The Medicines Co. v. Hospira, Inc.

The parties failed to meet their respective burdens of proving infringement and invalidity concerning patents that claim maximum impurity levels within pharmaceutical batches.

Spring 2014

GENERICally Speaking

Case Name: The Medicines Co. v. Hospira, Inc., Civ. No. 09-750-RGA, 2014 U.S. Dist. LEXIS 43126 (D. Del. Mar. 31, 2014) (Andrews, J.)

Drug Product and Patent(s)-in-Suit: Angiomax® (bivalirudin); U.S. Patent Nos. 7,582,727 (“the ’727 patent”) and 7,598,343 (“the ’343 patent”) 

Nature of the Case and Issue(s) Presented: The Medicines Co. (“TMC”) brought suit against Hospira for infringement of the ’727 and ’343 patents as a result of Hospira’s submission of an ANDA to the FDA seeking approval to engage in the commercial manufacture, importation, use, or sale of a bivalirudin drug product for injection before the expiration of the patents-in-suit. TMC asserted that Hospira has infringed, and will continue to infringe, claims 1-3, 7-10, and 17 of the ’727 patent, and claims 1-3 and 7-11 of the ’343 patent. Hospira countered that the asserted claims are invalid under the on-sale bar of 35 U.S.C. § 102(b), are obvious under 35 U.S.C. § 103(a), and are invalid under 35 U.S.C. § 112 because the claims lack written description, are not enabled, and are indefinite. The court held a three day bench trial and ultimately found that TMC did not prove infringement by a preponderance of the evidence, and that Hospira did not prove invalidity by clear and convincing evidence.

Why Hospira Prevailed:  Hospira contended that TMC failed to prove three claim limitations: “efficient mixing,” “pharmaceutical batches,” and “a maximum impurity level of Asp9-bivalirudin that does not exceed about 0.6%.” The court found that Hospira infringed the first two terms, but not the third. The court construed “efficient mixing” to mean “[a] pH-adjusting solution is added to a bivalirudin solution slowly and in a controlled manner, and mixed together by a process comprising high shear mixing conditions (i.e., mixer speeds above 1000 rpms).” When making the Exhibit Batch, Hospira added the pH-adjusting solution in three portions; the first two portions were added rapidly with about 2-minute mixing time; and the third portion is “added gradually over a period of approximately 10 minutes.” TMC argued that because the third portion is added gradually, it met the “slowly and in a controlled manner” requirement of the claim construction. Hospira responded that the rapid addition of the first two portions entirely negated the “slowly requirement. The court found that whether one looks at the addition of the pH-adjusting solution piecemeal or as an overall process, TMC has not shown that the addition is “slowly.” The examples in the patent show a constant and metered rate of addition in a controlled manner. Hospira’s first two additions are rapid. The third addition is added gradually at the operator’s discretion, likely using a graduated cylinder—“this is not consistent with a constant and metered rate.” Moreover, Hospira did not use mixing speeds above 1000 rpm. Hospira also did not use a high shear mixer, but a convective or paddle mixer, which the patent differentiates. And because TMC’s infringement by equivalence argument “merely parrots” its literal infringement argument, the court likewise rejected it.

Concerning invalidity, Hospira argued that the asserted claims are invalid under the on-sale bar of 35 U.S.C. § 102(b), are obvious under 35 U.S.C. § 103, and are invalid under 35 U.S.C. § 112 because the claims lack written description, are not enabled, and are indefinite. Hospira argued that the invention was sold or offered for sale before the critical date because TMC paid its contract manufacturer, Ben Venue Laboratories (“Ben Venue”), to manufacture Angiomax according to the new method, and because TMC offered to sell the new Angiomax to its distributor, Integrated Commercial Solutions (“ICS”). Hospira also argued that the inventions would have been obvious to one of ordinary skill in the art at the time of the invention, that because the patents fail to disclose the impurity levels of the starting material, they fail to comply with the written description requirement, and that the term “maximum” is indefinite and not enabled

The parties describe the Ben Venue transaction very differently. Hospira describes the transaction as a sale of the validation batches. TMC describes the transaction as a contract manufacturer relationship in which Ben Venue was paid to manufacture Angiomax for TMC, but wherein title to the Angiomax always resided with TMC. The court agreed with TMC. At the time of the supposed sale, the batches manufactured by Ben Venue were not for commercial purposes, but experimental batches made in order to verify that the invention worked for its intended purpose. With regard to ICS, the court found that TMC’s agreement with ICS is a contract to enter into a contract. ICS was bound to place an order at some later date, which could be rejected by TMC. The contract deals mainly with ICS providing distribution services, not with the sale of Angiomax from TMC to ICS.

Next, Hospira asserted that claim 1 of each patent is invalid because “efficient mixing” was an obvious change to the prior art compounding process. The old compounding process for Angiomax is prior art because TMC sold bivalirudin made by that process before the critical date. It was also known in the prior art literature that a “known degradation product of bivalirudin involves the deamidation of asparagine in position 9 to [A]sp[9]-bivalirudin.” Additionally, it was known in the art that peptides such as bivalirudin are sensitive to degradation when exposed to basic conditions, and that base must be added to bivalirudin to make it safe for human injection. The court did not agree. TMC identified ten potential causes for the high Asp9-bivalirudin impurity problem: residual peroxides, residual perchlorates, speed of base addition, base viscosity, timing of the base addition, mixing speed, properties of the precipitated bivalirudin, the location of pH addition, stirrer heights and location, and batch scale. The question of residual peroxides and perchlorates as causing the impurities was quickly dismissed. But that still left eight potential variables, all of which deal with the base addition step. Second, other than a conclusory opinion that a person of ordinary skill would add base slowly and in a controlled manner, Hospira offers little support for such an assertion. Third, while Hospira argued that a person of ordinary skill in the art would not have been dissuaded from using a high shear mixer, the evidence suggests otherwise. Hospira’s expert testified that high shear mixers were routinely used with peptides similar to bivalirudin. But the inventor testified that peptides often experience foaming under vigorous mixing, and TMC’s expert testified that foaming leads to degradation. As such, Hospira had not met its burden of proving obviousness.

Finally, Hospira argued that the patents-in-suit did not satisfy the requirements of Section 112 because the specification does not disclose the amount of Asp9-bivalirudin in the API starting material. Hospira reasoned that without knowing the impurity level of the starting material, the person of ordinary skill in the art would not be able to gauge the effectiveness of the invention. Additionally, Hospira argued that claim 7 of each patent, which limited the level of D-Phe12-bivalirudin, is invalid because the claimed levels of D-Phe12-bivalirudin were known in the prior art. Again, the court disagreed. The specifications explain that the Asp9-bivalirudin levels in the final product account for the Asp9-bivalirudin levels in the API. The claimed subject matter is the finished “pharmaceutical batch,” not the starting compound. The court reasoned, “It appears that Hospira’s argument is premised on the assumption that Asp9-bivalirudin levels do not decrease during compounding, which is contrary to my factual findings.” As for the D-Phe12-bivalirudin levels, there is no requirement that every limitation be novel over the prior art. Where an independent claim is novel, the dependent claims do not have to add further novel features. Hospira next argued that the claims are not enabled because the claim term “maximum” does not reasonably apprise those skilled in the art how to determine the number of samples needed to calculate the “maximum” impurity level for a pharmaceutical batch. But the Court’s claim construction allowed for “pharmaceutical batches” to be a “single batch wherein the single batch is representative of all commercial batches and wherein the levels of impurities and reconstitution time in a single batch represent levels for all potential batches made by said process.” This claim construction allows for one batch to be representative of other batches. Where the Asp9-bivalirudin levels of a representative batch can be determined, the person of ordinary skill can determine the “maximum” impurity levels. Therefore, it is not indefinite or non-enabled.

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