In The Medicines Co. v. Mylan, Inc., the Federal Circuit construed composition claims of two Angiomax patents as requiring the recited “batches” to be made by a specific “efficient mixing” process illustrated in one of the examples. While doing so may have preserved the validity of the patents, it required reversal of the district court’s infringement ruling. 

The Angiomax Patents At Issue

The patents at issue were U.S. Patent No. 7,582,727 and U.S. Patent No. 7,598,343, which are Orange Book-listed patents for Angiomax® (bivalirudin), which is “used to prevent blood clotting in patients undergoing cardiac catheterization.” These are the same patents almost lost to the on-sale bar. Claim 1 of the ‘727 patent recites:

1. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier for use as an anticoagulant in a subject in need thereof, wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp(^9)-bivalirudin that does not exceed about 0.6% as measured by HPLC.

None of the claims of the ‘727 patent use product-by-process language or recite method steps. Claim 1 of the ‘343 patent recites (with emphasis added):

1. Pharmaceutical batches of a drug product comprising bivalirudin (SEQ ID NO: 1) and a pharmaceutically acceptable carrier, for use as an anticoagulant in a subject in need thereof, said batches prepared by a compounding process comprising: (i) dissolving bivalirudin in a solvent to form a first solution; (ii) efficiently mixing a pH-adjusting solution with the first solution to form a second solution, wherein the pH-adjusting solution comprises a pH-adjusting solution solvent; and (iii) removing the solvent and pH-adjusting solution solvent from the second solution; wherein the batches have a pH adjusted by a base, said pH is about 5-6 when reconstituted in an aqueous solution for injection, and wherein the batches have a maximum impurity level of Asp(^9)-bivalirudin that does not exceed about 0.6% as measured by HPLC.

(Asp(^9)-bivalirudin is an impurity having aspartic acid instead of asparagine as its 9th amino acid residue.)

According to the Federal Circuit decision, the FDA required The Medicines Company to limit the level of asp(^9)-bivalirudin to less than 1.5 percent. Prior to the invention at issue, The Medicines Company made and sold individual batches of bivalirudin with  Asp(^9)-bivalirudin levels below 0.6%, although there was batch-to-batch variability that required The Medicines Company to reject batches that did not satisfy this purity requirement. Thus, the court characterized the invention at issue as addressing the problem of batch variability.

The Federal Circuit Decision

The Federal Circuit decision was authored by Judge Dyk and joined by Judges Wallach and Hughes. The decision focuses on claim construction, and interprets the recited term “batches” as requiring the “efficient mixing” discussed in the specification, as performed in Example 5 of the patents.

Claim Construction: “Batches” = “Compounding Process”

The court focused on the recitation of “batches [that] have a maximum impurity level of Asp(^9)-bivalirudin that does not exceed about 0.6%.” The court noted that the patents define “batches” as follows:

As used here, “batch” or “pharmaceutical batch” refers to material produced by a single execution of a compounding process of various embodiments of the present invention. “Batches” or “pharmaceutical batches” as defined herein may include a single batch, wherein the single batch is representative of all commercial batches (see generally, Manual of Policies and Procedures, Center for Drug Evaluation and Research, MAPP 5225.1, Guidance on the Packaging of Test Batches at 1), and wherein the levels of, for example, Asp(^9)- bivalirudin, total impurities, and largest unknown impurity, and the reconstitution time represent levels for all potential batches made by said process. “Batches” may also include all batches prepared by a same compounding process.” ’727 patent, col. 5 ll. 24–36; ’343 patent, col. 5

The district court adopted this definition with the further clarification that the “batches” must be made “by a particular compounding process.” According to the Federal Circuit decision, The Medicines Company argued that the “batches” limitation “is satisfied whenever an accused infringer consistently produces batches having Asp(^9) levels below 0.6 percent, and that the claims do not require the use of a particular process that achieves batch consistency.” The court gave the following reasons for rejecting such a claim construction:

• “adopting Medicines’ interpretation of the batches limitation would yield an unworkable claim construction” requiring “forward-looking assessments of whether an accused infringer’s production of future … batches would be likely to generate Asp(^9) levels greater than ‘about 0.6%.'”

• “the specification and prosecution history of the patents in suit … demonstrate that the invention disclosed by the ’727 and ’343 patents is a compounding process that achieves batch consistency.”

• “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, the Federal Circuit concluded:

[W]e … 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.

Claim Construction: “Compounding Process” = “Efficient Mixing”

The decision also explains why the “compounding process” required by the claims “must use ‘efficient mixing'”:

• “[A]part from efficient mixing, no part of the patents’ disclosure teaches another method capable of producing consistent batches.”

• The patents state 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.'”

• The patents state 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.'”

• Statements in the Petitions to Make Special filed in each application “stated that ‘various embodiments’ of the ‘present invention . . . relate to a process [that] involves efficiently mixing the pH-adjusting solution and the dissolved bivalirudin solution, which is not performed in the Applicants’ prior compounding process.'”

Thus, the court read the patents as teaching “efficient mixing as a necessary and sufficient condition for achieving batch consistency.”

Claim Construction: “Efficient Mixing” = Example 5

With regard to what “efficient mixing” means, the court gave two reasons for rejecting The Medicines Company’s reliance on the following statement in the specification:

Efficient mixing of the pH-adjusting solution with the bivalirudin solution will minimize levels of Asp.sup.9-bivalirudin in the compounding solution.

First, the court noted that it did not follow the “linguistic formula” used in the rest of the specification “to signal … defined terms,” i.e., “the defined term in quotation marks, followed by the terms ‘refers to’ or ‘as defined herein.'” Second, the court found the sentence to provide “a mere recitation of the results obtained from ‘efficient mixing’ rather than a definition of what the efficient mixing process is.” Turning to the remainder of the specification, the court acknowledged teachings that “‘[e]fficient mixing . . . may be achieved through various methods,'” but found them to be “vague and unhelpful”—a “laundry list of mixing techniques that individually (or in combination) may (or may not) constitute efficient mixing.” Instead, the court focused on Examples 4 and 5, which it characterized as “clearly stat[ing] what efficient mixing is and is not.” Although the district court had construed “efficient mixing” as excludingthe inefficient mixing of Example 4, the Federal Circuit determined that “efficient mixing” is defined by the mixing of Example 5:

Example 5 … 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.

Thus, the court “construe[d] the ‘efficient mixing’ required by the patents … to require using the efficient mixing conditions of Example 5.” Since Mylan did not use that methodology, the court determined that “Mylan’s ANDA cannot infringe the asserted claims of the ’727 patent and the ’343 patent.”

Should The Product Claims Be Limited To The Exemplified Method?

Reading this decision I was struck by the contrast with the Federal Circuit’s 2013 decision in AstraZeneca LP v. Breath Limited, where the court refused to limit the recited “micronized powder composition” having a purity level of “at least 98.5%” to products sterilized by the specific method described in the specification. There, the court cited earlier decisions for the principle that a specific “method of manufacture, even when cited as advantageous, does not of itself convert product claims into claims limited to a particular process. . . . A novel product that meets the criteria of patentability is not limited to the process by which it was made.” Although the AstraZeneca decision was non-precedential, the cases it relied upon were not.