Medicines Co. v. Mylan,Inc. United States Court of Appeals of the Federal Circuit,2017 853 F.3d 1296

I.

The '727 and '343 patents are directed to pharmaceutical formulations—or “batches”—of the drug bivalirudin produced through a process that consistently minimizes impurities. Bivalirudin's pharmacological properties were known in the art, well before the filing of the patents in suit, and were covered by a patent owned by Medicines that expired in 2015, U.S. Patent No. 5,196,404.

The claimed inventions of the '727 and '343 patents are directed to minimizing impurities in batches of bivalirudin that have been compounded with a base.

II.

Medicines received approval from the Food & Drug Administration (“FDA”) to market a base-compounded bivalirudin drug product in 2000, and has sold the approved product since 2001 under the tradename ANGIOMAX^®, well before the critical date of the patents in suit. In approving ANGIOMAX^®, the FDA required Medicines to limit the level of “Asp9-bivalirudin”—an impurity generated during the compounding process that shortens bivalirudin's shelf life—to less than 1.5 percent.

Between 2001 and 2005, Medicines and its contract manufacturer, Ben Venue Laboratories (“BVL”), produced and sold numerous batches of compounded bivalirudin having Asp9 levels of less than 1.5 percent. Although the “old compounding process” used by Medicines and BVL to produce ANGIOMAX^® “resulted in variable and sometimes high levels of Asp9 impurities,” the overriding majority of these batches in fact had Asp9 levels below 0.6 percent (the level specified in the asserted claims). See Medicines Co. v. Mylan Inc., 72 F.Supp.3d 837, 850 (N.D. Ill. 2014).

In 2005 and 2006, however, Medicines produced two batches of ANGIOMAX^® with Asp9 levels above the 1.5 percent limit specified by the FDA. After failing to solve the problem of inconsistent batches internally, Medicines retained a consultant, Dr. Gary Musso, who together with Dr. Gopal Krishna, an employee of Medicines at the time, identified the compounding process used by BVL as the source of the problem. Drs. Krishna and Musso are the named co-inventors of the '727 and '343 patents.

The process of compounding bivalirudin generally involves three steps: (1) forming a bivalirudin solution by dissolving the drug in an aqueous solution; (2) mixing the bivalirudin solution with a pH-adjusting solution containing a base; and (3) removing solvents to yield the final compounded drug product. The '727 and '343 patents explain that in mixing the pH-adjusting solution into the bivalirudin solution, “concentrated sites in the compounding solution that have much higher pH levels” are formed. These localized “hot spots” catalyzed the degradation of bivalirudin to Asp9-bivalirudin, resulting in undesirable high levels of the impurity in some instances.

Based on this principle, Drs. Krishna and Musso developed an improved, “efficient mixing” process for mixing the pH-adjusting solution with the bivalirudin solution that minimized the formation of these hotspots. This improved “efficient mixing” process resulted in batches that consistently satisfied the FDA's 1.5 percent limit on the level of Asp9-bivalirudin. Moreover, based on Drs. Krishna and Musso's experiments, Medicines discovered that the Asp9 level of batches compounded using the improved “efficient mixing” process never exceeded 0.6 percent.

This batch consistency of bivalirudin drug products compounded using “efficient mixing” is the invention disclosed and claimed by the patents in suit, which were filed on the same day and share nearly identical specifications.

Representative claim 1 of the '727 patent provides:

Representative claim 1 of the '343 patent provides:

The emphasized claim limitation is common to both patents, and we refer to this shared limitation as the “batches limitation.” The term “pharmaceutical batches” is defined by the patents as follows:

III.

Seeking to market a generic version of ANGIOMAX^®, Mylan submitted an ANDA to the FDA in 2010. In its ANDA, Mylan stated that it would limit the Asp9 level of its generic product to less than 2.0 percent. Mylan also made a paragraph IV certification under the provisions of the Hatch-Waxman Act, 21 U.S.C. § 355(j)(2)(A)(vii)(IV), asserting that its product would not infringe the '727 and '343 patents (listed in the FDA's Orange Book), or that these patents were invalid. In response, Medicines filed suit in the district court alleging infringement of the '727 and '343 patents under 35 U.S.C. § 271(e)(2). Mylan filed counterclaims seeking declaratory judgments of invalidity.

The parties disputed the meaning of two claim terms: “pharmaceutical batches” and “efficiently mixing.” With respect to “pharmaceutical batches,” the district court construed the term consistent with the definition set forth in the patents' specification to refer to either: (1) “a single batch, wherein the single batch is representative of all commercial batches … made by a compounding process, and wherein the levels of, for example, Asp9-bivalirudin, total impurities, and largest unknown impurity, and the reconstitution time represent levels for all potential batches made by said process”; or (2) “all batches prepared by a same compounding process.” The district court's construction—to which both parties ultimately consented—adds the emphasized language to the specification's definition of “batches,” thereby clarifying that the definition requires a particular process.

With respect to “efficiently mixing,” the district court relied on two examples set forth in the patents' specifications comparing Medicines' “old compounding process” using “inefficient mixing conditions” (Example 4) with the improved “efficient mixing” process developed by Drs. Krishna and Musso (Example 5).

Based on these claim constructions, the district court held on summary judgment that Mylan's ANDA did not infringe the '343 patent because the material facts concerning Mylan's compounding process were not in dispute and these “undisputed facts show[ed] that Mylan's compounding process is more inefficient than the ‘inefficient mixing’ process” of Example 4.

The district court conducted a six-day bench trial with respect to infringement and validity of the '727 patent. In its post-trial opinion, the court rejected Mylan's invalidity contentions and held that Mylan's ANDA infringed the '727 patent as a matter of law. In so holding, the district court appeared to assume that any batch with an Asp9 level below 0.6 percent would infringe the claims, even though the court had earlier determined that the prior art disclosed such batches. The court reasoned that “Mylan's ANDA specification [would] allow[ ] it to market a drug product with Asp9 … levels from 0.0%–2.0%, a range that includes the '727 patent's claimed ranges of 0.0–0.6%,” and “[w]hat a generic applicant asks for and receives approval to market, if within the scope of a valid claim, is an infringement.” The court rejected Mylan's argument that the claims of the '727 patent required “efficient mixing” and entered final judgment in favor of Medicines on all claims and counterclaims with respect to the '727 patent.

Mylan has appealed the district court's judgment of infringement of the '727 patent, and Medicines has cross-appealed the district court's summary judgment of noninfringement of the '343 patent.

I.

Mylan argues on appeal that the district court erred by declining to interpret the claims of the '727 patent to require “efficient mixing” as part of the batches limitation. We agree with Mylan that “efficient mixing” is required by the batches limitation and is therefore a limitation of both the '727 and '343 patents.

The batches limitation restricts the claims of the '727 patent (as well as the '343 patent) to “batches hav[ing] a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6%.” At the outset, we note that the batches limitation cannot be literally construed to cover individual batches of base-compounded bivalirudin having Asp9 levels that “do[ ] not exceed about 0.6%.” Such a construction would render the claims of the '727 patent invalid in light of Medicines' numerous pre-critical-date sales of ANGIOMAX^® batches having Asp9 levels below 0.6 percent.

Rather, properly construed, what the batches limitation requires is the use of a process that achieves batch consistency. This requirement follows from simply reading the batches limitation against the specification's definition of the term “batches,” as slightly revised by the district court with the agreement of the parties to clarify that the “batches” must be made by a particular compounding process. That definition limits the “batches” claimed by the patents in suit to either “all batches prepared by a same compounding process,” or “a single batch … wherein the levels of [Asp9-bivalirudin] represent levels for all potential batches made by said process.” The batches limitation therefore requires a process that achieves consistency between batches produced from the “same compounding process”—i.e., batch consistency.

The patentee, however, takes the position that the batches limitation is not necessarily limited to a compounding process that achieves batch consistency. Instead, according to Medicines, the batches limitation is satisfied whenever an accused infringer consistently produces batches having Asp9 levels below 0.6 percent, and that the claims do not require the use of a particular process that achieves batch consistency.

We disagree, for several reasons. First, adopting Medicines' interpretation of the batches limitation would yield an unworkable claim construction. Under Medicines' interpretation, proof of infringement would necessitate forward-looking assessments of whether an accused infringer's production of future or “potential” batches would be likely to generate Asp9 levels greater than “about 0.6%.” To illustrate, if a defendant using the same compounding process produced fifty batches each having an Asp9 level below 0.6 percent, each of those fifty batches would infringe. But the defendant would not know whether any of the batches infringed until all fifty batches had been produced because if even one of those batches was determined to have an Asp9 level higher than 0.6 percent, none of the batches would infringe.

Medicines' interpretation also fails to consider the specification and prosecution history of the patents in suit, both of which demonstrate that the invention disclosed by the '727 and '343 patents is a compounding process that achieves batch consistency. The specification, for example, states that “development of a compounding process for formulating bivalirudin that consistently generates formulations having low levels of impurities is desirable,” and that “the compounding process … of the invention described herein may consistently generate pharmaceutical batches … having the same characteristics.

During prosecution of the '727 patent (as well as the '343 patent), Medicines further represented that “[i]n the present invention, various embodiments relate to a less subjective and more consistent process for the mixing of the pH-adjusting solution with the bivalirudin solution.” Medicines also took pains to distinguish its pre-critical date sales of ANGIOMAX^® in observing that “[p]harmaceutical batches … as described [by the patents in suit], and as prepared by the new process of the present invention … have not been on sale/marketed/or offered for sale for more than one (1) year as of the [patents'] filing date.”

Finally, any remaining doubt that the batches limitation requires a compounding process is dispelled by Medicines' admission to the district court that “[w]hen viewed in the context of the specification, it is readily apparent that the [definition of ‘pharmaceutical batches’] refers to the compounding processes described in the patents-in-suit.”

Thus, we reject Medicines' interpretation and conclude that the batches limitation requires the use of a compounding process that achieves batch consistency. In doing so, we note that our decision does not impermissibly add a process limitation to a product claim that does not require a process because the specification's definition of “batches” by itself injects a compounding process as a limitation in the asserted claims.

The question remains as to what that compounding process entails. Based on the intrinsic evidence of the patents in suit, the answer is that the compounding process must use efficient mixing.

The patents' specification unequivocally states that the “pH-adjusting solution will be efficiently mixed,” and that “[e]fficient mixing of the pH-adjusting solution … will minimize levels of Asp9-bivalirudin.” Indeed, apart from efficient mixing, no part of the patents' disclosure teaches another method capable of producing consistent batches. In comparing the batches resulting from the “inefficient mixing conditions” of Example 4 with those from the “efficient mixing conditions” of Example 5, the specification teaches that “the characteristics of the batches generated by [Example 4] may be variable,” and that “the [efficient mixing] process demonstrated in Example 5 produced batches generally and consistently having lower levels of impurities than the [inefficient mixing] process of Example 4. Finally, the specification teaches that consistent “batch(es) may be prepared by a compounding process comprising dissolving bivalirudin in a solvent to form a bivalirudin solution, efficiently mixing a pH-adjusting solution with the bivalirudin solution to form a compounding solution, and removing solvents from the compounding solution. This compounding process includes all of the embodiments as described.” The specification therefore teaches efficient mixing as a necessary and sufficient condition for achieving batch consistency.

The prosecution history confirms that achieving batch consistency requires efficient mixing. Medicines expedited the examination of the applications giving rise to the '727 and '343 patents by filing substantially the same Petition to Make Special in both applications. In these petitions, Medicines explained the problem of high Asp9 levels of batches from its “old compounding process” and stated that “various embodiments” of the “present invention … relate to a less subjective and more consistent process for the mixing of the pH-adjusting solution with the bivalirudin solution. This process involves efficiently mixing the pH-adjusting solution and the dissolved bivalirudin solution, which is not performed in the Applicants' prior compounding process.”

II.

The next question is what is meant by “efficient mixing.” Medicines argues that the patents' common specification defines “efficient mixing” as “mixing [that] is characterized by minimizing levels of Asp9-bivalirudin in the compounding solution,” i.e., below 0.6 percent Asp9-bivalirudin in the intermediate solution. Medicines argues that this definition is controlling. We disagree. Although this statement is taken verbatim from the specification, it does not purport to be definitional because it does not accord with the linguistic formula used by the patentee to signal the designation of other defined terms—including “batches.” As the district court observed, in defining terms, “the patentees use[d] a similar format: the defined term in quotation marks, followed by the terms ‘refers to’ or ‘as defined herein.’” Because it departs from this format, the statement Medicines relies on lacks the clear expression of intent necessary for a patentee to act as its own lexicographer.

More importantly, Medicines' construction is problematic because it amounts to a mere recitation of the results obtained from “efficient mixing” rather than a definition of what the efficient mixing process is. Before the district court, Medicines conceded that its proposed definition construes that term functionally—i.e., by its intended result.

Although functional limitations in patent claims are not per se objectionable even when the means-plus-function format is not invoked, they cannot be “so broad that [they] cause[ ] the claim to have a potential scope of protection beyond that which is justified by the specification disclosure.” In re Swinehart, 439 F.2d 210, 213 (C.C.P.A. 1971). Here, Medicines' construction would expand the scope of “efficient mixing” to cover any way of mixing that achieves a compounding solution having an Asp9 level of less than 0.6 percent. The patentee's construction of “efficient mixing” thus attempts to claim all solutions to the identified “impurities” problem, without describing the entire range of solutions to that problem. Medicines' construction is therefore not permissible. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1352–53 (Fed. Cir. 2010) (en banc) Rather, efficient mixing must be defined in terms of the particular process or processes identified in the specification.

There is no contention that “efficient mixing” carries an accepted meaning to one of ordinary skill in the art. We therefore turn to the remainder of the specification, “the single best guide to the meaning of a disputed term” and “a concordance for the claims” to determine the process of efficient mixing. Phillips, 415 F.3d at 1315. The specification's detailed description teaches that “[e]fficient mixing … may be achieved through various methods. One such method may be to add … the pH-adjusting solution and bivalirudin solution portion-wise.” “Efficient mixing may also be achieved by adding the pH-adjusting solution to the bivalirudin solution at a constant rate … [or] at [a] variable rate. … ” “Furthermore, efficient mixing may be achieved through the use of one or more mixing devices … [such as] a paddle mixer, magnetic stirrer, shaker, re-circulating pump, homogenizer, and any combination thereof. The mixing rate of … a paddle mixer may be between about 100 rpm and 1000 rpm … The mixing rate for … a homogenizer (i.e., high shear mixing) may be between about 300 and about 6000 rpm … The mixing device may mix continuously … or at specific periods of time.” “Moreover, efficient mixing may be achieved through adding the pH-adjusting solution to specific sites within the bivalirudin solution … In cases wherein a mixing device is used, the pH-adjusting solution may be added to the site of the mixing device. … ”

In our view, these portions of the specification's detailed description of efficient mixing are “vague and unhelpful.” Rather than teaching what efficiently mixing is, the detailed description provides a laundry list of mixing techniques that individually (or in combination) may (or may not) constitute efficient mixing. Thus, unsurprisingly, neither the district court nor the parties relied on this portion of the specification to ascertain the meaning of “efficient mixing.”

Apart from the detailed description, two embodiments disclosed by the specification—Examples 4 and 5—clearly state what efficient mixing is and is not.

Example 4 describes “inefficient mixing”:

Example 5 describes “efficient mixing”:

The district court relied on the “inefficient mixing conditions” of Example 4 to construe “efficient mixing” as “not using inefficient mixing conditions such as described in Example 4.” On appeal, Medicines repeatedly criticizes the court's negative construction as failing to define what “efficient mixing” is, as opposed to what it is not. Although there is no per se rule against negative constructions. Medicines' argument carries some force. The logic of the argument suggests that that we should look to the specification's only clear delineation of what “efficient mixing” is—Example 5.

Critically, Medicines relied on the mixing parameters of Example 5 to overcome prior art cited during prosecution and did not cite any other examples of efficient mixing—including the generic teachings of the detailed description. In response to an anticipation rejection based on inherency, Medicines argued that the properties of the batches obtained from the mixing conditions of Example 5 were not “inherent … but rather [were] influenced by the process used to generate the product.” Medicines emphasized that although Example 4 used “two paddle mixers located at the top and bottom of the bivalirudin solution” and “added … the bivalirudin solution either all at once, or rapidly in multiple portions,” “the batches of Example 5 were prepared by a different protocol” in which “the pH-adjusting solution was added to the bivalirudin solution at a controlled rate of 2L/min using a peristaltic pump,” and that “[a] homogenizer was used to provide a high shear mixing environment (between about 1000 rpm and 1300 rpm) within the bivalirudin solution as the pH-adjusting solution was added.”

We conclude that one of ordinary skill in the art would rely on Example 5 to ascertain the metes and bounds of “efficiently mixing.” As the only embodiment of efficient mixing, Example 5 is “highly indicative of the scope of the claims.” Example 5, however, is not merely the only disclosed embodiment of efficient mixing—it is the only description of efficient mixing in the patents in suit that casts light on what efficient mixing is and that enables one of ordinary skill in the art to achieve the objects of the claimed invention. Although the specification provides that Example 5 is “non-limiting,” no other part of the patents' written description sufficiently teaches the affirmative steps that constitute efficient mixing. In this circumstance, we think it entirely appropriate to limit the term “efficiently mixing” to the sole portion of the specification that adequately discloses “efficient mixing” to the public.

We therefore construe the “efficient mixing” required by the patents in suit to require using the efficient mixing conditions of Example 5.

III.

The net effect of our claim construction is that to infringe either the '727 patent or the '343 patent, infringing batches must be compounded using a process that employs the efficient mixing conditions of Example 5. Under this claim construction, Mylan's ANDA does not infringe the asserted claims since is undisputed that, for example, Mylan does not use multiple mixing devices as required by Example 5.