Ethington, Barnes, Kisselle, PC, of Troy, Michigan, argued for plaintiff-appellant. With him on the brief were Andrew M. Grove, Matthew J. Schmidt, and William H. Francis. Of counsel on the brief was Douglas E. Whitney, Morris, Nichols, Arsht & Tunnell, of Wilmington, Delaware.
Eric J. Lobenfeld, Clifford Chance US, LLP, of New York, New York, argued for defendants-cross appellants. With him on the brief were Drew M. Wintringham, III and Mark W. Rueh.
Before NEWMAN, BRYSON, and LINN, Circuit Judges.
LINN, Circuit Judge.

1
TI Group Automotive Systems, L.L.C. ("TI Group"), appeals from a post-trial decision of the United States District Court for the District of Delaware, granting a motion for judgment as a matter of law ("JMOL") that VDO North America, L.L.C., Mannesmann VDO AG, Siemens VDO Automotive Corp., and Siemens VDO Automotive AG (collectively "VDO" or "defendants") do not infringe U.S. Patent No. 4,860,714 ("the '714 patent"). TI Group Auto. Sys. (N. Am.), Inc. v. VDO N. Am., L.L.C., No. 00-432-GMS, 2002 WL 31051602 (D.Del. Sept. 4, 2002) ("JMOL Infringement Opinion"). The defendants cross-appeal the district court's denial of their motion for JMOL of invalidity of the '714 patent. TI Group Auto. Sys. (N. Am.), Inc. v. VDO N. Am., L.L.C., No. 00-432-GMS, 2003 WL 21302951 (D.Del. June 6, 2003) ("JMOL Invalidity Opinion"). Because we affirm the district court's claim constructions of the disputed terms "reservoir" and "within," and further, because we conclude that the facts presented at trial are sufficient to support the district court's grant of judgment of non-infringement in VDO's favor, we affirm the district court's JMOL Infringement Opinion. However, because we reverse some of the district court's claim constructions, we vacate the district court's JMOL Invalidity Opinion and remand the invalidity issues to the district court for further proceedings in light of the claim constructions set forth in this opinion.

BACKGROUND

2
TI Group is an automotive supplier that makes fuel tanks, fuel pump assemblies, and complete fuel tank systems. TI Group has sold over thirty million fuel pump assemblies that embody the '714 patent, and has licensed the technology to other suppliers, including Delphi, a former subsidiary of General Motors. Beginning in the late 1990s, General Motors sought a second source for its "supply-side" pump assemblies because Delphi was having labor difficulties. Although TI Group submitted bids, General Motors awarded the contracts to VDO. The fuel pump assemblies supplied to General Motors by VDO were essentially drop-in replacements for the licensed Delphi assemblies.

A. The '714 Patent

3
TI Group owns the '714 patent which is directed to fuel pump assembly technology. The '714 patent is directed to an intank fuel assembly for fuel-injected engines. The assembly provides a constant and reliable supply of fuel even when the fuel in the fuel tank is low, or when the vehicle is navigating a sharp turn, traveling over a steep incline, or after the vehicle has been parked on an incline for an extended period of time. '714 patent, Abstract; id. at col. 1, II. 26-34. This constant supply prevents engine fuel starvation, a problem that can cause the engine to rattle, lurch, or stall.

4
NOTE: OPINION CONTAINING TABLE OR OTHER DATA THAT IS NOT VIEWABLE

5
Figure 1 of the '714 patent illustrates an embodiment of the invention. Although Figure 1 illustrates a dual fuel tank arrangement, single tank arrangements are more common and offer the advantages of compactness and ease of repair or replacement. Id. at col. 4, II. 21-26; id. at col. 6, II. 11-38. The assembly includes a reservoir 10 having top and bottom openings 12 and 14. A high pressure pump 26 sits in reservoir 10 and pumps fuel to the engine's fuel injectors 116 by way of line 106. Jet pump 30, including nozzle 54 and venturi tube 58, supplies the reservoir with fuel by drawing fuel from the fuel tank via opening 14. Even when the fuel in the tank is low, the action of jet pump 30 will maintain a comparatively high level of fuel in reservoir 10 and around inlet 42 to the high pressure pump 26. Preferred embodiments include check valve 22 that prevents fuel above the valve from leaking out when the unit is not operating. Check valve 22 does not retain fuel in the reservoir while the unit is operating, because it moves away from opening 14 by the action of jet pump 30, and further is not a necessary component for operation. Id. at col. 4, I. 39-col. 5, I. 35.

6
Prior art fuel starvation prevention systems sent all of the output of a high pressure pump to the engine and used fuel returning from the engine to drive a jet pump that pumped fuel into a reservoir. These systems are known as "return-side" systems. Because the amount of fuel returning from the engine varied in such return-side systems, they were inefficient and unreliable. Id. at col. 1, II. 25-29. The invention of the '714 patent is a "supply-side" system and provides advantages over return-side systems by supplying fuel to the jet pump directly from the high pressure pump. In the system described in the '714 patent, only part of the output from the high pressure pump is routed to the engine, while the other part is routed directly to the jet pump for an essentially constant supply of fuel to the jet pump that does not vary with engine demand. Id. at col. 2, II. 3-8.

7
Independent claim 2 is at issue in this appeal, and recites:

8
2. Apparatus for pumping fuel from a fuel tank to an engine comprising:

9
(a) a supply port for carrying fuel from the apparatus to the engine;

10
(b) a fuel reservoir which includes an opening for connecting the interior of the reservoir to the interior of the fuel tank;

11
(c) means for mounting the reservoir in the fuel tank so as to locate the opening of the reservoir in the region of the bottom of the fuel tank;

12
(d) pumping means for pumping fuel into the reservoir, said means being located within the reservoir in the region of the opening and including a nozzle and a venturi tube in alignment with the nozzle, the passage of fuel out of the nozzle and through the venturi tube causing fuel to be entrained through the opening into the interior of the reservoir;

13
(e) a high pressure pump having an inlet connected to the interior of the reservoir and an output of high pressure fuel; and

14
(f) means for routing a first portion of the output of high pressure fuel to the supply port and a second portion of the output of high pressure fuel to the pumping means whereby fuel is delivered to the engine from the reservoir through the supply port and fuel is entrained into the reservoir by means of the fuel passing through the pumping means.

15
Claims 7 and 8, dependent from claim 2, are also at issue. Claim 7 adds a baffle that separates the pumping means outlet from the inlet to the high pressure pump. Claim 8 requires the opening to be located at the bottom of the reservoir, and further, recites an arrangement where the flow of fuel in the reservoir exceeds the flow of fuel to the engine, creating a net flow of fuel from the bottom to the top of the reservoir.

B. The VDO Device

16
The accused VDO device is a single unit, supply-side jet pump assembly. During operation, fuel travels from an output on one side of the electric pump, through a jet tube, and to a jet pump comprising a nozzle and a mixing tube. Fuel from a second output on the other side of the electric pump travels to the engine. The mixing tube mixes fuel entrained from the fuel tank with the fuel being sprayed out of the nozzle. Fuel traveling through the mixing tube forces a valve open so that fuel from the jet pump is pushed into the reservoir, and keeps fuel above it from leaking out of the reservoir and back into the fuel tank where it would not be available to be pumped to the engine.

C. Procedural History

17
TI Group sent written notice of suspected infringement of the '714 patent to both VDO and General Motors. On April 25, 2000, VDO filed a declaratory judgment action against TI Group concerning VDO's alleged infringement of the '714 patent, seeking findings of both non-infringement and invalidity. The parties were subsequently realigned, and TI Group asserted independent claim 2 and dependent claims 7 and 8 against the defendants. TI Group also alleged that VDO's infringement was willful. Upon realignment, VDO's invalidity assertions became essentially a counterclaim.

18
The district court held a Markman hearing on November 6, 2001, and rendered its claim construction opinion on December 3, 2001. VDO N. Am., L.L.C. v. TI Group Auto. Sys. (N. Am.), Inc., No. 00-432-GMS, 2001 WL 1530363 (D.Del. Dec. 3, 2001) ("Markman Order"). TI Group timely filed for reconsideration of the claim constructions, but the request was denied.

19
A jury trial was held between June 3 and June 11, 2002. During the course of trial, VDO moved for judgment as a matter of law, at the appropriate times, on both non-infringement and invalidity grounds under Rule 50 of the Federal Rules of Civil Procedure. The court reserved judgment on these motions. On June 12, 2002, the jury returned a verdict finding that: (1) VDO infringed each of claims 2, 7, and 8, both literally and under the doctrine of equivalents; (2) claims 2, 7, and 8 were not invalid; (3) VDO's infringement was willful; (4) certain accused fuel pump assemblies were not covered by license; (5) TI Group is not entitled to lost profit damages; and (6) TI Group is entitled to compensatory damages in the form of a reasonable royalty of 5%, or $10,773,492.

20
Both parties then filed post-trial motions. VDO renewed its JMOL motions, or in the alternative, requested a new trial under Rule 59 of the Federal Rules of Civil Procedure. TI Group filed motions seeking: (1) prejudgment and post-judgment interest; (2) to alter or amend the judgment; (3) injunctive relief; and (4) enhanced damages, attorneys' fees, and expenses. The district court granted VDO's JMOL motion for non-infringement, concluding that no reasonable juror could have found the '714 patent infringed. JMOL Infringement Opinion at 17-18. Based on its finding of non-infringement, the court specifically declined to address VDO's arguments that the '714 patent was invalid, that the infringement was not willful, and that VDO had a license to produce certain fuel assemblies. Id. at 18 n. 7. The district court also concluded that all of TI Group's post-trial motions were moot. Id. at 18.

21
TI Group filed a timely appeal with this court, asserting errors in both the district court's claim constructions and its grant of VDO's JMOL motion of non-infringement. Because the district court did not resolve VDO's JMOL motion on invalidity, leaving open VDO's counterclaim, this court determined that it lacked jurisdiction over the appeal. TI Group Auto. Sys. (N. Am.), Inc. v. VDO N. Am., L.L.C., 66 Fed.Appx. 868 (Fed.Cir.2003) ("Dismissal Order"); see also 28 U.S.C. § 1295(a)(1) (2000) (giving this court jurisdiction over an "appeal from a final decision of a district court of the United States" if that court's jurisdiction was based, in whole or in part, on 28 U.S.C. § 1338 (emphasis added)); Cunningham v. Hamilton County, Ohio, 527 U.S. 198, 204, 119 S.Ct. 1915, 144 L.Ed.2d 184 (1999) (defining a final judgment as one that "ends the litigation on the merits and leaves nothing for the court to do but execute judgment"). The district court then entertained VDO's invalidity counterclaim and issued a second opinion, denying VDO's JMOL motion on invalidity. JMOL Invalidity Opinion. TI Group moved for reinstatement of the appeal, in accordance with our Dismissal Order, and filed a renewed notice of appeal. VDO filed a notice of cross-appeal from the district court's JMOL decision on invalidity, docketed in this court as 03-1482. We reinstated TI Group's appeal, Docket No. 02-1630, pursuant to our Dismissal Order, and consolidated it with VDO's appeal, Docket No. 03-1482. TI Group Auto. Sys. (N. Am.), Inc. v. VDO N. Am., L.L.C., 70 Fed.Appx. 580 (Fed.Cir.2003). This court opinion addresses both appeals. We now have jurisdiction under 28 U.S.C. § 1295(a)(1).

ANALYSIS
A. Standard of Review

22
The grant or denial of a JMOL motion is a procedural issue not unique to patent law, reviewed under the law of the regional circuit in which the appeal from the district court would usually lie. Riverwood Int'l Corp. v. R.A. Jones & Co., Inc., 324 F.3d 1346, 1352 (Fed.Cir.2003); BBA Nonwovens Simpsonville, Inc. v. Superior Nonwovens, LLC, 303 F.3d 1332, 1336 (Fed.Cir.2002). JMOL is appropriate when "there is no legally sufficient evidentiary basis for a reasonable jury to find for that party on that issue." Fed.R.Civ.P. 50(a)(1); see also Blanche Road Corp. v. Bensalem Township, 57 F.3d 253, 262 (3d Cir.1995). "[J]udgment as a matter of law should be granted sparingly." Johnson v. Campbell, 332 F.3d 199, 204 (3d Cir.2003). However, it is appropriate where "the record is critically deficient of the minimum quantum of evidence" in support of the verdict. Gomez v. Allegheny Health Servs., Inc., 71 F.3d 1079, 1083 (3d Cir. 1995). "The question is not whether there is literally no evidence supporting the unsuccessful party, but whether there is evidence upon which a reasonable jury could have found its verdict." Id.

23
Claim construction is a matter of law that we review de novo. Markman v. Westview Instruments, Inc., 52 F.3d 967, 970-71 (Fed.Cir.1995) (en banc), aff'd, 517 U.S. 370, 116 S.Ct. 1384, 134 L.Ed.2d 577 (1996); Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1456 (Fed.Cir.1998) (en banc). A determination of infringement, both literal and under the doctrine of equivalents, is a question of fact, reviewed for substantial evidence when tried to a jury. Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1323 (Fed.Cir.2002). An invalidity determination based on anticipation is a question of fact, and is reviewed following a jury verdict for substantial evidence. Id. As to obviousness, "[t]his court reviews a jury's conclusions on obviousness, a question of law, without deference, and the underlying findings of fact, whether explicit or implicit within the verdict, for substantial evidence." LNP Eng'g Plastics, Inc. v. Miller Waste Mills, Inc., 275 F.3d 1347, 1353 (Fed.Cir.2001).

B. Claim Construction

24
The claim construction analysis begins with the words of the claim. See Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed.Cir.1996). Absent an express intent to impart a novel meaning to a claim term, the words take on the ordinary and customary meaning attributed to them by those of ordinary skill in the art. Brookhill-Wilk 1, LLC v. Intuitive Surgical, Inc., 334 F.3d 1294, 1298 (Fed.Cir.2003). To determine the ordinary and customary meaning of a claim term, we may review sources including the claims themselves, see Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357 (Fed.Cir.1999); dictionaries and treatises, Tex. Digital Sys., Inc. v. Telegenix, Inc., 308 F.3d 1193, 1202 (Fed.Cir. 2002); and the written description, drawings, and prosecution history, see, e.g., DeMarini Sports, Inc. v. Worth, Inc., 239 F.3d 1314, 1324 (Fed.Cir.2001).

25
TI Group argues that the district court erred in construing several of the claim terms at issue in the asserted claims. Specifically, TI Group alleges that each of the claim terms on appeal was given a narrow definition, when in fact, TI Group should have been afforded a broad construction based on the ordinary and customary meaning of the term, as supported by the written description of the '714 patent. VDO argues that the district court correctly construed each of the terms at issue and that TI Group is not entitled to the broad definitions for which it argues. We address each of the disputed claim constructions, agreeing with the district court's determinations of some and disagreeing with others.

1. Fuel Reservoir

26
TI Group first argues that the district court's construction of the term "fuel reservoir" is too narrow and is not consistent with the written description of the patent. In particular, the district court construed the term to mean "the portion of the apparatus for pumping fuel in which fuel is collected and retained apart from fuel in the fuel tank." Markman Order at 1. TI Group argues that this definition unnecessarily imports the limitation of retaining fuel apart from the fuel in the fuel tank and is inconsistent with both the term's ordinary and customary meaning and the term's usage in the written description. Instead, TI Group urges that we adopt the broadest dictionary definition as the ordinary and customary meaning of the term "reservoir" — "any receptacle for fluids." 13 The Oxford English Dictionary 703-04 (2d ed. 1989). VDO argues, in response, that the correct construction of "reservoir" is one of the more narrow definitions provided in the dictionary: "a part of some apparatus in which fluid or liquid is contained," id., or "a part of an apparatus in which a liquid is held," Webster's Third New International Dictionary 1931 (1986) ("Webster's").

27
The dictionary entries for "reservoir" in both The Oxford English Dictionary and Webster's have several definitions that are facially relevant to the claimed invention. Each of the definitions implicates some sort of containment of liquid. Even the definition urged by TI Group, i.e., "any receptacle for fluids," requires that the fluid be retained apart or contained. See 13 The Oxford English Dictionary 320 (2d ed. 1989) (defining "receptacle" as "that which receives and holds a thing; ... a containing vessel, place, or space" (emphases added)). Thus, TI Group's argument that the district court's construction is unduly narrow is not persuasive. The notion of retaining or containing liquid in the receptacle is a common theme in each of the dictionary definitions. As the district court correctly observed, in the context of this invention, the fuel in the reservoir is contained, or held apart, from the fuel in the fuel tank.

28
The written description fully supports the ordinary meaning of the term "reservoir" identified by the district court, and there is no indication that TI Group disclaimed or disavowed meaning or acted as its own lexicographer in giving the term another meaning. We therefore affirm the district court's definition of the term "reservoir" as meaning "the portion of the apparatus for pumping fuel in which fuel is collected and retained apart from fuel in the fuel tank."

2. Pumping Means

29
TI Group next argues that the district court erroneously construed the term "pumping means" as a means-plus-function limitation under 35 U.S.C. § 112, paragraph 6, resulting in a more narrow definition than called for by the written description. TI Group argues that the district court should not have analyzed the limitation under § 112, paragraph 6, because the limitation specified any necessary structure required. See Cole v. Kimberly-Clark Corp., 102 F.3d 524, 530-31 (Fed.Cir.1996) (noting that, in order to invoke § 112, paragraph 6, "the alleged means-plus-function claim element must not recite a definite structure which performs the described function"). VDO argues that the phrase "pumping means" clearly gives rise to a presumption that § 112, paragraph 6 applies and that TI Group has not rebutted the presumption, because the structure recited does not perform the stated function.

30
The claim limitation at issue recites not only a pumping means, but its structure ("including a nozzle and a venturi tube in alignment with the nozzle"), location ("being located within the reservoir in the region of the opening"), and operation ("the passage of fuel out of the nozzle and through the venturi tube causing fuel to be entrained through the opening into the interior of the reservoir"). While the use of the word "means" gives rise to a presumption that § 112, paragraph 6 applies, the presumption is overcome by the recitation of the structure needed to perform the recited function. The written description informs and fully supports the structure recited in the claims: "Jet pump 30 includes nozzle 54 and venturi tube 58." '714 patent, col. 4, II. 61-66.

31
The district court's construction, urged before this court by VDO, concludes that the pumping means must also include check valve 22, connecting tube 164, and jet block 144. Markman Order at 2. This construction, however, includes elements that are not necessary for performing the recited function. There is no indication in the patent that the function found by the district court, namely "to pump fuel into the reservoir," id. at 1, requires anything other than the structure recited in the claim. Therefore, the proper construction of the "pumping means" limitation in claim 2 is "a pump including a nozzle and a venturi tube in alignment with the nozzle."

32
In light of our conclusion that § 112, paragraph 6, is not invoked, we need not, and do not, address TI Group's alternative arguments about structure corresponding to "pumping means," including its arguments regarding check valve 22 and connecting tube 164.

3. Within

33
TI Group next argues that the district court's definition of the term "within" is also unnecessarily narrow. The district court construed "within" to mean that "the pumping means components are located inside the reservoir." Markman Order at 2. TI Group argues that this construction is more narrow than the ordinary and customary meaning of the term "within," and is not consistent with the written description. VDO argues that the narrower construction is appropriate in light of the dictionary definitions and written description.

34
Again, both parties offer competing dictionary definitions in support of their argument. TI Group urges us to adopt the definition "in the limits of, not outside or beyond," 20 The Oxford English Dictionary 456-58 (2d ed. 1989), or "in the limits or compass of, not beyond," Webster's at 2627. VDO points instead to the definitions reciting "in the inner part or interior of," 20 The Oxford English Dictionary 456-58 (2d ed. 1989), or "on the inside or on the inner side," Webster's at 2627. Because all of the offered definitions are facially relevant, we rely on the written description to "point away from the improper meanings and toward the proper meanings." Renishaw, 158 F.3d at 1250.

35
TI Group argues that the written description does not require the pumping means to be located within the reservoir, and further argues that, if the patentee had wished to draw such a distinction, the language for doing so was available. TI Group argues that because the patentee used the allegedly broader term "within," rather than "inside" or "on the interior," the full breadth should be afforded to the scope of the limitation. VDO argues in response: (1) that the structures illustrated in the drawings of the written description show the pumping means located inside of the reservoir; (2) that TI Group's argument "ignores the primary (and most relevant) definition of `within'"; and (3) that statements made by TI Group during prosecution of a Japanese counterpart application confirm that the patentee intended "within" to mean "inside."

36
With respect to VDO's first argument, regarding the drawings being limited to the construction it urges, we have held that "the mere fact that the patent drawings depict a particular embodiment of the patent does not operate to limit the claims to that specific configuration." Anchor Wall Sys. v. Rockwood Retaining Walls, Inc., 340 F.3d 1298, 1306-07 (Fed. Cir.2003) (citing Hockerson-Halberstadt, Inc. v. Avia Group Int'l, Inc., 222 F.3d 951, 956 (Fed.Cir.2000)). The drawings, without more, are insufficient to cabin the scope of the ordinary and customary meaning of the term "within" in this case. As to VDO's second argument, regarding the "primary definition" of "within," we again reiterate that a patentee is entitled to a definition that encompasses all consistent meanings. Brookhill-Wilk, 334 F.3d at 1300. Finally, with respect to VDO's argument regarding statements made during foreign prosecution, we decline to comment, given our conclusion below, and note only that "the varying legal and procedural requirements for obtaining patent protection in foreign countries might render consideration of certain types of representations inappropriate" for consideration in a claim construction analysis of a United States counterpart. Caterpillar Tractor Co. v. Berco, S.p.A., 714 F.2d 1110, 1116 (Fed.Cir.1983).

37
Although VDO's arguments in favor of the district court's construction are not persuasive, we nonetheless conclude that the district court's construction of "within" was correct because the dictionary definitions TI Group urges us to adopt are not so different from those urged by VDO and adopted by the district court. TI Group's definition is "within the limits of, not outside or beyond." VDO's definition is "on the inside." Certainly, in ordinary and customary usage, what is not outside is on the inside. Thus, we affirm the district court's construction of the term "within" as meaning "inside."

4. Routing Means

38
TI Group argues that the district court made two errors in construing the claim limitation "means for routing a first portion of the output of high pressure fuel to the supply port and a second portion of the output of high pressure fuel to the pumping means," also referred to as the "routing means limitation." The district court construed this limitation by first determining that the function is "to route the fuel to jet pump 30 and through check valve 38 to the injectors." Markman Order at 2. The district court then determined that the structure that performed this function encompasses "main housing 140, check valve 38, supply nozzle 134, and the associated structure leading to jet pump 30." Id. TI Group asserts the district court erred by considering only one preferred embodiment when determining the scope of the term. TI Group contends that the district court's construction of "routing means" considered only the embodiment of Figures 2-9 and disregarded the embodiment shown in Figure 1, particularly the structure for routing fuel consisting of supply lines 98 and 106. See '714 patent, col. 5, II. 23-26; id. at Fig. 1. TI Group also contends that the district court included unnecessary structure in its construction of the routing means limitation. In particular, TI Group asserts that the inclusion of check valve 38 as part of the structure for the routing means was an error, because the check valve hinders the flow of fuel instead of routing it. VDO counters that Figure 1 is not an appropriate embodiment to consider when analyzing the structure that performs routing, because it is merely a schematic diagram. VDO also argues that the additional structures included by the district court in its determination of the structure of the "routing means" are required by the written description. Finally, VDO argues that TI Group's argument that check valve 38 does not "route" is incorrect.

39
Neither party disputes that "routing means" is a means-plus-function limitation, subject to interpretation under § 112, paragraph 6. Further, neither party disputes the district court's correct conclusion that the function of the "routing means" is "to route the fuel to jet pump 30 and through check valve 38 to the injectors." Markman Order at 2. The sole dispute is over the structure corresponding to this function. TI Group correctly notes that, generally, "[w]hen multiple embodiments in the specification correspond to the claimed function, proper application of § 112, [paragraph 6] reads the claim element to embrace each of those embodiments." Micro Chem., Inc. v. Great Plains Chem. Co., 194 F.3d 1250, 1258 (Fed.Cir.1999) (citing Serrano v. Telular Corp., 111 F.3d 1578, 1583 (Fed.Cir.1997)). Although VDO attempts to argue that Figure 1 is not a separate embodiment but is instead a schematic representation of the same embodiment illustrated in Figures 2-9, it fails to find support for that position in the written description. According to the patent, Figure 1 is a schematic diagram representing the disclosed invention, see '714 patent, col. 4, II. 29-31, and Figures 2-9 illustrate "a particularly preferred construction" for the invention, see id. at col. 6, II. 62-64. A fair reading of the written description is that Figure 1 is a generalized representation of the invention and that Figures 2-9 depict a specific, and preferred, embodiment. Nothing in the written description indicates otherwise. VDO's other arguments have been carefully considered and are not persuasive. Therefore, we conclude that the structure in the '714 patent corresponding to the "routing means" claim limitation includes, in one embodiment, the main housing 140, the connecting tube 164, the nozzle 134, and the hose 130, and in another representation, lines 98 and 106.

5. Opening for Connecting

40
TI Group next contends that the district court's definition of the term "an opening for connecting the interior of the reservoir to the interior of the fuel tank" is unduly narrow. The district court concluded that the phrase means "an aperture disposed adjacent to both the interior of the reservoir and the interior of the fuel tank, allowing fuel from the fuel tank to be entrained directly into the reservoir." Markman Order at 2. TI Group argues that this construction simply ignores the ordinary and customary meanings of the words and is inconsistent with the written description. VDO contends that the district court's construction is proper, based on the meanings of the terms and based on the notion that without the additional requirements, the claim limitation would be meaningless. We agree with TI Group.

41
The parties do not disagree about the general meanings of the terms at issue. An "opening" is "a gap, hole, or passage; an aperture." 10 The Oxford English Dictionary 845 (2d ed. 1989). To "connect" is "to join, fasten, or link together usually by means of something intervening." Webster's at 480. Thus, the ordinary and customary meaning of the limitation requires only that there be a hole, passage, or aperture for joining or linking the interior of the reservoir to the exterior of the reservoir. Nothing in the ordinary and customary meaning of the term, nor in the written description, requires that the aperture be "disposed adjacent to both the interior of the reservoir and the interior of the fuel tank." VDO's other arguments have no merit. The correct construction of "an opening for connecting the interior of the reservoir to the interior of the fuel tank" requires only that the interior of the reservoir and the interior of the fuel tank be joined or linked by a hole, passage, or aperture.

6. Opening at the Bottom

42
Finally, TI Group argues that dependent claim 8, reciting that the opening for connecting, defined above, is "at the bottom of the reservoir" was construed too narrowly by the district court. The district court determined that the opening must be "in the bottom surface of the reservoir." Markman Order at 2. TI Group argues that this construction is more narrow than the ordinary and customary meaning of the term "bottom" and is inconsistent with the written description. VDO counters that the district court's construction is consistent with every drawing in the patent. As we have already discussed, the fact that the drawings are limited to a particular embodiment does not similarly limit the scope of the claims. Anchor, 340 F.3d at 1306-07. Rather, TI Group is entitled to the full breadth of claim scope supported by the words of the claims and the written description. VDO's argument again focuses on a single, narrow dictionary definition, when many equally apt, and broader, definitions are also provided. The written description does not restrict the ordinary and customary meaning of "bottom" in any respect. Therefore, we conclude that the "bottom" of the reservoir means "the lower or lowest part," Webster's at 259, of the reservoir, and is not restricted only to the bottom surface thereof.

C. JMOL Grant on Non-infringement

43
Having addressed TI Group's claim construction arguments, we now turn to its contention that the district court's JMOL of non-infringement was improperly granted. "[W]hen we determine on appeal, as a matter of law, that a trial judge has misinterpreted a patent claim, we independently construe the claim to determine its correct meaning, and then determine if the facts presented at trial can support the appealed judgment." Exxon Chem. Patents, Inc. v. Lubrizol Corp., 64 F.3d 1553, 1560 (Fed.Cir.1995). Infringement requires the patentee to show that the accused device contains or performs each limitation of the asserted claims, Mas-Hamilton Group v. LaGard, Inc., 156 F.3d 1206, 1211 (Fed.Cir.1998), or an equivalent of each limitation not satisfied literally, Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S. 17, 117 S.Ct. 1040, 137 L.Ed.2d 146 (1997). Although the jury found infringement under the district court's claim constructions, the district court determined that no reasonable juror could have concluded that VDO's device infringed. We have affirmed the district court's claim constructions with respect to the terms "reservoir" and "within." Rather than citing specific evidence of record to support the jury's verdict of infringement, TI Group largely rests its arguments in favor of reversing the district court's grant of JMOL on the district court's claim construction errors.

44
Claim 2 refers to "an opening for connecting the interior of the reservoir to the interior of the fuel tank." The pumping means is then characterized as "causing fuel to be entrained through the opening into the interior of the reservoir," and is described as being "located within the reservoir in the region of the opening." Claim 8 then describes fuel that "enters the reservoir through the opening." From the use of these phrases in the patent, it is fair to infer that the opening separates the reservoir from the fuel tank and that in order to be "within the reservoir," the pumping means must be inboard of the opening — i.e., it must be on the reservoir side of the opening that divides the fuel tank from the reservoir. As the district court pointed out, the pumping means in VDO's accused device is outboard of the opening — i.e., it is on the fuel tank side of the opening that divides the fuel tank from the reservoir. It is therefore not "located within the reservoir" as that term is used in the patent. Because a finding of infringement requires that all limitations be found in the accused device, we affirm the district court's determination that no reasonable juror could have concluded that VDO's device infringed. Thus, we affirm the judgment of non-infringement in favor of VDO.

D. JMOL Denial on Invalidity

45
On cross-appeal, VDO argues that the district court erred in denying its motion for JMOL of invalidity based on obviousness and in upholding the jury's verdict that the '714 patent is not invalid. JMOL Invalidity Opinion at 3-4. In particular, VDO argues that if TI Group's claim constructions are adopted, the '714 patent is anticipated by at least U.S. Patent No. 2,953,156 and German Patent Application No. 2 849 461 A1, neither of which was before the U.S. Patent and Trademark Office during the prosecution of the '714 patent. TI Group argues in response that substantial evidence in the record supports the jury's verdict finding the '714 patent not invalid, that VDO has not rebutted this evidence, and that VDO failed to present a case of obviousness before the district court.

46
Our validity analysis is a two-step procedure: "The first step involves the proper interpretation of the claims. The second step involves determining whether the limitations of the claims as properly interpreted are met by the prior art." Beachcombers, Int'l, Inc. v. WildeWood Creative Prods., Inc., 31 F.3d 1154, 1160 (Fed.Cir.1994). We have determined the proper interpretation of the claims, see Section B, supra, thus leaving for review whether a reasonable juror, in performing the second step of the analysis, could have found less than clear and convincing evidence of invalidity under the new claim constructions. Because the jury could only have compared the prior art to the erroneously narrowly construed claims, we vacate the district court's JMOL Invalidity Opinion and remand the invalidity question to the district court for further proceedings consistent with this opinion.

CONCLUSION

47
Because we affirm some of the district court's claim constructions, and because as to those limitations TI Group points to no evidence supporting the jury's finding of infringement, we affirm the district court's grant of VDO's JMOL motion with respect to infringement. However, because we have broadened a number of the district court's claim constructions, thus affecting the invalidity analysis, we vacate the district court's denial of VDO's JMOL motion with respect to invalidity and remand that issue for further proceedings consistent with this opinion.

AFFIRMED-IN-PART, VACATED-IN-PART, AND REMANDED

COSTS

48
No costs.


Transcriptional regulatory regions for expression of the rat fatty acid synthase.
We previously mapped the sequences responsive to insulin/glucose stimulation and polyunsaturated fatty acid (PUFA) suppression in proximal promoter region from -57 to -35 of fatty acid synthase (FAS) gene of rat liver [Fukuda et al. (1996) Biochem. Mol. Biol. Int. 38, 987-9961. When two copies of the sequences spanning -57 to -35 were linked to a reporter gene containing heterologous promoter and were used for transfection, the reporter activity significantly increased in response to insulin/glucose treatment in hepetocytes. This increase was inhibited by addition of PUFA. Gel mobility shift assays using the sequence from -57 to -35 as a probe revealed nuclear factor(s) from rat liver that specifically complexed with the sequences. In addition, by antibody supershift assays, we have detected the binding of the transcriptional factor Sp1 at the GC-rich region located within -57 to -35 of the FAS promoter. Cotransfection studies in rat hepatocytes, with the Sp1 expression vector and FAScat constructs, showed the inactivation of the promoter. These results were similar to those for the region from -68 to -52 of FAS gene (an insulin response element). The region from -68 to -52 of FAS gene competed for the formation of DNA-protein complexes to the region from -57 to -35 in the gel shift assay. Mutational analysis showed that the overlapping region of these two sequences was essential for the binding of Sp1. It has been demonstrated that both the regions from -57 to -35 and from -68 to -52 of the FAS gene are responsible for regulation due to insulin/glucose and PUFA, and Sp1 may be involved in the regulation.


Amazona auropalliata (Yellow-naped Parrot; Yellow-naped Amazon)

Wikipedia Abstract

The yellow-naped amazon or yellow-naped parrot (Amazona auropalliata) is an amazon parrot sometimes considered to be a subspecies of yellow-crowned amazon, Amazona ochrocephala (Gmelin, 1788). Deforestation is reducing the number of these parrots in the wild together with illegal removal of young for the pet trade. This parrot readily mimics sounds, and in captivity this includes human speech, which is probably the reason it is popular in aviculture. Like all parrots, however, mimic abilities vary greatly between individuals.


Amplifiers are often used in various electronic applications. An amplifier is an electrical device that alters the amplitude and/or phase characteristics of a signal. Additionally, an amplifier may have filtering characteristics to pass signals in certain frequency ranges and attenuate signals in other frequency ranges. The behavior of an amplifier may be described mathematically in the frequency-domain in terms of its transfer function. The transfer function describes, among other things, the ratio between the input signal amplitude and the output signal amplitude applied of the amplifier. The amplitude response curve describes the effect of the amplifier on the amplitude of the input signal at various frequencies.


Detection of Shigella spp. nucleic acids in the synovial tissue of Tunisian rheumatoid arthritis patients and other forms of arthritis by quantitative real-time polymerase chain reaction.
Enterobacterial components in the joints of patients are believed to contribute to a perpetuating inflammation leading to a reactive arthritis (ReA), a condition in which microbial agents cannot be recovered from the joint. At present, it is unclear whether nucleic acids from Shigella spp. are playing a pathogenic role in causing not only ReA but also other forms of arthritis. Quantitative real-time polymerase chain reaction assay (qPCR) is the method of choice for the identification of bacteria within the synovium. The aim of our study was to detect the presence of Shigella spp. nucleic acids in the synovial tissue (ST) of Tunisian arthritis patients. We investigated 57 ST samples from rheumatoid arthritis (RA) n = 38, undifferentiated oligoarthritis (UOA) n = 12, and spondyloarthritis (SpA) n = 7 patients; 5 ST samples from healthy individuals were used as controls. Shigella spp. DNA and mRNA transcripts encoding the virulence gene A (VirA) were examined using an optimized qPCR with newly designed primers and probes. Using qPCR, Shigella spp. DNA was found in 37/57 (65%) ST samples (24/38, i.e., 63.2% of RA, 8/12, i.e., 67% of UOA, and 5/7, i.e., 71.4% of SpA patients). Paired DNA and mRNA were extracted from 39 ST samples, whose VirA cDNA was found in 29/39 (74.4%) patients. qPCR did not yield any nucleic acids in the five healthy control ST samples. The qPCR assay was sensitive and showed a good intra- and inter-run reproducibility. These preliminary findings generated by an optimized, highly sensitive PCR assay underline a potential role of past gastrointestinal infections. In Tunisian patients, a bacterial etiology involving Shigella spp. in the manifestation of arthritic disorders including RA might be more common than expected.


Q:

Работа с числами

Здравствуйте, мне нужен класс для работы с числами. Просто при делении у меня будет получаться не всегда целые числа, нужно чтобы был метод округления, и метод для операциями над нецелыми числами, допустим 231.3738277237 + 4822.3672676272819190, просто обычно пхп округляет до десятитысячных. Прошу не написать, а есть ли готовые решения ибо изобретать велосипед не очень охото.

A:

Вам подойдет BC
<?php
$num1=bcsqrt('2', 1000);
$num2=bcsqrt('3', 1000);
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пример с BC


INTRODUCTION {#s1}
============

Cancer is a worldwide health problem and the second leading cause of morbidity and mortality in human diseases \[[@R1]\]. Cancer metastasis to other parts of the body is the major cause of death \[[@R2]\]. Chen et al. reported that approximately 4,292,000 new cancer cases and 2,814,000 cancer deaths would occur in China in 2015 \[[@R3]\]. It is obvious that cancer is a major threat to human health. However, the exact mechanism of carcinogenesis is still poorly understood. An increasing number of studies have reported that cancer is a complex disease, resulting from environmental and genetic factors and their interactions \[[@R4], [@R5]\]. In addition, genetic factors play important roles in the pathogenesis of cancer, and many genes have been identified as cancer-susceptible genes \[[@R6]\].

The tumor suppressor p53 plays an important role in many physiological processes, such as maintenance of genomic stability and control of cell growth and apoptosis \[[@R7], [@R8]\]. Inactivation of the p53 tumor suppressor is critical for tumorigenesis. The activity of p53 is strictly regulated, predominantly by MDM2 and its homolog MDM4 \[[@R9]\]. MDM4 shares an N-terminal p53-binding domain with MDM2 and can inhibit p53 activity during various malignancies \[[@R10]--[@R12]\]. Overexpressed MDM4 in human tumors may contribute to reduced p53 activity and tumorigenesis \[[@R13]\]. Many studies \[[@R14], [@R15]\] have demonstrated that mouse embryos lacking MDM4 die during embryogenesis. Migliorini et al. found MDM4 regulates p53-induced growth arrest and neuronal cell death during early embryonic mouse development \[[@R14]\]. Furthermore, transgenic mice overexpressing MDM4 showed spontaneous carcinogenesis and accelerated tumorigenesis \[[@R16]\]. Additionally, MDM4 is reported to be highly expressed in a significant percentage of human cancers, including 65% of retinoblastomas, 80% of adult pre-B lymphoblastic leukemia, 39% of head and neck squamous carcinomas, 19% of colon cancers, 19% of breast cancers, and 18% of lung cancers \[[@R17]--[@R20]\]. All above studies indicated that *MDM4* gene may be significantly associated with cancer susceptibility.

Recently, many studies \[[@R13], [@R21]--[@R30]\] have described the associations between *MDM4* gene polymorphisms and risks of various cancers, including colon cancer, lung cancer, breast cancer, gastric cancer, squamous cell carcinoma of the head and neck, non-Hodgkin lymphoma (NHL), and esophageal squamous cell carcinoma (ESCC). However, the results of these studies were conflicting and inconclusive. The clinical heterogeneity, different ethnic populations, and small sample sizes of previous studies may have contributed to these disparities. To overcome these limitations, we performed a meta-analysis of the contradictory results from these relevant studies to clarify the possible associations between *MDM4* gene polymorphisms and cancer risk.

RESULTS {#s2}
=======

Characteristics of the included publications {#s2_1}
--------------------------------------------

A total of 149 publications were identified after our initial search. After removing duplicates and screening the titles and abstracts, 128 publications were removed. Finally, 21 publications were selected for further full text review. The following publications were excluded: four \[[@R31]--[@R34]\] in which the experimental designs were not case control studies; two publications \[[@R35], [@R36]\] that did not describe *MDM4* polymorphisms (rs4245739, rs1563828, rs11801299, rs10900598, and rs1380576) and cancer risk, three \[[@R37]--[@R39]\] that not provide detailed genotyping data, and two \[[@R28], [@R40]\] that might have described partially overlapping populations, so we included the study \[[@R28]\] with the larger sample size. We finally identified 11 eligible publications \[[@R13], [@R21]--[@R30]\] including 56 studies (18,910 cases and 51,609 controls) in this meta-analysis. Selection for eligible publications included in this meta-analysis was presented in Figure [1](#F1){ref-type="fig"}. The characteristics of these included studies are summarized in Table [1](#T1){ref-type="table"}. These publications were published from 2011 to 2015. Five single nucleotide polymorphisms (SNPs) (rs4245739, rs1563828, rs11801299, rs10900598 and rs1380576) of *MDM4* gene were investigated. Genotype distributions of the controls about rs1380576 in one study \[[@R26]\] did not conform to HWE (*P* \< 0.001). The NOS scores of all included studies ranged from 5 to 7 stars, suggesting that they were studies of high methodological quality. Four papers \[[@R13], [@R22], [@R27], [@R28]\] were carried out in Caucasian populations, and seven \[[@R21], [@R23]--[@R26], [@R29], [@R30]\] in Asian populations. The research \[[@R27]\] conducted by Garcia-Closaset et al. consisted of three genome-wide association studies (GWASs) involving 40 studies among Caucasian populations.

###### Characteristics of included studies

  Author and year     Country   Ethnicity   Case   Control   Cancer type   HWE     NOS
  ------------------- --------- ----------- ------ --------- ------------- ------- ------- ------ ----------------- --------- ---
  **rs4245739**                             AA     AC        CC            AA      AC      CC
  Gansmo2015          Norway    Caucasian   823    600       108           2042    1439    266    Colon cancer      0.566     6
  Gansmo2015          Norway    Caucasian   715    515       101           2042    1439    266    Lung cancer       0.566     6
  Gansmo2015          Norway    Caucasian   1412   927       161           2042    1439    266    Prostate cancer   0.566     6
  Gansmo2015          Norway    Caucasian   966    643       108           2042    1439    266    Breast cancer     0.566     6
  Gao2015             China     Asian       297    22        1             548     90      2      SCLC              0.399     5
  Gao2015             China     Asian       183    17        0             321     77      2      SCLC              0.248     7
  Fan2014             China     Asian       187    13        0             346     53      1      NHL               0.487     6
  Liu2013             China     Asian       733    67        0             686     111     3      Breast cancer     0.505     6
  Liu2013             China     Asian       278    22        0             501     96      3      Breast cancer     0.484     6
  Zhou2013            China     Asian       501    37        2             478     70      2      ESCC              0.740     6
  Zhou2013            China     Asian       529    56        3             510     88      2      ESCC              0.379     6
  Garcia-Closas2013   Mixed     Caucasian   3318   2637      557           22825   15798   2828   Breast cancer     0.183     5
  **rs1563828**                             CC     CT        TT            CC      CT      TT
  Zhang2012           China     Asian       98     91        21            90      88      22     NPC               0.944     7
  Song2012            China     Asian       53     57        14            44      43      14     Breast cancer     0.506     5
  **rs11801299**                            GG     AG        AA            GG      AG      AA
  Wang2012            America   Caucasian   195    Na        Na            201     Na      Na     Oral cancer       Na        6
  Yu2011              America   Caucasian   684    351       40            665     376     38     SCCHN             0.086     6
  **rs10900598**                            GG     GT        TT            GG      GT      TT
  Wang2012            America   Caucasian   107    Na        Na            94      Na      Na     Oral cancer       Na        6
  Yu2011              America   Caucasian   307    545       223           296     552     231    SCCHN             0.377     6
  **rs1380576**                             CC     CG        GG            CC      CG      GG
  Wu2015              China     Asian       188    281       173           212     290     218    Gastric cancer    \<0.001   5
  Wang2012            America   Caucasian   141    Na        Na            149     Na      Na     Oral cancer       Na        6
  Yu2011              America   Caucasian   487    477       111           518     455     106    SCCHN             0.677     6

HWE, Hardy--Weinberg equilibrium; NOS, Newcastle--Ottawa scale; NPC, Nasopharyngeal carcinoma; SCCHN, squamous cell carcinoma of the head and neck; SCLC, Small Cell Lung Cancer; NHL, Non-Hodgkin lymphoma; ESCC, esophageal squamous cell carcinoma; Na, not available.

![Selection for eligible publications included in this meta-analysis](oncotarget-07-55611-g001){#F1}

Meta-analysis of rs4245739 {#s2_2}
--------------------------

Six publications \[[@R13], [@R21], [@R24], [@R25], [@R27], [@R29]\] including 51 studies with 16,539 cases and 49,188 controls examined rs4245739 polymorphism. As shown in Table [2](#T2){ref-type="table"}, rs4245739 polymorphism was significantly associated with a decreased risk of overall cancer risk in three models (C vs. A: OR, 0.78; 95% CI, 0.68--0.89, *P* \< 0.001; CC+AC vs. AA: OR, 0.75; 95% CI, 0.64--0.87, *P* \< 0.001; AC vs. AA: OR, 0.75; 95% CI, 0.64--0.87, *P* \< 0.001, Figure [2](#F2){ref-type="fig"}). Stratification analyses were conducted according to ethnicity, cancer type, sex and smoking status. Our data indicated that rs4245739 polymorphism was also significantly associated with a decreased risk of cancer among Asian populations in three models (C vs. A: OR, 0.53; 95% CI, 0.45--0.62, *P* \< 0.001; CC+AC vs. AA: OR, 0.51; 95% CI, 0.43--0.60, *P* \< 0.001; AC vs. AA: OR, 0.51; 95% CI, 0.43--0.60, *P* \< 0.001, Figure [3](#F3){ref-type="fig"}). Stratification analyses of smoking status indicated rs4245739 decreased the risk of nonsmokers (CC+AC vs. AA: OR, 0.44; 95% CI, 0.31--0.63, *P* \< 0.001, Figure [4](#F4){ref-type="fig"}). However, stratification analyses of cancer type suggested rs4245739 was not related with the risks of lung cancer, breast cancer, gastrointestinal cancer and other cancers. Stratification analyses of sex also indicated this SNP was not associated with cancer risk. All included studies conform to HWE, indicating their controls subjects were representative of the general population.

###### Meta-analysis of associations between the rs4245739 polymorphism and cancer risk

  Comparison                Overall and Stratification analyses   Studies                OR (95% CI)            *P*-value   Random/Fixed effect model   *P* for heterogeneity   I^2^ (%)
  ------------------------- ------------------------------------- ---------------------- ---------------------- ----------- --------------------------- ----------------------- ----------
  C vs. A                   Overall                               51                     **0.78(0.68,0.89)**    \<0.001     Random                      \<0.001                 90.6
  Caucasian                 44                                    1.02(0.92,1.12)        0.301                  Random      \<0.001                     88.5
  Asian                     7                                     **0.53 (0.45,0.62)**   \<0.001                Random      0.584                       0.0
  Gastrointestinal cancer   3                                     0.74(0.49,1.12)        0.157                  Random      0.001                       85.6
  Lung cancer               3                                     0.61(0.31,1.19)        0.148                  Random      \<0.001                     90.4
  Breast cancer             43                                    0.78 (0.59,1.02)       0.070                  Random      \<0.001                     94.4
  Other cancers             2                                     0.70(0.35,1.39)        0.307                  Random      0.024                       80.5
  CC vs. AA+AC              Overall                               47                     1.04(0.88,1.21)        0.666       Random                      0.016                   59.5
  Caucasian                 44                                    1.03 (0.86,1.23)       0.748                  Random      0.584                       0.0
  Asian                     3                                     1.20(0.38,3.84)        0.754                  Random      0.032                       78.1
  Gastrointestinal cancer   3                                     1.00 (0.80,1.26)       0.996                  Random      0.895                       0.0
  Lung cancer               2                                     1.07(0.85,1.36)        0.556                  Random      0.953                       0.0
  Breast cancer             41                                    1.08(0.75,1.55)        0.696                  Random      0.003                       88.4
  Other cancers             1                                     0.90 (0.74,1.10)       0.312                  Na          Na                          Na
  CC+AC vs. AA              Overall                               51                     **0.75(0.64,0.87)**    \<0.001     Random                      \<0.001                 90.1
  Caucasian                 44                                    1.02(0.91,1.14)        0.740                  Random      \<0.001                     85.5
  Asian                     7                                     **0.51(0.43,0.60)**    \<0.001                Random      0.662                       0.0
  Gastrointestinal cancer   3                                     0.72 (0.45,1.14)       0.157                  Random      \<0.001                     87.0
  Lung cancer               3                                     0.59(0.29,1.20)        0.142                  Random      \<0.001                     90.5
  Breast cancer             43                                    0.76(0.56,1.04)        0.089                  Random      \<0.001                     94.0
  Other cancers             2                                     0.69 (0.34,1.39)       0.294                  Random      0.025                       80.0
  Male                      5                                     0.72 (0.49,1.07)       0.107                  Random      0.008                       70.8
  Female                    5                                     0.62 (0.32,1.19)       0.150                  Random      \<0.001                     83.4
  Smoker                    4                                     0.83 (0.61,1.13)       0.237                  Fixed       0.413                       0.0
  Nonsmoker                 4                                     **0.44 (0.31,0.63)**   \<0.001                Fixed       0.480                       0.0
  CC vs. AA                 Overall                               47                     1.04(0.85,1.26)        0.360       Random                      0.001                   71.8
  Caucasian                 44                                    1.03(0.83,1.28)        0.769                  Random      \<0.001                     83.8
  Asian                     3                                     1.13 (0.35,3.59)       0.840                  Random      0.938                       0.0
  Gastrointestinal cancer   3                                     1.01(0.80,1.28)        0.915                  Random      \<0.001                     90.6
  Lung cancer               2                                     1.08(0.85,1.38)        0.522                  Random      \<0.001                     88.5
  Breast cancer             41                                    1.09 (0.70,1.71)       0.698                  Random      0.584                       0.0
  Other cancers             1                                     0.88(0.71,1.08)        0.208                  Random      0.032                       78.1
  AC vs. AA                 Overall                               51                     **0.75 (0.64,0.87)**   \<0.001     Random                      \<0.001                 88.6
  Caucasian                 44                                    1.02 (0.93,1.12)       0.694                  Random      0.001                       77.3
  Asian                     7                                     **0.51(0.43,0.60)**    \<0.001                Random      0.747                       0.0
  Gastrointestinal cancer   3                                     0.70(0.43,1.14)        0.157                  Random      \<0.001                     87.7
  Lung cancer               3                                     0.58(0.29,1.19)        0.136                  Random      \<0.001                     90.0
  Breast cancer             43                                    0.78(0.58,1.04)        0.091                  Random      \<0.001                     92.6
  Other cancers             2                                     0.70(0.35,1.39)        0.307                  Random      0.028                       79.3

\*Bold values are statistically significant (*P* \< 0.05). OR, odds ratio; 95% CI, 95% confidence interval; Na, not available.

![Forest plot shows odds ratio for the associations between rs4245739 and cancer risk (a: C vs. A; b: CC+AC vs. AA; c: AC vs. AA)](oncotarget-07-55611-g002){#F2}

![Stratification analyses of ethnicity between rs4245739 and cancer risk (a: C vs. A; b: CC+AC vs. AA; c: AC vs. AA)](oncotarget-07-55611-g003){#F3}

![Stratification analyses of smoke status between rs4245739 and cancer risk (CC+AC vs. AA)](oncotarget-07-55611-g004){#F4}

Meta-analysis of rs1563828, rs11801299, rs10900598 and rs1380576 {#s2_3}
----------------------------------------------------------------

Two publications \[[@R23], [@R30]\] with 334 cases and 301 controls examined rs1563828 polymorphism; two publications \[[@R22], [@R28]\] with 1,395 cases and 1,400 controls studied rs11801299 polymorphism; two publications \[[@R22], [@R28]\] with 1,395 cases and 1,400 controls studied rs10900598 polymorphism; three publications \[[@R22], [@R26], [@R28]\] with 2,037 cases and 2,120 controls studied rs1380576 polymorphism. With regard to rs11801299, rs10900598 and rs1380576, we could only calculate the data in dominant model as they did not provide enough data. As shown in Table [3](#T3){ref-type="table"}, we found these four SNPs were not associated with cancer risk. For these four SNPs, we did not perform stratification analyses due to limited data. Genotype distributions of the controls about rs1380576 in one study \[[@R26]\] did not conform to HWE (*P* \< 0.001). By exclusion of this study, the pooled estimates of the remaining studies showed that rs1380576 polymorphism was also not associated with cancer risk (CG+GG vs. CC: OR, 1.11; 95% CI, 0.96--1.29, *P* = 0.164), suggesting that the results of this SNP was stable.

###### Meta-analysis of associations between rs1563828, rs11801299, rs10900598 and rs1380576 polymorphisms and cancer risk

  Comparison       OR(95%CI)         *P*-value   Random/Fixed effect model   *P* for heterogeneity   I^2^ (%)
  ---------------- ----------------- ----------- --------------------------- ----------------------- ----------
  **rs1563828**
  T vs. C          0.95(0.75,1.20)   0.658       Fixed                       0.928                   0.0%
  TT+CT vs. CC     0.96(0.70,1.32)   0.814       Fixed                       0.744                   0.0%
  TT vs. CC+CT     0.86(0.52,1.40)   0.536       Fixed                       0.804                   0.0%
  CT vs. CC        1.00(0.72,1.39)   0.997       Fixed                       0.678                   0.0%
  TT vs. CC        0.86(0.51,1.45)   0.566       Fixed                       0.921                   0.0%
  **rs11801299**
  AG+AA vs. GG     0.95(0.82,1.11)   0.529       Fixed                       0.399                   0.0%
  **rs10900598**
  GT+TT vs. GG     0.91(0.78,1.08)   0.288       Fixed                       0.483                   0.0%
  **rs1380576**
  CG+GG vs. CC     1.08(0.95,1.22)   0.227       Fixed                       0.785                   0.0%

\*Bold values are statistically significant (*P* \< 0.05).

Sensitivity analysis and publication bias {#s2_4}
-----------------------------------------

We assessed sensitivity by omitting each study once at a time in every genetic model for rs4245739. The pooled ORs for the effects of rs4245739 on the risk for cancer risk indicated that our data were stable and trustworthy about this SNP (Figure [5](#F5){ref-type="fig"}). We did not perform sensitivity analyses about rs1563828, rs11801299, rs10900598 and rs1380576 due to limited data. Both Egger\'s and Begg\'s tests were used to evaluated the publication bias of this meta-analysis. Our data revealed that there was obvious publication bias in three models for rs4245739 (C vs. A, *P*~begg~ = 0.075 and *P*~egger~ \< 0.001; CC+AC vs. AA, *P*~begg~ = 0.055 and *P*~egger~\< 0.001; AC vs. AA, *P*~begg~ = 0.040 and *P*~egger~ \< 0.001). Due to limited studies, we did not conduct Egger\'s and Begg\'s tests about rs1563828, rs11801299, rs10900598 and rs1380576.

![Sensitivity analyses between rs4245739 and cancer risk in five models (a: allele model; b: dominant model; c: recessive model; d: homozygous model; e: heterozygous model)](oncotarget-07-55611-g005){#F5}

DISCUSSION {#s3}
==========

To the best of our knowledge, this is the first meta-analysis emphasizing the associations between *MDM4* gene polymorphisms and cancer risk. Our data indicated that the rs4245739 polymorphism was significantly associated with a decreased risk of cancer overall. In addition, stratification analyses of ethnicity indicated that rs4245739 decreased the risk of cancer in the Asian population, and stratification analyses of smoking status indicated that rs4245739 decreased the risk of cancer among nonsmokers. However, stratification analyses of cancer type suggested rs4245739 was not related to the risks of lung cancer, breast cancer, gastrointestinal cancer, and other cancers. Stratification analyses of sex also indicated this SNP was not associated with cancer risk in male or female populations. With regard to the remaining four SNPs, no associations were found between rs1563828, rs11801299, rs10900598, or rs1380576and overall cancer risk.

One of most important tumor suppressors in human cells is p53. MDM2, a key regulator of the p53 tumor suppressor signaling pathway, can induce degradation of p53 through the ubiquitin-proteasome pathway \[[@R41]\]. MDM4 is structurally homologous to MDM2, and MDM4 can cooperate with MDM2 to inhibit p53 activities \[[@R10]\]. Furthermore, MDM4 can interact with MDM2 via the Really Interesting New Gene finger domain that inhibits the degradation of MDM2 protein \[[@R12], [@R42]\]. In light of these findings, we hypothesize that MDM4 may play pivotal roles in the pathogenesis of cancer, and that *MDM4* is a candidate susceptibility gene for cancer. Currently, many studies \[[@R13], [@R21]--[@R30]\] have investigated the associations between *MDM4* gene polymorphisms and cancer risk. However, these studies showed inconsistent results, because they had inadequate statistical power due to relatively small samples.

To provide a comprehensive and reliable conclusion, we conducted a meta-analysis to assess the associations between *MDM4* gene polymorphisms and cancer risk. Our data indicated that the rs4245739 polymorphism was significantly associated with a decreased risk of overall cancer. Six publications \[[@R13], [@R21], [@R24], [@R25], [@R27], [@R29]\] including 51 studies involving 16,539 cases and 49, 188 controls investigated this SNP. Among these included publications, four \[[@R21], [@R24], [@R25], [@R29]\] from China assessed this variant in ESCC, small cell lung cancer (SCLC), and NHL and breast cancer and concluded that rs4245739 was associated with a reduced risk of cancer. Studies from Norway \[[@R13]\] suggested that rs4245739 is associated with a reduced risk of breast cancer but is not associated with lung cancer, colon cancer, or prostate cancer. Studies by Garcia-Closaset et al. \[[@R27]\], consisting of three GWAS studies among Caucasian populations, indicated that rs4245739 increased the risk of breast cancer. As mentioned previously, we found that the associations between rs4245739 and breast cancer risk were inconsistent. Two studies \[[@R13], [@R24]\] reported that rs4245739 decreased the risk of breast cancer, while the study by Garcia-Closaset et al. \[[@R27]\] reported that it increased the risk of breast cancer. It is noteworthy that Garcia-Closaset et al. reported that rs4245739 increased the risk of estrogen receptor (ER)-negative but not ER-positive breast cancer, which was consistent with the conclusion of two other GWAS studies \[[@R37], [@R38]\]. There are important differences in genetic susceptibility with these two types (ER-negative and ER-positive) of breast cancer. Garcia-Closaset et al. reported that rs4245739 is located in an ER-negative-specific breast cancer risk locus. It is therefore reasonable to hypothesize that this SNP may specifically affect susceptibility to ER-negative breast cancer. Stratification analyses of cancer type in this meta-analysis concluded that rs4245739 is not associated with overall breast cancer. The reasons why the results of Garcia-Closaset et al. differed from the results of those two studies \[[@R13], [@R24]\] and this meta-analysis are unclear, but it may be partially explained by differences in the genetic susceptibility of different types of breast cancer. Due to limited data, we could not conduct stratification analyses of ER status. Larger studies are therefore needed to identify the possible association between rs4245739 and ER-negative and ER-positive breast cancer.

Stratification analyses of ethnicity suggested rs4245739 decreased the risk of cancer in Asian population. The genetic background of cancer may vary among different ethnicities. We did not find that rs4245739 was associated with the risk of cancer in Caucasians, although three GWAS studies \[[@R27], [@R37], [@R38]\] reported that this SNP increased the risk of ER-negative or triple negative breast cancer (defined by the absence of ER, progesterone receptor and human epidermal growth factor receptor-2) in the Caucasian population. In this meta-analysis, a large difference was found in the distribution of rs4245739 between Caucasians and Asians, with minor allele frequencies of 26.2% and 6.2%, respectively, and this was possibly affected by the power of the studies conducted in Asian populations and the final relationships between the rs4245739 polymorphism and cancer risks among different racial groups \[[@R13]\]. Furthermore, the etiology of ER-negative breast cancer is different from that of ER-positive breast cancer, including differences in genetic predisposition \[[@R43], [@R44]\]. Therefore, it is reasonable to assume that the genetic susceptibility of ER-negative or triple negative breast cancer is different than those of other breast cancer subtypes or overall breast cancer, which may explain why the results of these GWAS studies in Caucasians are different from the results of this meta-analysis in Caucasians. The reasons why rs4245739 decreased the risk of cancer among Asian population may be that the functional rs4245739 SNP A\>C locating in the MDM43′-untranslated (3′-UTR) region creates a miR-191-5p or miR-887-3p targeting sites \[[@R23]\]. MiR-191-5p and miR-887-3p could bind to MDM43′-UTR with the rs4245739 C allele selectively \[[@R23]\]. These changes could result in decreased expression of oncogene MDM4, which could reduce the inhibition of p53 activities. Stratification analyses of smoking status indicated that rs4245739 decreased the risk of cancer among nonsmokers. Two studies \[[@R21], [@R29]\] investigating SCLC and ESCC were included in those stratification analyses. The studies also revealed significant multiple interactions between rs4245739 and smoking. Notably, SCLC and ESCC share similar environmental etiologies such as heavy smoking.

Regarding the remaining four SNPs, we failed to identify any associations between rs1563828, rs11801299, rs10900598, and rs1380576 and cancer risk. We cannot definitively conclude that these four SNPs are not associated with cancer risk, because this meta-analysis included only a few studies with limited sample sizes, and any associations between gene polymorphisms and disease are greatly affected by the number of participants. Given the limited sample size, the relationships between these four SNPs and cancer risk should be interpreted with caution. Genotype distributions of the controls in one study \[[@R26]\] on rs1380576 did not conform to HWE. After excluding this study, the conclusions of the remaining studies did not significantly change, suggesting that the result of rs1380576 was trustworthy.

Several potential limitations of this meta-analysis should be considered. First, our data indicated that publication bias existed with respect to studies regarding rs4245739, and potential language bias may have resulted from the inclusion of published studies in English or Chinese only. Second, the number of studies on rs1563828, rs11801299, rs10900598, and rs1380576 included in the meta-analysis was small, and the sample size was limited, which prevented further stratification analyses of other potential factors. Third, our results were based on unadjusted estimates for confounding factors, which might have affected the final results. Fourth, we could not assess potential gene-gene and gene-environment interactions because of the lack of original data. Fifth, this meta-analysis only included Asian and Caucasian populations; future studies on other ethnic groups are necessary because of ethnic differences in gene polymorphisms. Sixth, heterogeneity was considerable in this meta-analysis because the included studies involved different ethnicities and environments. Although sensitivity analyses indicated that our data were stable and trustworthy, we should interpret these data with caution.

In conclusion, this meta-analysis indicates that rs4245739 polymorphism of *MDM4* gene plays important roles in cancer pathogenesis, especially among Asian populations. Stratification analyses also indicate that rs4245739 decreases the risk of cancer among nonsmokers. However, the other four SNPs are not associated with cancer risk. Larger well-designed studies are necessary to validate these findings.

MATERIALS AND METHODS {#s4}
=====================

Literature search {#s4_1}
-----------------

We systematically searched the PubMed, Embase, and China Knowledge Resource Integrated Database to identify studies through January 1, 2016. The following search terms were used: "cancer," "carcinoma," "neoplasm," "tumor," "MDM4," "MDMX," "HDMX," "polymorphism," "SNP" and "polymorphisms". Two independent authors conducted the search. No language or other restrictions were placed on the search. Additional initially omitted studies have been identified by hand screening.

Criteria of inclusion and exclusion {#s4_2}
-----------------------------------

The included studies conformed to the following criteria: (1) studies that evaluated the associations between cancer risk and *MDM4* gene polymorphisms (at least one of the five polymorphisms), (2) studied on human beings, (3) study provided sufficient data to calculate the odds ratios (ORs) and 95% confidence intervals (CIs), and *P* value, and (4) case-control study. Exclusion criteria were: (1) duplication of previous publications; (2) case reports or review articles; (3) studies without detailed genotype data.

Data extraction and quality assessment {#s4_3}
--------------------------------------

Relevant information was carefully extracted from all eligible studies. The extracted information including: name of first author, publication year, country of origin, ethnicity, numbers of cases and controls, and cancer type. Two authors independently performed the extraction of data and assessed the study quality based on the Newcastle-Ottawa Scale (NOS) \[[@R45]\]. Total NOS scores ranged from 0 to 9. A score ranging 5 to 9 stars is considered to be a generally high methodological quality whereas a score ranging 0 to 4 is regarded as a relatively poor quality. All disagreements were discussed and resolved with consensus.

Statistical analysis {#s4_4}
--------------------

All statistical analyses were performed using the Stata 11.0 software (StataCorp, College Station, TX, USA). The strength of associations between *MDM4* gene polymorphisms and cancer risk were estimated for each study by crude ORs and 95% CIs. Stratification analyses were carried out by ethnicity, cancer type, sex and smoking status. *P* \< 0.05 was considered statistically significant. When a significant Q test (*P* \< 0.1) or I^2^ \< 50% indicated heterogeneity across studies, a fixed-effect model was used. Otherwise, the fixed-effects model was applied \[[@R46]\]. Pooled ORs were calculated for allele model, dominant model, recessive model, homozygous model, and heterozygous model. We performed sensitivity analyses by omitting each study in turn to determine the effect on the test of heterogeneity and evaluated the stability of the overall results. Hardy--Weinberg equilibrium (HWE) was assessed in the controls using Pearson\'s χ^2^ test. Potential publication bias was assessed by Begger\'s and Egger\'s linear regression test \[[@R47]\]; *P* \< 0.05 was considered to indicate statistically significant.

This study was supported by National Natural Science Foundation of China, No. 81371927.

**CONFLICTS OF INTEREST**

The authors declare no conflicts of interest.

SCCHN

:   squamous cell carcinoma of the head and neck

NHL

:   Non-Hodgkin lymphoma

ESCC

:   esophageal squamous cell carcinoma

SCLC

:   small cell lung cancer

CI

:   confidence interval

OR

:   odds ratio

NOS

:   Newcastle-Ottawa Scale

HWE

:   Hardy--Weinberg equilibrium

SNP

:   single nucleotide polymorphism