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Ortho-McNeil Pharmaceutical, Inc. v. Kali Laboratories

April 4, 2007

ORTHO-MCNEIL PHARMACEUTICAL, INC., PLAINTIFF AND OUNTERCLAIM DEFENDANT,
v.
KALI LABORATORIES, INC., PAR PHARMACEUTICAL COMPANIES, INC., PAR PHARMACEUTICAL, INC., DEFENDANTS AND OUNTERCLAIMANTS.
ORTHO-MCNEIL HARMACEUTICAL, INC., PLAINTIFF AND COUNTERCLAIM DEFENDANT,
v.
TEVA PHARMACEUTICAL INDUSTRIES, LTD., TEVA PHARMACEUTICALS USA, INC., BARR LABORATORIES, INC. DEFENDANTS AND COUNTERCLAIMANTS.



The opinion of the court was delivered by: Lifland, District Judge

OPINION

In these two consolidated patent infringement actions, Defendant generic drug manufacturers Kali Laboratories, Inc. ("Kali"), Par Pharmaceutical Companies, Inc., Par Pharmaceutical, Inc. (collectively "Par"),*fn1 Teva Pharmaceutical Industries, Ltd., Teva Pharmaceuticals USA, Inc. (collectively "Teva"), and Barr Laboratories, Inc. ("Barr"),*fn2 move for summary judgment against Plaintiff Ortho-McNeil Pharmaceutical, Inc. ("Ortho-McNeil"). Ortho-McNeil asserts that Defendants have infringed, under the Hatch-Waxman Act, its patent covering the pain-relief drug it sells under the name-brand, Ultracet. Defendants dispute Ortho-McNeil's infringement claims, and counterclaim that, in any event, Ortho-McNeil's patent is invalid. For the reasons that follow, the Court will grant summary judgment of non-infringement to Kali, and deny summary judgment of non-infringement to Teva/Barr. Furthermore, the Court will grant summary judgment of infringement in favor of Ortho-McNeil against Teva/Barr. As for Defendants' invalidity counterclaims, the Court will deny summary judgment of invalidity to Kali on the grounds of indefiniteness and the public-use bar. However, the Court concludes that Claim 6 of the '691 patent is invalid for anticipation, and for obviousness, and thus, will grant summary judgment of invalidity to Teva/Barr and Kali.

I. Background

A. Ortho-McNeil's Patented Invention

United States Patent No. 5,336,691 ("the '691 patent") contains 15 claims, several of which disclose a pharmaceutical composition comprising the analgesic compounds tramadol and acetaminophen combined at various weight ratios. The '691 patent inventors found that when administered together, certain amounts of tramadol and acetaminophen exhibit "synergistic" effects. In other words, the analgesic effectiveness of the two drugs in combination is greater than the sum of their parts, as predicted by data demonstrating the individual effectiveness of each drug. Claim 6, the only claim Ortho-McNeil asserts as infringed, reads: "[A] pharmaceutical composition [comprising a tramadol material and acetaminophen, wherein the ratio of the tramadol material to acetaminophen is a weight ratio of] about 1:5."*fn3 '691 patent, col. 11, ll. 18-34.

At first, the United States Patent and Trademark Office ("PTO") rejected the '691 patent's claims for obviousness in view of the patent covering tramadol, U.S. Patent No. 3,652,589 ("the '589 patent" or "the Flick patent"). (Kushan Decl., Ex. 10, at KAL 0016264.) The examiner pointed out that the Flick patent disclosed tramadol's "considerable therapeutic value when used in combination with other therapeutically active agents whereby frequently a synergistic effect is observed," and reasoned that it therefore would have been obvious to one of ordinary skill in the art to combine tramadol and acetaminophen in varying amounts to achieve synergistic effects in treating pain. (Kushan Decl., Ex. 10, at KAL 0016264 (quoting '589 patent, col. 12, ll. 45-48).)

After the inventors counterargued that it was not obvious that tramadol and acetaminophen would exhibit synergistic analgesic activity in the particular weight ratios claimed, the PTO allowed the claims. (Kushan Decl., Ex. 10, KAL016272.) The '691 patent issued on August 9, 1994 to co-inventors Robert Raffa and Jeffrey Vaught, and was assigned to McNeilab, Inc., Ortho-McNeil's predecessor in interest.

On the basis of the '691 patent, Ortho-McNeil developed Ultracet, which contains one part tramadol hydrochloride*fn4 (37.5 milligrams ("mg")), to 8.67 parts acetaminophen (325 mg). Ultracet was approved for sale by the Food and Drug Administration ("FDA") in 2001.

B. Kali's and Teva/Barr's Abbreviated New Drug Applications

In fall 2002, Kali filed an Abbreviated New Drug Application ("ANDA") with the FDA seeking approval to sell a generic version of Ultracet containing the identical 1:8.67 weight ratio of tramadol to acetaminophen. (Kushan Decl., Ex. 24.) Kali's ANDA included a certification under section 505(j)(2)(A)(vii)(IV) of the Federal Food and Drug Cosmetic Act ("FDCA"), 21 U.S.C. § 335 ("Paragraph IV certification"), alleging that the sale of its generic would either not infringe the '691 patent, or that the '691 patent was invalid, or both. Kali notified Ortho-McNeil of its Paragraph IV certification as required under 21 U.S.C. § 355(j)(2)(B), and Ortho-McNeil responded by filing an infringement suit against Kali under the Hatch-Waxman Act, 35 U.S.C. § 271(e)(2)(A). Kali denies infringing the '691 patent, and asserts, as affirmative defenses and in counterclaims, that the '691 patent is invalid as anticipated, for obviousness, for indefiniteness, and under the public-use bar. After discovery, Kali filed the instant motion for summary judgment. On April 22, 2005, the 30-month stay on FDA approval of Kali's ANDA expired, see 21 U.S.C. § 355(j)(5)(B)(iii)(I)-(III), the FDA approved the ANDA, and Kali began marketing its generic form of Ultracet.*fn5

In a separate suit, Ortho-McNeil filed a Hatch-Waxman Act infringement action against Teva on February 25, 2004, after Teva filed an ANDA with a Paragraph IV certification seeking to market a generic form of Ultracet. Like Kali, Teva responded by denying infringement, and by asserting a counterclaim alleging the invalidity of Claim 6. Teva/Barr now move for summary judgment on those grounds. On July 26, 2006, Barr began marketing its Ultracet generic after the 30-month stay on FDA approval expired.*fn6

On July 10, 2006, the two cases were consolidated for pretrial purposes.

C. The '691 Patent Reissue Application

On January 20, 2004, during the discovery phase of its suit against Kali, and about one month prior to filing suit against Teva/Barr, Ortho-McNeil filed a reissue application with the PTO for the '691 patent, admitting that certain claims were anticipated by the prior art. Ortho-McNeil explained to the PTO that "it was not appreciated, by the inventors and the attorney prosecuting the underlying patent application [for the '691 patent], that a composition within the scope of at least claim 1 as issued appears to have been disclosed in at least [the Flick patent]." (Brown Decl., Ex. 10, Reissue Appl. Decl. of Jan. 20, 2004.) The reissue application canceled all claims of the '691 patent, except for Claims 6 and 15, and applied for dozens of new claims.

On August 1, 2006, the PTO reissued the '691 patent as U.S. Reissue Patent No. RE39,221 E ("the RE221 patent"). The RE221 patent retains Claim 6, only now recast as an independent claim,*fn7 and adds 62 additional new claims.*fn8 As required by the FDCA, Ortho-McNeil surrendered the '691 patent to the PTO. Because Claim 6 of the RE221 patent is "substantially identical" to Claim 6 of the '691 patent, the surrender of the '691 patent does not abate the current action. See 35 U.S.C. § 252. Ortho-McNeil amended its complaints in both actions to allege that Defendants' ANDAs infringed Claim 6 of the RE221 patent, and Kali and Teva/Barr amended their counterclaims to allege the invalidity of Claim 6 of the RE221 patent.*fn9

II. Summary Judgment

Summary judgment is appropriate if there is no genuine issue as to any material fact and the moving party is entitled to a judgment as a matter of law. Fed. R. Civ. P. 56; Serbin v. Bora Corp., 96 F.3d 66, 69 n.2 (3d Cir. 1996). When evaluating a summary judgment motion, the Court must "draw all reasonable inferences in favor of the non-moving party." Armour v. County of Beaver, 271 F.3d 417, 420 (3d Cir. 2001) (internal quotations omitted). The burden of showing that no genuine issue of material fact exists rests initially on the moving party. Celotex Corp. v. Catrett, 477 U.S. 317, 323 (1986); Huang v. BP Amoco Corp., 271 F.3d 560, 564 (3d Cir. 2001). Once the moving party has made a properly supported motion for summary judgment, the burden shifts to the non- moving party to "set forth specific facts showing that there is a genuine issue for trial." Fed. R. Civ. P. 56(e); Anderson, 477 U.S. at 242.

The mere existence of some alleged factual dispute between the parties will not defeat an otherwise properly supported motion for summary judgment. Matsushita Elec. Indus. Co. v. Zenith Radio Corp., 475 U.S. 574, 586 (1986); Quiroga v. Hasbro, Inc., 934 F.2d 497, 500 (3d Cir. 1991) (noting that a motion for summary judgment is not defeated by mere allegations, general denials, or other "vague statements"). Rather, only disputes regarding facts that might affect the outcome of the lawsuit under the governing law will preclude the entry of summary judgment. Anderson, 477 U.S. at 247-48. If the evidence is "such that a reasonable jury could return a verdict for the nonmoving party," summary judgment should not be granted. Id. at 248; Lawrence v. Nat'l Westminster Bank of New Jersey, 98 F.3d 61, 65 (3d Cir. 1996).

III. Discussion

Kali and Teva/Barr claim that, as a matter of law, Ortho-McNeil has failed to carry its burden of proving infringement, and that they have carried their burden of proving the invalidity of the '691 patent on grounds of anticipation. Kali also seeks summary judgment on its additional invalidity counterclaims of indefiniteness, obviousness, and the public-use bar. The Court's first step in evaluating Defendants' motions is to objectively construe the disputed limitations of Claim 6 to the extent necessary to settle the controversy, and without reference to Defendants' allegedly infringing products. See Vivid Techs., Inc. v. American Science & Eng'g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999).

A. Claim Construction

"[T]he claims of a patent define the invention to which the patentee is entitled the right to exclude," Phillips v. AWH Corp., 415 F.3d 1303, 1312 (Fed Cir. 2005) (internal quotations omitted), and therefore an interpretation of the words of those claims is necessary in order to determine whether the invention is infringed, or invalid, see, e.g., Lemelson v. Gen. Mills, Inc., 968 F.2d 1202, 1206 (Fed. Cir. 1992) ("It is elementary in patent law that, in determining whether a patent is valid and, if valid, infringed, the first step is to determine the meaning and scope of each claim in suit."). The proper construction of a disputed claim limitation is decided by the Court as a matter of law, Bayer AG v. Elan Pharm. Research Corp., 212 F.3d 1241, 1247 (Fed. Cir. 2000), and is applicable to both the Court's infringement and invalidity analyses, Amazon.com, Inc. v. Barnesandnoble.com, Inc., 239 F.3d 1343, 1351 (Fed. Cir. 2001).

The Court of Appeals for the Federal Circuit has repeatedly stated that "the words of a claim 'are generally given their ordinary and customary meaning,'" as viewed through the eyes of "a person of ordinary skill in the art in question at the time of the invention." Phillips, 415 F.3d at 1312-13 (quoting Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed Cir. 1996)). In some cases, the ordinary and customary meaning of a limitation may be "readily apparent even to lay judges," and thus, can be simply applied to a claim with the assistance of a dictionary. Id. at 1314. In most cases, however, the "meaning of a claim term as understood by persons of skill in the art is . . . not immediately apparent," and therefore the court must look to "'those sources available to the public that show what a person of skill in the art would have understood disputed claim language to mean.'" Id. (quoting Innova/Pure Water, Inc. v. Safari Water Filtration Systems, Inc., 381 F.3d 1111, 1116 (Fed. Cir. 2004)).

"[T]hose sources" can be divided into two general categories: intrinsic evidence and extrinsic evidence. Intrinsic evidence consists of the words of the claims themselves, the specification, and, if in evidence, the prosecution history. Key Pharms. v. Hercon Lab. Corp., 161 F.3d 709, 716 (Fed. Cir. 1998). Extrinsic evidence consists of any evidence outside of the patent record, id., such as, "expert and inventor testimony, dictionaries, and learned treatises," Markman v. Westview Instruments, Inc., 52 F.3d 967, 980 (Fed. Cir. 1995), aff'd, 516 U.S. 370 (1996). Such evidence "may be helpful to explain scientific principles, the meaning of technical terms, and the terms of art that appear in the patent and prosecution history"--in a nutshell, extrinsic evidence "'aid[s] the court in the construction of the patent.'" Id. The Federal Circuit has stressed, however, that intrinsic evidence has primacy in the claim construction analysis; extrinsic evidence cannot be used to alter a construction of the claims mandated by the intrinsic evidence. Key Pharms, 161 F.3d at 716. "[I]f the meaning of a disputed claim term is clear from the intrinsic evidence . . . that meaning, and no other, must prevail." Id.

Despite the, at times, seemingly factual nature of this exercise,*fn10 claim construction is purely a question of law. "Testimony about construction . . . amounts to no more than legal opinion," which the "court has complete discretion to" wholly adopt, use as guidance, ignore or exclude. Markman, 52 F.3d at 983. As a result, conflicts between expert testimony or between testimony and the intrinsic evidence does not create a question of fact that can preclude summary judgment. See id.

As stated above, Claim 6 of the '691 patent reads: "[A] pharmaceutical composition [comprising a tramadol material and acetaminophen, wherein the ratio of the tramadol material to acetaminophen is a weight ratio of] about 1:5."

'691 patent, col. 11, ll. 18-34. The parties dispute the meaning of the limitations "about 1:5" and "pharmaceutical composition." The Court will construe each in turn.

1. "About 1:5"

a. The Parties' Positions

It is undisputed that, at a minimum, "about 1:5" is equivalent to "approximately 1:5," and therefore permits some amount of deviation from exactly 1:5. The parties' positions diverge, however, as to the amount of deviation "about" permits. Ortho-McNeil argues that "about 1:5" should encompass at least 1:3.6 to 1:7.1, because, in terms of efficacy, the ratios in this range are statistically equivalent to 1:5. Kali and Teva/Barr counter that "about" should only encompass minor deviations from 1:5 resulting from "measurement error," and that this range should span, at most, from 1:4.9 to 1:5.1. Before the Court examines the intrinsic and extrinsic evidence, two preliminary issues must first be addressed.

b. The Effect of the Federal Circuit's Decision in Ortho-McNeil v. Caraco

On January 19, 2007, the Court of Appeals for the Federal Circuit issued a decision construing the "about 1:5" limitation in Claim 6 of the '691 patent in a nearly identical Hatch-Waxman Act infringement case brought by Ortho-McNeil against another generic drug manufacturer. See Ortho-McNeil Pharm., Inc. v. Caraco Pharm. Labs, Ltd., 476 F.3d 1321, 2007 U.S. App. LEXIS 1133 (Fed. Cir. Jan. 19, 2007). There, the Federal Circuit held that the District Court for the Eastern District of Michigan properly interpreted "about 1:5" to mean "approximately 1:5, encompassing a range of ratios no greater than 1:3.6 to 1:7.1." Id. at *18-19.

Ortho-McNeil argues that this holding settles the claim construction dispute in this case, and definitively sets "about 1:5" as equal to 1:3.6 to 1:7.1. The Court disagrees. The facts and analysis of Caraco make clear that the Federal Circuit was not deciding the exact parameters of "about 1:5," but instead was only placing a ceiling on what range of ratios "about" could possibly represent. In Caraco, the defendant generic manufacturer's ANDA would have permitted it to sell a generic Ultracet with a weight ratio of 1:8.67; however, the ANDA also included a manufacturing variance that would have allowed the defendant to legally sell its generic with a weight ratio ranging as low*fn11 as 1:6.41. See Ortho-McNeil Pharm. Inc. v. Caraco Pharm. Labs., Ltd., No. 04-CV-73698, 2005 U.S. Dist. LEXIS 24998, at *2 (E.D. Mich. Oct. 19, 2005). Ortho-McNeil argued there, as it does here, that "about 1:5" encompasses at least 1:3.6 to 1:7.1, the range of ratios representing the statistical variation in efficacy of 1:5. Id. at *7-8. However, during the litigation, the defendant amended its ANDA to "cut its authorized manufacturing variability in half to a minimum of 1:7.5." Id. at *2-3. Thus, under the facts presented in Caraco, the Federal Circuit only needed to decide whether "about 1:5" could extend higher than 1:7.1, as urged in that case by Ortho-McNeil,*fn12 in order to determine whether there was literal infringement. Absent language in Caraco to the contrary, this Court will not assume that the Federal Circuit decided more. See NTP, Inc. v. Research in Motion, Ltd., 418 F.3d 1282, 1311 (Fed Cir. 2005) (stating that a court need only construe a claim term "to the extent necessary to resolve the controversy") (quoting Vivd Techs., Inc., 200 F.3d at 803); see also Pall Corp. v. Micron Separations, Inc., 66 F.3d 1211, 1219 (Fed. Cir. 1995) (construing "about 5:1" to "not include the [allegedly infringing] ratio of 4:1," without determining exactly how far "about" expands 5:1).

The Federal Circuit's analysis also indicates that it only decided whether the scope of "about 1:5" was broader, not equal to or narrower, than 1:3.6 to 1:7.1. First, Caraco simply held that "about 1:5" was "no greater" than 1:3.6 to 1:7.1, rather than using language indicating an equivalence to this range, such as "extends to" or "no greater and no lesser than." Second, Caraco's claim construction stressed that "the qualifier 'about' is narrow," and that it "was meant to encompass compositions very close to" 1:5, Caraco, 2007 U.S. App. LEXIS 1133, at *16-17 (emphases added), thus indicating that the Court was only concerned with whether the scope of "about 1:5" was broader than 1:3.6 to 1:7.1. Third, the Federal Circuit in Caraco never considered the defendant's argument there (and Defendants' argument in this case) that "about 1:5" should be construed more narrowly than 1:3.6 to 1:7.1 using measurement error. See Caraco, 2007 U.S. App. LEXIS 1133, at *5.

Finally, although the Caraco Court did rely in part on the opinion of OrthoMcNeil's expert, Donald R. Stanski, M.D., that "'about 1:5' . . . includes a ratio up to and including 1:7.1," Caraco, 2007 U.S. App. LEXIS 1133, at *18-19 (emphasis added), it did so only to undercut Ortho-McNeil's argument that "about 1:5" extends beyond 1:7.1, not to definitively state that "about 1:5" is equivalent to the full scope of 1:3.6 to 1:7.1. This is clearly how the District Court used Dr. Stanski's testimony in its analysis, when it explained that the "'[u]p to' 1:7.1," language Dr. Stanski used "would put an upper limit on the range, while [OrthoMcNeil's argument for] 'at least' 1:3.6 to 1:7.1 has no upper limit," and would "result[] in a meaningless and boundless construction." Caraco, 2005, U.S. Dist. LEXIS 24998, at *8-9. The Federal Circuit said that it "s[aw] no error in the district court's construction," and cited it approvingly. Caraco, 2007 U.S. App. LEXIS 1133, at *18.

The Court concludes that Caraco's holding that "about 1:5" extends "no greater than 1:3.6 to 1:7.1" did not answer whether the scope of "about 1:5" extends to a range narrower than 1:3.6 to 1:7.1. As a result Caraco does not settle the infringement issue here since Defendants' ANDAs would also permit them to legally sell their generic drug with a weight ratio as low as 1:6.41, and Defendants' have not voluntarily amended their ANDAs to limit this range. Thus, the Court must decide whether the meaning of "about 1:5" encompasses 1:6.41. This is the question the Court will address below.

c. Construing the Term "About"

The second preliminary issue the Court must address is Kali and Teva/Barr's suggestion that courts unvaryingly "interpret 'about' based on the imprecision inherent in measurement of the claimed element in question," (see, e.g., Kali Reply Br. at 7), and that therefore, this Court should do the same.

Not surprisingly, the proper interpretation of the word "about," when used in front of a numerical measurement in a patent claim, has been the subject of relatively frequent litigation before the Courts. See, e.g., Caraco, 2007 U.S. LEXIS 1133, at *18-19 (construing "about 1:5"); Merck, 395 F.3d at 1370 (interpreting "about 70 mg"); Pall, 66 F.3d at 1217-18 (interpreting "about 5:1 to about 7:1"); Hybritech, Inc. v. Abbott Labs., 849 F.2d 1446, 1455-56 (Fed Cir. 1988) (construing "about 10[8] liters/mole"); W.L. Gore & Assoc. Inc. v. Garlock, Inc., 842 F.2d 1275, 1280 (Fed. Cir. 1988) (construing "about 100% per second"). In support of their position, Kali and Teva/Barr cite Hybritech Inc. v. Abbott Laboratories, where the Federal Circuit, with little elaboration, affirmed a district court's construction of a claim requiring antibodies with an affinity of "at least about 10[8] liters/mole," as encompassing "two- to three-fold measurement errors inherent in affinity measurements." 849 F.2d at 1455.

The Federal Circuit has explained that "'the word 'about' does not have a universal meaning in patent claims, [and instead,] the meaning depends on the technological facts of the particular case.'" Caraco, 2007 U.S. App. LEXIS 1133, at *13 (quoting Pall, 66 F.3d at 1217). Therefore, the limitation "about" is not exempt from the Federal Circuit's instruction that the meaning of a claim limitation must be that which would be usual and customary to the person of ordinary skill in the particular art at the time of the particular invention. See Phillips, 415 F.3d at 1312-13. Presumably, the Federal Circuit used this same context-specific approach in Hybritech, and, on the basis of intrinsic and extrinsic evidence relevant to that particular invention, concluded that measurement error was the appropriate benchmark for defining "about." See Hybritech, 849 F.2d at 1455. In other cases, involving different technologies, claims, and specifications, "about" may mean something different. For instance, in Pall, the Federal Circuit construed "about 5:1" not to encompass a ratio of 4:1 because test data in the patent specification and testimony of the inventor showed that a nylon resin membrane with a methylene to amide ratio of 4:1 lacked the desirable properties present in the claimed 5:1 ratio. Id. at 1217-18. In other words, the extent of "about" was limited by what worked as well as 5:1. Thus, the Court rejects Defendants' suggestion that Hybritech created a per se rule that "about" is always consistent with "measurement error." The meaning of "about 1:5" is dictated primarily by the intrinsic evidence in this case, to which the Court now turns.

d. The Intrinsic Evidence

i. The '691 Patent Claims

The claims of the '691 patent provide the starting point for an examination of the intrinsic evidence. See Phillips, 415 F.3d at 1314. Those claims make clear that "about 1:5" was intended to be relatively narrow in scope because it is "distinctly claimed and distinguished from other broader weight ratio ranges in the patent," such as Claim 1 which contains the limitation: "a weight ratio from about 1:1 to about 1:1600." Caraco, 2007 U.S. App. LEXIS 1133, at *14-15. Besides Claim 6, only Claim 4, which claims "about 1:1," distinctly claims a single ratio as opposed to a range. Noting this, the Federal Circuit observed in Caraco that this is further evidence that "about" must be "narrow" because otherwise the scope of "about 1:5" would "encompass a range of ratios that could potentially render meaningless" the "about 1:1" limitation. Id. at *16-17.

Kali and Teva/Barr argue that the words of the claims support their measurement-error theory of claim construction. Defendants' position is that because the word "about" in the claim describes a weight ratio, "about" must be referring to imprecision in the measurement of the weights of tramadol and acetaminophen. Defendants argue further that, in contrast, Ortho-McNeil's claim construction theory (explained in detail below) is not supported by the words of the claims because it is based on animal testing data that does not appear in the claims.

Defendants are correct that the words of the claims do not refer to the test data, found in the specification, upon which Ortho-McNeil relies. But the claims also do not refer to errors in the measurement of the weights of tramadol and/or acetaminophen. There are two gaps in Defendants' position. First, the fact that "about" modifies weight ratios only informs the reader that some degree of variation in those ratios is permitted. The language says nothing about what standard shall determine the correct degree of that variation, and therefore makes it no more likely that the inventors intended that variation to reflect errors in measuring the weight of tramadol or acetaminophen as opposed to the statistical imprecision inherent in the method of using the specification's test data to find efficacy at that ratio, as urged by Ortho-McNeil. Both could cause variation in the weight ratios, and the words of the claims are silent as to both.

Second, imprecision in a weight ratio is not the same thing as imprecision in a measurement of the weight of the drugs that constitute that ratio. A measuring error will not always cause imprecision or variation in the corresponding weight ratio. If a scientist intended to create a drug with a 1:5 weight ratio containing 25 mg of tramadol and 125 mg of acetaminophen, but mistakenly measured 30 mg of tramadol and 150 mg of acetaminophen, the scientist still would have created a drug with precisely a 1:5 weight ratio. While such an error may be unlikely, its possibility illustrates that using "about" to describe a weight ratio does not necessarily refer to errors in measuring the weights of the drugs constituting that ratio.

In sum, the fact that "about" modifies weight ratios does not support Defendants' measurement error argument. It simply begs the question: what standard shall give meaning to the word "about"? Because the words of the claims do not answer this question, the Court will move on and examine the patent specification.

ii. The Specification

The Federal Circuit has described the patent specification as "the single best guide to the meaning of a disputed term." See Vitronics, 90 F.3d at 1582. It "acts as a dictionary when it expressly defines terms used in the claims or when it defines terms by implication." Id. (citing Markman, 52 F.3d at 979). The '691 patent specification does not explicitly define "about." Implicitly, however, the specification (1) supports a definition of "about" that encompasses the full extent of the variation inherent in the statistical method of determining whether tramadol/acetaminophen doses in certain weight ratios demonstrate efficacy, and

(2) is wholly lacking in support for a definition linked to measurement error.

(a) Statistical Variation in Efficacy

According to the specification, the inventors only claimed weight ratios of tramadol and acetaminophen that demonstrated synergistic effects when administered to test mice. '691 patent, col. 2, ll. 55-67; col. 3, l. 63-col. 4, l. 6; col 8 ll. 38-68. The specification also explains how the testing was performed and charts the resulting data. The mice were administered precise doses of tramadol and acetaminophen in each weight ratio tested, for example, 1000:1, 1:1, 1:5, and 1:5.7. Each weight ratio was tested using different dosages of the drugs. For example, the mice received the drugs at a 1:5 weight ratio in three ways: (1) 2.5 mg of tramadol and 12.5 mg of acetaminophen; (2) 5 mg of tramadol and 20 mg of acetaminophen; and (3) 10 mg of tramadol and 50 mg of acetaminophen. At each dosage, the inventors recorded what number out of 30 test mice experienced pain relief. See '691 patent, cols. 9-10.

Using the resulting data, the inventors then statistically estimated how many milligrams of tramadol and acetaminophen must be administered in order for 50 percent of the 30 test mice to experience pain relief at each particular weight ratio. The resulting value is called the "median effective dose" of the weight ratio, or "ED50" for short. See '691 patent, col. 8 ll. 29-30 (explaining that the "ED50 [value] was estimated from the dose-response curve for a specific fixed-ratio" (emphasis added)); (Smith Inf. Rep., at pp. 8-9, ¶¶ 1-5.).*fn13

To illustrate, at 1:5, the test data found that 2.5 mg of tramadol and 12.5 mg of acetaminophen caused seven of 30 mice to experience pain relief; at 5 mg/25 mg, 18*fn14 of 30 mice experienced pain relief; and at 10 mg/50 mg, all 30 mice experienced pain relief. '691 patent, cols. 9-10, Table 1. Using that data, the inventors "estimated" that in order for 50 percent of 30 test mice to experience pain relief, it would be necessary to administer 4 mg of tramadol and 19.8 mg of acetaminophen. See '691 patent, col. 8 ll. 29-30; cols. 9-10. Therefore, 4 mg/19.8 mg is the ED50 for tramadol/acetaminophen at a 1:5 weight ratio. The ED50 data points for each weight ratio tested by the inventors are plotted in a graph found at Figure 1 of the specification.

Importantly, each ED50 value is only a statistical estimate, based upon the experimental data, of what the true ED50 value would be if it were possible to test an infinite number of animals at a particular dose. (See Smith Inf. Rep., at pp. 4-5, ¶¶ 2-4.) Obviously, only a finite number of mice can be tested, here 30. If further experiments were conducted, the result would be "a slightly different proportion of animals testing 'positive' or 'negative,'" for pain relief, and thus, the ED50 value estimated from those results would also vary. (See id., at p. 5, ¶ 4.) To represent this uncertainty, Table 1 lists, and Figure 1 plots, the "95 percent confidence interval" of each weight ratio's ED50 values. '691 patent, Figure 1; col. 8, ll. 61-64; Table 1, cols. 9-10. "A confidence interval describes the variation in the estimate by using upper and lower values that represent a possible range of values that could be obtained from repeated experiments." (Smith Inf. Rep., at p. 5, ¶ 4.) Therefore, a 95 percent confidence interval means that if the inventors' mice experiment was repeated 100 times, roughly 95 percent of results would fall within the 95 percent confidence interval ranges. (Id. at p. 5, ¶ 4.)

The 95 percent confidence intervals for the 1:5 weight ratio's ED50 value (4.0 mg tramadol/19.8 mg acetaminophen) are 3.3 mg to 4.7 mg of tramadol, and 16.7 mg to 23.4 mg of acetaminophen. According to Ortho-McNeil's experts, Dr. Stanski, and Eric Smith, Ph.D., a range of weight ratios that are "statistically indistinguishable" from 1:5 can be discerned from these 95 percent confidence interval figures. (Smith Inf. Rep., at pp. 24-25, ¶¶ 1-3; Stanski Inf. Rep., at pp. 5- 7, ¶¶ 7, 10, 12.) The low end of the ratio range is determined by combining the lowest acetaminophen weight, 16.7 mg, with the highest tramadol weight, 4.7 mg. This combination results in a weight ratio of 1:3.6. The high end is then determined by combining the highest acetaminophen weight, 23.4 mg, with the lowest tramadol weight, 3.3 mg. This results in a weight ratio of 1:7.1. Thus, in Dr. Stanski's and Dr. Smith's opinions, the data in the specification demonstrates that a 1:5 weight ratio is statistically indistinguishable from a range of 1:3.6 to 1:7.1. (Smith Inf. Rep., at p. 24, ¶ 1*fn15 ; Stanski Inf. Rep., at p. 6, ¶ 7; p. 7, ¶ 10, 12.) A person of skill in the art of analgesic drugs reading this data would find, Dr. Stanski concludes, that "about" encompasses this "statistical variation in efficacy" of the 1:5 weight ratio, and therefore, "'about 1:5' would not be statistically different from a ratio up to and including 1:7.1 and a ratio down to and including 1:3.6." (Stanski Inf. Rep., at p. 6, ¶ 7; p. 7, ¶ 12 (emphases added).)

Defendants seek to discredit Ortho-McNeil's theory of claim construction as mere manufactured "statistical machinations" (Kali Supp. Br. at p. 10.), and "statistical gymnastics," (Teva/Barr Reply Br. at p. 2.). However, Ortho-McNeil's expert states that the methodology used by the inventors is not novel in the pharmaceutical industry. (Smith Inf. Rep., at p. 8, ¶ 3.) Defendants do not offer extrinsic evidence to the contrary, and as explained further below, do not offer a more persuasive reading of the intrinsic evidence. Despite the use of data and statistics, Plaintiff's claim construction theory is not as complicated as Defendants would have it seem: the patent teaches that the inventors claimed 1:5 because it demonstrated efficacy, and, according to Plaintiff's experts, the patent data proving 1:5's efficacy also shows that the ratios 1:3.6 through 1:7.1 would, statistically speaking, demonstrate the same efficacy as 1:5. Thus, the Court concludes that this range of ratios offers a sound basis, grounded in the patent specification, for measuring the full breadth of "about 1:5." In contrast, Defendants have failed to show any reason, supported by the patent specification or otherwise, why "about" was intended to represent variation caused by measurement error.

(b) Measurement Error

Measurement error is not mentioned in any manner in the specification. This omission is significant, in light of the fact that the specification carefully details how the inventors prepared the tramadol/acetaminophen combinations administered to mice for testing. See '691 patent, col. 5, ll. 39-61; col. 6, ll. 32-52. If the occurrence of measurement errors were important enough, or common enough, that the inventors felt the need to represent the variation created by such errors with the word "about" in the patent claims, one would think such errors would be accounted for in the specification's description of how the drug is prepared and measured for administration. Instead, the specification's description uses precise measurements. For example, in describing how the drugs at a 1:50 ratio were prepared, the specification states that 400 mg of [acetaminophen] as the free base is suspended with 10 mL of the 8 mg tramadol solution and 2 drops of TWEEN 80, a pharmacological dispersant, manufactured by Fisher Scientific Company, to yield the 1:50 ratio, i.e., (8 mg: 400 mg) combination per 10 mL of water.

'691 patent, col. 5, ll. 54-59. There is no mention of any variation in the amounts of tramadol or acetaminophen administered to the mice, with the word "about" or otherwise. Indeed, as Kali and Teva/Barr point out, the specification demonstrates that the inventors were capable of measuring the weight of the drugs with accuracy up to at least a hundred-thousandth of a milligram. See '691 patent, cols. 9-10 (stating that, at a weight ratio of 1:800, the inventors administered 0.03125 mg of tramadol to the test mice). Defendants argue that this precision proves that "about" should at most represent a one-tenth of decimal point variation from 1:5, i.e., 1:4.9 to 1:5.1. However, this argument prematurely assumes that measurement error has already been established as the guidepost for measuring the variation represented by "about." It has not. Moreover, it also assumes that measurement errors are made. Simply because the data shows that the inventors could accurately measure tramadol to the fifth decimal place, in no way suggests that the inventors could not also do so to the sixth, seventh, or twentieth decimal places. Instead of proving that minute measurement errors should guide the meaning of "about," the precision measurements shown in the specification suggest that there were no imprecisions at all in weights of the drugs administered to the test rats. Even if measurement errors are made, the absence of any reference to them in the specification suggests that such errors were not contemplated by the inventors. As a result, a person of ordinary skill reading the patent would not contemplate that "about 1:5" refers to imprecision resulting from measurement errors.

Kali and Teva/Barr point out that the specification states that, in addition to testing tramadol and acetaminophen at a 1:5 weight ratio, the inventors also tested a 1:5.7 weight ratio. From this, Defendants argue that "about 1:5" cannot extend to 1:5.7 because the inventors recognized 1:5.7 and 1:5 as distinct ratios. This argument overlooks that, unlike the '691 patent's claims, the specification's test data does not use the word "about" before its tested ratios. Therefore, the specification does not show that "about 1:5" in Claim 6 does not encompass 1:5.7; it only shows that the inventors considered exactly 1:5 to be distinct from exactly 1:5.7 for testing purposes. Furthermore, the fact that 1:5.7 was tested and ultimately not claimed, if anything, could suggest that the inventors thought that "about 1:5" already encompassed 1:5.7, and that therefore it was unnecessary to separately claim this data point. This is especially so in light of the test data, which shows that the 95 percent confidence intervals for the ED50 values of 1:5 (3.3-4.7 mg tramadol / 16.7-23.4 mg acetaminophen) encompass the ED50 values for 1:5.7 (4.1 mg tramadol / 23.3 mg acetaminophen). '691 patent, cols. 9-10, Table 1. Thus, Defendants' argument based on testing at a ratio of 1:5.7 further supports Ortho-McNeil's construction of "about 1:5."

In conclusion, the Court finds no basis in the intrinsic*fn16 or extrinsic evidence for using measurement error as a guide for construing the scope of "about 1:5." In contrast, the Court finds that the statistical variation in efficacy provides an appropriate benchmark. As explained above, the Federal Circuit in Caraco used this standard to set a ceiling for "about 1:5." This Court finds that it provides a floor as well, and holds that "about 1:5" encompasses ratios up to and including 1:7.1 and ratios down to and including 1:3.6.

2. "Pharmaceutical Composition"

Ortho-McNeil and Kali*fn17 also disagree over the proper construction of the Claim 6 limitation: "pharmaceutical composition [comprising a tramadol material and acetaminophen]." (emphasis added). Kali argues that the co-administration of tramadol and acetaminophen in separate but concurrent or sequential doses qualifies as a "pharmaceutical composition." Ortho-McNeil counterargues that the term is limited to "a medicinal preparation comprising an 'intimate admixture' of " tramadol and acetaminophen, "prepared outside the body, generally in the form of a 'dosage unit' such as a 'tablet' or 'capsule.'" (Pl.'s Opp. Br., p. 27.) The Court concludes that the intrinsic evidence favors Ortho-McNeil's construction.

The specification describes "[p]harmaceutical compositions comprising the tramadol material and acetaminophen," as "an intimate admixture with a pharmaceutical carrier . . . ." '691 patent, col. 4, ll. 42-45. The pharmaceutical carrier can take various forms, such as water, alcohols, starches, or sugars, depending on whether the composition is to be administered orally, intravenously, or parenterally. Id. at ll. 47-49, 53-59. The specification further explains that the "pharmaceutical compositions will generally be in the form of a dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like," and that this dosage unit will "contain[] . . . preferably from about 0.3 to 200 mg/kg of the active ingredients," id. at col. 5, ll. 3-7 (emphasis added). Therefore, a "pharmaceutical composition" necessarily contains both tramadol and acetaminophen. Additionally, examples one, two, and three of the specification, which give instructions on the "Preparation of the Combined Doses of Tramadol and [acetaminophen]," all state that the tramadol/acetaminophen "combinations are . . . made by adding 10 mL of each [tramadol] dilution to the appropriate mg of [acetaminophen]." '691 patent, col. 5, ll. 38-53; col. 6, ll. 32-44; col. 7, ll. 23-36. Thus, the specification makes clear that a pharmaceutical composition was intended to be a single dosage unit containing a mixture of both active ingredients.

The prosecution history also supports this construction. In an April 2, 1993 letter, the PTO informed the inventors that their claims had been rejected as obvious over the Flick patent, because "it would have been obvious to one with ordinary skill in the art to combine two compounds (i.e. tramadol and acetaminophen) in varying amounts in the same composition since both compounds are known to useful (sic) for treating the same condition (i.e. pain)." (Kushan Decl., Ex. 10, at KAL016264 (emphases added).) Thus, it is apparent that the patent examiner understood "pharmaceutical composition" to require the combination of the two compounds in the same unit. In its response, Ortho-McNeil did not attempt to change the examiner's understanding of the invention. (Kushan Decl., Ex. 10, at KAL016271-73.)

Ortho-McNeil also presents extrinsic evidence supporting its construction. First, in the expert opinion of Dr. Stanski, based on how the phrase is "commonly used in medical terminology, a pharmaceutical composition of Tramadol and [acetaminophen] would not extend to tablets in which the Tramadol and the [acetaminophen] were not in an 'intimate admixture' (e.g., two tablets, one solely containing tramadol and one solely containing [acetaminophen])." (Stanski Inf. Rep., at p. 5.) Second, Ortho-McNeil notes that the word "pharmaceutical" is defined as "relating to the preparation, use, or sale of medicinal drugs," The Oxford English Dictionary, at p. 662 (2d ed., Vol. XI, 1989)), and that "composition" is defined as "[t]he forming (of anything) by combination of various elements, parts, or ingredients," id., vol. III, p. 624. Accordingly, it argues, a "pharmaceutical composition" should be understood as a medicinal drug formed by combining two or more active ingredients.

In response, Kali points out that Dr. Raffa, a co-inventor of the '691 patent, stated in his deposition testimony that he "would not expect it to make a difference" whether tramadol and acetaminophen were administered mixed together or separately to test mice, "as long as they were given within a reasonable proximity in terms of time." (Brown Decl., Ex. 16, p. 301, ll. 6-12.) While this testimony may indicate that the two methods of administration are equally effective, Dr. Raffa was not purporting to construe "pharmaceutical composition" in his testimony. He was only asked whether the method used to administer the two drugs would affect the test results in the specification. Furthermore, although Dr. Raffa could not recall which method of administration was used during the mice testing (Brown Decl., Ex. 16, p. 300, ll. 16-21), the specification indicates that the mice were indeed given "combined doses of tramadol hydrochloride and acetaminophen." '691 patent, col. 8, ll. 16-17.

Kali also cites for support the Federal Circuit's decision in PIN/NIP, Inc. v. Platte Chem. Co., 304 F.3d 1235, 1245 (Fed Cir. 2002), where the Court construed the claim limitation, "composition," to mean "a mixture that is formed at any time during use, such as through simultaneous application of the constituent chemicals, as long as a mixture is indeed formed." PIN/NIP, however, did not involve pharmaceuticals, or the limitation "pharmaceutical composition," and in any event, there is nothing in the intrinsic evidence that supports Kali's proposed claim construction, and much that supports Ortho-McNeil's.

In sum, after examining the intrinsic and extrinsic evidence, the Court construes "pharmaceutical composition" to mean a medicinal preparation comprising an intimate admixture, prepared outside the body, generally in the form of a dosage unit, such as a tablet or capsule.

B. Infringement

The Court must engage in two inquiries to determine whether Kali and Teva/Barr have infringed Claim 6 of the '691 patent. First, as the Court has already done, the meaning and scope of the claim being asserted as infringed must be construed as a matter of law. See Bayer AG, 212 F.3d at 1247; Markman, 52 F.3d at 976. Second, the construed claim is then compared to the product accused of infringement. Markman, 52 F.3d at 976. Determining whether the accused device infringes the construed claim is a question of fact. See SRI Int'l v. Matsushita Elec. Corp. of Am., 775 F.2d 1107, 1125 (Fed Cir. 1985). The patentee bears the burden of proving "by a preponderance of the evidence that the accused device infringes one or more claims of the patent either literally or under the doctrine of equivalents." Advanced Cardiovascular Sys. Inc. v. Scimed Life Sys. Inc., 261 F.3d 1329, 1336 (Fed Cir. 2001). In this case, Ortho-McNeil accuses Defendants of infringing Claim 6 both literally and under the doctrine of equivalents. Defendants seek summary judgment of non-infringement; Ortho-McNeil argues that genuine issues of material fact exist, precluding summary judgment.

1. Literal Infringement

To prove literal infringement, the patentee must show "that the accused device contains each limitation of the asserted claim(s)." Bayer AG, 212 F.3d at 1247 (citing Mas-Hamilton Group v. LaGard, Inc., 156 F.3d 1206, 1211 (Fed. Cir. 1998)). "If any claim limitation is absent from the accused device, there is no literal infringement as a matter of law." Id.

Typically, the "accused device" is one that is already being manufactured, marketed, or sold when an infringement suit is brought, but in the Hatch-Waxman Act context this is not the case. Under 35 U.S.C. § 271(e)(2)(A) the submission of an ANDA, with the purpose of obtaining the FDA's approval to manufacture, use, or sell a drug claimed in a patent, is defined as "an act of infringement." It is only an act of infringement, however, in the sense that it "creates case-or-controversy jurisdiction to enable the resolution of an infringement dispute before the ANDA applicant has actually made or marketed the proposed product." Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1365 (Fed. Cir. 2003). This "artificial" act of infringement is not determinative of whether Defendants are liable for infringement; instead the issue "is determined by traditional patent infringement analysis, just the same as it is in other infringement suits . . . the only difference being that the inquiries now are hypothetical because the allegedly infringing ...


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