Dexmedetomidine - USA

On Jan 22, 2018, District court of Delaware issued its ruling in Precedex (dexmedetomidine) injection product. Court found 3 patents invalid & infringed and remaining 1 patent valid & infringed by ANDA filer in Hatch-Waxman litigation.

Plaintiff (Hospira) brought this patent infringement action against Amneal Pharmaceuticals, LLC in 2015. At issue in this case are ready-to-use formulations of the compound dexmedetomidine.  Amneal filed Abbreviated New Drug Application ("ANDA") No. 207551, seeking to engage in the commercial manufacture, use, and sale of generic versions of Hospira's 4μg/mL dexmedetomidine products ("Precedex premix") in 50 mL and 100 mL glass vials. Since its FDA approval in 1999, Hospira's original Precedex product (100 μg/mL dexmedetomidine hydrochloride), also known as Precedex concentrate, has been sold in a 2 mL glass vial. Before Precedex concentrate is administered to a patient, it must be diluted to an appropriate concentration per the instructions on the Precedex concentrate label. The delay in drug administration to patients and increased risks of dosing error and contamination associated with this dilution step led Hospira to develop ready-to-use formulations of Precedex.

The Court held a bench trial from August 21-24, 2017. Plaintiff asserted that Defendant's ANDA submission constitutes infringement of claims 3 and 4 of U.S. Patent No. 8,242,158; claim 4 of U.S. Patent No. 8,338,470; claim 5 of U.S. Patent No. 8,455,527 and claim 6 of U.S. Patent No. 8,648,106. The' 158, '470, and' 106 patents each describe ready-to-use pharmaceutical compositions of dexmedetomidine or a pharmaceutically acceptable salt thereof for parenteral administration, disposed within a sealed glass container. Defendant argued that all the asserted claims are invalid as obvious, and further asserts that claim 3 of the '158 patent, claim 4 of the '470 patent, and claim 5 of the '527 patent are invalid as anticipated. Additionally, Defendant contends that claim 6 of the '106 patent is indefinite under 35 U.S.C. § 112.

OBVIOUSNESS OF THE '158, '470, AND '527 PATENTS:

Defendant argued that in view of pharmaceutical packaging knowledge in the art, the asserted claims are obvious over the prior art Precedex concentrate product in combination with the 2010 label accompanying it, or obvious over Trissel. Plaintiff responded that the asserted claims are not obvious because the prior art did not disclose a ready-to-use 4 μg/mL dexmedetomidine solution or suggest development of such a solution, the USPTO issued the patents-in-suit over the Precedex concentrate product and the accompanying label, and commercial success of the Precedex premix product supports nonobviousness.

The parties did not dispute that the Precedex concentrate product and its accompanying 2010 label taught many elements of the asserted claims. The 2010 label discloses that Precedex concentrate, once diluted to a concentration of 4 μg/mL, is to be administered intravenously to achieve patient sedation. Additionally, the label directs a POSA to prepare 50mL of a 4 μg/mL dexmedetomidine formulation by diluting the Precedex concentrate product with 0.9% sodium chloride. The parties dispute whether a POSA would have been motivated to develop a ready-to-use 4 μg/mL dexmedetomidine formulation disposed within a sealed glass container with reasonable expectation of success.

Court agreed with Defendant that a POSA would have been motivated to develop a ready-to-use dexmedetomidine formulation, and would have combined the Precedex concentrate product with the 2010 label to do so. The 2010 label is a package insert that is included with the Precedex concentrate product with the intent that it be used in combination with the product to ensure its safe and effective use. Cain's disclosure that a hospital pharmacy was routinely making available to physicians for clinical use premixed 10 mL syringes of 4 μg/mL dexmedetomidine demonstrates that at least one large medical institution (Children's Hospital of Pittsburgh) recognized the value of ready-to-use dexmedetomidine formulations. Court also held that Based on the Precedex concentrate product and the 2010 label, a POSA would have known that Precedex concentrate is stable in a sealed glass container.   Because like the inventors, a POSA would have been familiar with the general knowledge that glass was the preferred packaging for small-volume injectables. Even crediting Plaintiff's assertion that glass vials are not interchangeable (which would increase the number of potential packaging options), the prior art supports a finding that a POSA would have reasonably expected to succeed in using a sealed glass container to store a 4 μg/mL ready-to-use dexmedetomidine formulation.

With respect to commercial success, court held that although the direct competition between the invention and the prior art provides evidence of the required nexus, that evidence is weakened by the confounding factor of Plaintiff's aggressive business practices that attempted to shift demand to Plaintiff's premix product before generic concentrate product market entry. Since the '214 blocking patent renders weak any evidence of commercial success, and Plaintiff's business practices further weaken evidence of the required nexus, it concluded that considerations of commercial success do not support finding the asserted patents nonobvious.

Thus considering all of the evidence, court concluded that Defendant has proven by clear and convincing evidence that claims 3 and 4 of the '15 8 patent, claim 4 of the '4 70 patent, and claim 5 of the '527 patent are invalid as obvious.

OBVIOUSNESS OF THE '106 PATENT:

Defendant argued that claim 6 of the '106 patent is obvious because the "no more than about 2% decrease" in dexmedetomidine concentration limitation is inherent in a 4 μg/mL dexmedetomidine formulation in normal saline disposed within a sealed glass container. Plaintiff counters that Defendant's evidence is insufficient to prove inherency. Court held that Defendant offers no expert testimony regarding the scientific principles underlying its inherency argument, and relies on just two examples of stability data covering the claimed 4 μg/mL dexmedetomidine concentration. As Plaintiff notes, Defendant's expert conceded that stability data for a 4 μg/mL dexmedetomidine formulation could not be inferred from the Precedex concentrate label, and that he would have had to confirm any stability hypothesis for a 4 μg/mL dexmedetomidine formulation through testing.

The lack of evidence of degradants or oxidation of dexmedetomidine formulations increases the weight of Defendant's affirmative examples of dexmedetomidine's stability at room temperature in a sealed glass container. It does not, however, provide additional affirmative evidence to support Defendant's contention. Despite this additional support for Defendant's examples, given the absence of supporting expert testimony, court found the examples insufficiently powered to establish inherency by clear and convincing evidence.

INDEFINITENESS OF THE '106 PATENT:

The essence of Defendant's indefiniteness argument is that because the '106 patent discloses concentration measurements performed under both long-term and accelerated conditions and claim 6 does not explicitly specify which condition to use, a POSA would not know whether the "no more than about 2% decrease" limitation should be measured under long-term or accelerated conditions.

Court held that although claim 6 of the '106 patent does not explicitly specify the storage condition under which dexmedetomidine concentration should be measured, the intrinsic evidence demonstrates that the claim is not indefinite. The language of claim 6 indicates that the purpose of the claimed invention is to administer the dexmedetomidine formulation to a patient. (' 106 patent at claim 1 ("A ready to use liquid pharmaceutical composition for parenteral administration to a subject ... ")). Additionally, the detailed description of the invention makes clear that the discovery that dexmedetomidine could be stored long-term contributed to generating the invention. Considering all of the evidence, court found that the '106 patent adequately conveys to a POSA that long-term storage is the condition relevant to claim 6. Defendant has failed to provide clear and convincing evidence that claim 6 of the ' 106 patent is invalid under 3 5 U.S. C. § 112.

INFRINGEMENT OF THE '158, '470, '527, AND '106 PATENTS:

At trial the parties stipulated that Defendant infringes all limitations of the asserted claims except (1) whether Defendant's ANDA covers products disposed within a "sealed glass container," and (2) whether Defendant's ANDA products, "when stored in the glass container for at least five months[,] exhibit[] no more than about 2% decrease in the concentration of dexmedetomidine," as required by the '106 patent.

Plaintiff argued that Defendant's ANDA documents and the testimony of Plaintiff's technical expert, Dr. Linhardt, establish that Defendant's ANDA products are disposed within a "sealed glass container" under any proposed construction of the term. Defendant does not argue in post-trial briefing that its ANDA products do not meet the "sealed glass container" limitation. Therefore, Defendant has conceded that its proposed ANDA products meet this limitation.

Plaintiff asserted that Defendant infringes the "no more than about 2% decrease" limitation of claim 6 of the '106 patent under two separate theories. First, Plaintiff asserts that Defendant infringes the "no more than about 2% decrease" limitation in claim 6 of the '106 patent as a matter of law. Second, Plaintiff argues that Defendant infringes this limitation as a matter of fact.

Defendant's ANDA specification provides that Defendant's proposed ANDA products, as measured by high performance liquid chromatography ("HPLC") assay, will remain within 90-110% of their initial dexmedetomidine concentration claimed on the products' label for the 2-year shelf life also claimed on the label. According to Defendant, the 3-5% variability inherent in the HPLC measurement technique specified by its ANDA precludes its ANDA specification from directly addressing the issue of infringement because the possible 3-5% variability in any concentration measurement exceeds the 2% limit of the claimed concentration loss.

Plaintiff argued that Defendant's proposed ANDA products infringe as a matter of law because the less than or equal to 10% dexmedetomidine concentration loss in Defendant's ANDA specification directly addresses the claim limitation of "no more than about 2% decrease" in dexmedetomidine concentration after at least 5 months of storage. According to Plaintiff, since a concentration loss of no more than 10% includes a concentration loss of no more than about 2%, Defendant's proposed ANDA products infringe under Sunovion. Citing Ferring, Defendant submits that Sunovion does not apply, because the ANDA product specification does not specify a dexmedetomidine concentration for the claimed five-month measurement time point.

Court held that with the knowledge that dexmedetomidine concentrations cannot increase under the relevant storage conditions, however, it becomes clear that a decrease of not more than 10% over 24 months imposes a limitation not just for 24 months, but for all time points less than 24 months as well. The concentration decrease of no more than 10% at 5 months necessarily present in Defendant's ANDA includes the claimed concentration decrease of no more than about 2% at 5 months. Therefore, Plaintiff has proven that Defendant's proposed AND A products infringe claim 6 of the ' 106 patent as a matter of law under Sunovion.

CONCLUSION:

Defendant has proven by clear and convincing evidence that the asserted claims of the '158, '470, and '527 patents are invalid. Defendant has failed to prove by clear and convincing evidence, however, that the asserted claim of the '106 patent is invalid. Plaintiff has proven that Defendant infringes the asserted claims of the’158,’470, and’527 patents as a matter of fact and that Defendant infringes the asserted claim of the’106 patent as a matter of law.