MOORE, Circuit Judge.
The defendants in these consolidated patent infringement actions (collectively, Appellants) appeal from the district court's judgment that various claims of the nine patents-in-suit asserted by the plaintiffs (collectively, Teva) are infringed, and from the court's holdings regarding indefiniteness, nonenablement, and obviousness.
Appellants submitted Abbreviated New Drug Applications (ANDAs) to the Food and Drug Administration (FDA) seeking approval to market generic versions of Copaxone®, a drug used in treating multiple sclerosis. Two proposed generic products, the Mylan accused product and the Sandoz accused product, are at issue in this appeal. Teva, which markets Copaxone®, sued Appellants for patent infringement under 35 U.S.C. § 271(e)(2)(A). The patents-in-suit, which share a common specification, are listed in the Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) entry for Copaxone®. The patents-in-suit include claims reciting a product called copolymer-1 and claims reciting methods of making copolymer-1.
Copolymer-1 consists of four different amino acids (alanine, glutamic acid, lysine, and tyrosine) combined in a certain ratio to make a polypeptide product. A sample of polymeric material like copolymer-1 typically consists of a mixture of individual polymer molecules that have varying molecular weights. There are different ways to describe the resulting distribution of molecular weight values. One approach uses statistical measures, including the peak average molecular weight (M
A second approach describes how many molecules in a polymer sample have molecular weights that fall within an arbitrarily set range. For example, if 99% of the constituent molecules in a sample have molecular weights between 1 kilodalton (kDa) and 100 kDa, the sample may be described as having 99% of its mole fraction within the molecular weight range of 1 kDa to 100 kDa.
The claims of the patents-in-suit use both approaches. Claim 1 of the '589 patent is representative of Group I claims, which use the first approach:
'589 patent claim 1 (emphases added). Claim 1 of the '430 patent is representative of Group II claims, which use the second approach: "Copolymer-1 having over 75% of its mole fraction within the molecular weight range from about 2 kDa to about 20 kDa...." '430 patent claim 1 (emphasis added).
In its claim construction order, the district court did not distinguish in detail between the different contexts in which the term "molecular weight" is used in Group I and Group II claims. The court rejected the Appellants' argument that the term "molecular weight" was insolubly ambiguous because it could refer to M
A patent's specification "must conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor ... regards as the invention." 35 U.S.C. § 112(b) (2012). "A claim is indefinite only when it is not amenable to construction or insolubly ambiguous." Biosig Instruments, Inc. v. Nautilus, Inc., 715 F.3d 891, 898 (Fed.Cir.2013). To prove indefiniteness, "an accused infringer must demonstrate by clear and convincing evidence that one skilled in the relevant art could not discern the boundaries of the claim based on the claim language, the specification, the prosecution history, and the knowledge in the relevant art." Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355, 1366 (Fed.Cir.2011). Indefiniteness is a question of law that we review de novo. Id. at 1365-66.
Appellants argue that the term "molecular weight" renders all of the asserted claims indefinite because it can refer to different measures, including M
Appellants also contend that their indefiniteness arguments apply equally to Group I and Group II claims. They argue that even Group II claims, which refer to a molecular weight range, "necessarily refer to a copolymer1 percentage above or below a certain average molecular weight." Sandoz Reply Br. 17. Appellants contend that, because all of the claims recite "molecular weight," they must be indefinite.
Teva counters that the prosecution history clarifies that "molecular weight" should be construed as M
Teva also contends that the specification resolves any ambiguity in the meaning of "molecular weight." Teva contends that the specification's reference to the Size Exclusion Chromatography (SEC) method indicates that "molecular weight" means M
Finally, Teva contends that Group II claims refer to exact molecular weight values and are therefore not ambiguous. It argues that Group II claims recite percentages of molecules in a copolymer-1 sample that fall within a specified molecular weight range, not average values.
During prosecution of the '539 patent, the Examiner rejected pending claims as indefinite, stating that "the term `average molecular weight' ... is indefinite since its method of measurement is not specified, i.e. [M
The specification does not resolve the ambiguity. Teva's expert, Dr. Gregory Grant, testified that after examining the curve depicted in Figure 1 and the accompanying legend, a skilled artisan would know that the claim terms "molecular weight" and "average molecular weight" denote M
On de novo review of the district court's indefiniteness holding, we conclude that Dr. Grant's testimony does not save Group I claims from indefiniteness. As Dr. Grant himself opined, SEC does not exclusively provide M
Group II claims, by contrast, do not recite average molecular weight values. Instead of describing copolymer-1 in terms of a statistical measure, such as M
A patent's specification must describe the invention and "the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains ... to make and use the same." 35 U.S.C. § 112(a). "To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation." MagSil Corp. v. Hitachi Global Storage Techs., Inc., 687 F.3d 1377, 1380 (Fed.Cir. 2012) (internal quotation marks omitted). Enablement is a question of law that we review without deference, based on underlying factual inquiries that we review for clear error after a bench trial. Cephalon, Inc. v. Watson Pharm., Inc., 707 F.3d 1330, 1336 (Fed.Cir.2013).
The district court held that Appellants failed to prove that the asserted claims are not enabled for making copolymer-1 at the claimed molecular weight because a person of skill in the art would be able to measure it using either of two known calibration methods, "self-standards" or "universal calibration." See Opinion, 876 F.Supp.2d at 382-99. The court determined that polymer literature at the time of filing described both methods in detail, and that those methods could be adapted to copolymer-1. The court also found that Teva's own extensive post-filing experimentation with measurement methods did not conclusively
Appellants argue that the district court erred in its enablement analysis. They contend that the specification states only that the SEC column should be "calibrated" and does not disclose which calibration standards should be used to measure the molecular weight. '808 patent, col. 3 ll. 6-8. Appellants argue that general SEC calibration methods do not readily apply because copolymer-1 is complex and exhibits unpredictable behavior. They further point to expert testimony that the commercially available standards that a skilled artisan would have been most likely to pick are in fact unreliable for measuring the molecular weight of copolymer-1.
Appellants also argue that the evidence of Teva's own difficulties with identifying appropriate calibration methods, which they contend the district court disregarded, confirms that the claims are not enabled. Appellants contend that Teva's various internal documents show the allegedly challenging development of calibration standards for measuring the molecular weight of copolymer-1, and point out that Teva deleted references to the standards from the patent application before filing. They argue that Teva's problems with molecular weight measurements continued after filing, noting that Teva switched calibration standards during the FDA approval process. Appellants thus contend that the asserted claims are not enabled because the specification does not teach which standards a skilled artisan must use to calibrate copolymer-1 molecular weight measurements.
We perceive no clear error in the fact findings on which the district court based its enablement conclusion. Dr. Grant testified at length that it would have been routine for a skilled artisan to measure the molecular weight of copolymer-1. See, e.g., J.A. 19671, 20474, 20752-54. He explained that, by calibrating the SEC column mentioned in the specification using methods that were well known at the time of filing, a skilled artisan could confirm the synthesis of copolymer-1 within the claimed molecular weight range. Id. The district court weighed this testimony against that of Appellants' experts and found it to be more convincing. See, e.g., Opinion, 876 F.Supp.2d at 398 (Appellants' expert "failed to address the extensive literature that existed [at the time of filing] regarding SEC, self-standards, and universal calibration."); see also id. at 392. We thus agree with Teva that the district court did not err in concluding that utilizing the calibration methods discussed by Dr. Grant would not require undue experimentation.
Appellants' arguments relating to Teva's own alleged calibration struggles also fail to demonstrate that the district court committed a reversible error. Appellants' assertion that the district court ignored Teva's internal experimentation is simply inaccurate. See id. at 391. Moreover, Appellants point to no evidence that undermines the district court's understanding that "it is entirely plausible that Teva experimented with different methods to deal with regulatory and other scale-up issues, rather than to correct faulty measurements." Id.; see also Edwards Lifesciences AG v. CoreValve, Inc., 699 F.3d 1305, 1309-10 (Fed.Cir.2012) (explaining that failure to enable a commercial embodiment does not demonstrate nonenablement under 35 U.S.C. § 112(a)). Nor do Appellants adequately explain why the claimed invention cannot be practiced without the calibration method that Teva deleted from its draft patent application.
A patent claim is invalid under 35 U.S.C. § 103 "if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains." "Obviousness ... is a legal conclusion based on underlying facts." Allergan, Inc. v. Sandoz Inc., ___ F.3d ___, 2013 WL 1810852, at *4 (Fed.Cir. May 1, 2013). "The underlying factual considerations in an obviousness analysis include the scope and content of the prior art, the differences between the prior art and the claimed invention, the level of ordinary skill in the art, and any relevant secondary considerations," which include "commercial success, long-left but unsolved needs, failure of others, and unexpected results." Id. (citations omitted).
The district court held that the asserted claims would not have been obvious in view of copolymer-1 compounds with a molecular weight higher than 10 kDa disclosed in U.S. Patent No. 3,849,550 (Teitelbaum) and other prior art references. Opinion, 876 F.Supp.2d at 401-19. It found that Teitelbaum disclosed a preference for copolymer-1 compositions having molecular weights of 18-20 kDa and greater, and that other references explicitly taught away from the claimed lower molecular weight copolymer-1. The court also determined that various secondary considerations supported the conclusion of nonobviousness.
Appellants argue that the asserted claims would have been obvious because the claimed copolymer-1 differs from known copolymer-1 by only one kilodalton unit and behaves similarly to the prior art material. Specifically, they contend that there is no evidence that copolymer-1 with a molecular weight less than 10 kDa exhibits an improved toxicity profile over the prior art copolymer-1. Appellants also dispute the district court's conclusion that the prior art taught away from the claimed invention. They acknowledge that one paragraph in a 1974 prior art reference stated that copolymer-1 with a molecular weight lower than 17 kDa was ineffective for treating multiple sclerosis. See J.A. 49058-59. But they counter that more recent art taught that copolymer-1 of lower molecular weight yielded promising results in human trials. See J.A. 36696-702. With regard to secondary considerations, Appellants urge that Teva failed to prove a nexus between lower molecular weight and Copaxone®'s commercial success. They further contend that there was no long-felt need for the claimed material because higher molecular weight copolymer-1 was known to be effective.
We see no error in the district court's obviousness analysis. The court did not clearly err when it found that the prior art expressed a preference for higher molecular weight copolymer-1, and therefore taught away from the claimed invention. See, e.g., Teitelbaum, col. 1 ll. 61-62, col. 2 ll. 19-32; see also J.A. 20391-93, 49058-59. The court also did not clearly err in the fact findings relevant to secondary considerations, which further support the conclusion of nonobviousness. For example, the court found that "Copaxone® is coextensive with the asserted claims," Opinion, 876 F.Supp.2d at 406, triggering a presumption of a nexus between the drug's commercial success and the claimed invention, see Brown & Williamson Tobacco Corp. v. Philip Morris, Inc., 229 F.3d 1120, 1130 (Fed.Cir.2000). Because Copaxone®'s commercial success is undisputed and Appellants have not rebutted the
Claim construction is an issue of law that we review de novo. Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1454-55 (Fed.Cir.1998) (en banc). In construing a claim term, we look at the term's plain meaning. Phillips v. AWH Corp., 415 F.3d 1303, 1313 (Fed.Cir.2005) (en banc). "There are only two exceptions to this general rule: 1) when a patentee sets out a definition and acts as his own lexicographer, or 2) when the patentee disavows the full scope of a claim term either in the specification or during prosecution." Thorner v. Sony Computer Entm't Am., LLC, 669 F.3d 1362, 1365 (Fed.Cir.2012). In order for the doctrine of prosecution disclaimer to apply, a statement in prosecution must constitute a clear and unmistakable disclaimer of claim scope. Omega Eng'g, Inc. v. Raytek Corp., 334 F.3d 1314, 1326 (Fed.Cir.2003). Infringement is a question of fact reviewed for clear error after a bench trial. Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286, 1289 (Fed.Cir. 2006).
The district court construed "copolymer-1" to mean "a mixture of polypeptides composed of alanine, glutamic acid, lysine, and tyrosine in a molar ratio of approximately 6:2:5:1." Markman Order, 810 F.Supp.2d at 585; see '808 patent, col. 1 ll. 32-43. This construction is not in dispute. The court explained after trial that, in order to facilitate a comparison with the accused products, it converted the 6:2:5:1 ratio into percentages (42.9% alanine, 14.3% glutamic acid, 35.7% lysine, and 7.1% tyrosine). Opinion, 876 F.Supp.2d at 336, 339-40. Based on various examples of copolymer-1 disclosed in the references cited in the specification, the court determined that an accused product meets the "approximately 6:2:5:1" limitation as long as its amino acid composition does not vary from the "ideal" percentages by an aggregate of more than 12%. Id. at 340. The court found that the Mylan accused product and the Sandoz accused product differ from the "ideal" percentages by an aggregate of 4.4% and 4.5% respectively, and thus infringe literally. Id. at 335-44, 356-63. The court also found that Mylan and Sandoz infringe under the doctrine of equivalents because the overall differences between the amino acid amounts in the claims and the accused products are insubstantial. Id. at 345-49, 358.
The parties dispute whether the district court's consideration of the percentages in conjunction with its consideration of the "approximately 6:2:5:1" limitation constitutes a "derivative" claim construction or a part of its infringement analysis. The former is a question of law; the latter is a question of fact. We hold that whether the amino acid percentages in the accused products meet the "approximately 6:2:5:1" limitation is a part of the district court's infringement analysis. Thus, we review the district court's conclusions for clear error.
Appellants argue that the district court erred in its analysis of "approximately 6:2:5:1." They contend that the 6:2:5:1 ratio captures relative proportions of the four amino acids in copolymer-1 to one another. Appellants argue that the court "eviscerated" these relationships by analyzing "approximately 6:2:5:1" in terms of an aggregate amount of percent variation in the amino acid content. Mylan Br. 30. Appellants urge that examples of copolymer-1 in the references cited in the specification
Appellants point out that their products contain the four amino acids in the ratios 4.6: 1.6: 3.7: 1.0 (Mylan product) and 4.6: 1.5: 3.7: 1.0 (Sandoz product). They argue that the accused products do not literally infringe the asserted claims because, for example, the ratio of lysine to tyrosine, 3.7: 1, deviates by more than 16% from the "ideal" ratio of 5:1. Appellants further contend that the district court erred in its finding of infringement under the doctrine of equivalents because its analysis vitiated the "6:2:5:1" requirement.
Teva counters that the district court rightly decided, based on the intrinsic record and expert testimony, that "approximately 6:2:5:1" covers compositions that differ from the "ideal" percentages by an aggregate of at most 12%. Teva argues that Appellants improperly seek to limit the scope of the claims to prior art examples of copolymer-1. It also contends that Appellants fail to adequately explain why the district court's analysis should have focused on the relative ratios of the four amino acids to one another rather than their proportions relative to the whole.
Teva further contends that Appellants perform a "mathematical sleight of hand" by normalizing the ratio relative to tyrosine, the least abundant amino acid in copolymer-1. Teva Br. 32. Teva points out that, while the 6:2:5:1 ratio sets the scale at 14 (= 6 + 2 + 5 + 1), Appellant Mylan's expression of the ratio in its product bases the scale on the incommensurate value of 10.9 (= 4.6 + 1.5 + 3.7 + 1.0).
We agree with Teva that the district court did not clearly err in concluding that the accused products literally infringe the asserted claims. We see no basis for overturning the district court's finding that the 6:2:5:1 ratio must be converted to percentages to ensure a comparison on the same scale with the amino acid percentages in the accused products. That comparison reveals that, in the aggregate, the four percentages in Mylan's product (42.7%, 14.4%, 33.6%, and 9.2%) differ from the "ideal" percentages (42.9%, 14.3%, 35.7%, and 7.1%) by only 4.5%.
The district court did not clearly err in determining that these small differences from the "ideal" percentages mean that the accused products literally infringe. The court's conclusion is supported by its findings regarding prior art examples of copolymer-1. See id. at 339-40. These
The district court also rejected Appellants' argument that Teva disclaimed copolymer-1 compositions having M
During prosecution of several of the asserted patents, Teva overcame rejections based on the Teitelbaum patent by arguing that, in contrast to Teitelbaum's copolymer-1 with a "minimum molecular weight of 10 kilodaltons," the pending claims cover "copolymer-1 having a molecular weight of about 5 to 9 kilodaltons." E.g., J.A. 34747. Teitelbaum does not explain whether its references to "molecular weight" mean M
Appellants argue that Teva's statements constitute a disclaimer of copolymer-1 compositions with M
We agree with Teva that its prosecution history statements do not constitute a clear and unmistakable disclaimer. The phrase "molecular weight of 10 kilodaltons" does not expressly refer to any specific molecular weight measurement — indeed, Group I claims are indefinite due in part to the ambiguity in the meaning of "molecular weight." The connection between this statement and the article cited in Teitelbaum is too attenuated to limit the scope of the claims to copolymer-1 with M
We have considered the parties' remaining arguments and do not find them to be persuasive. We hold that the district court did not err in its conclusions that the claims are infringed, that Appellants failed to prove that the claims would have been obvious and are not enabled, and that Appellants failed to prove that Group II claims are indefinite. We also hold that the district court erred in concluding that Group I claims have not been proven indefinite. Accordingly, we affirm the district court's judgments of infringement and no invalidity with respect to Group II
No costs.