Post-filing clarification of an ambiguous feature in a pre-filing reference is not sufficient to establish inherent properties of the feature in the earlier publication
| July 31, 2018
Endo Pharmaceuticals Solutions et al. v. Custopharm Inc.
July 16, 2018
Before Moore, Linn and Chen. Opinion by Chen.
Summary
Custopharm argued that Endo’s patents were invalid due to anticipation or obviousness of three features of a drug and its administration: the dosage, the content of the vehicle, and the administration schedule. The arguments regarding the dosage were rejected on the grounds that they relied on a lesser-used industry treatment guideline. The arguments regarding the vehicle were rejected on the grounds that they relied on an improper inherency position, and that it would not have been obvious to modify the vehicle in view of a reference teaching a similar vehicle in a different context. Finally, the arguments regarding the administration schedule were rejected on the grounds that they relied upon an unsupported claim construction position, as well as an improper combining of the teachings of two references.
Details
Background
Endo owns U.S. Patent Nos. 7,718,640 and 8,338, 395, which are directed to a testosterone undecanoate (TU) injection composition and method. Custopharm’s predecessor-in-interest filed an ANDA challenging the validity of the ‘640 and ‘395 patents.
Endo’s patents relate to a testosterone replacement therapy which resolves three problems previously found in the art: (1) the requirement for patients to visit the doctor every 2-3 weeks for an injection, (2) the requirement to adjust dosage or intervals of administration on a person-by-person basis and frequently monitor testosterone levels, and (3) unstable testosterone levels between treatments. Endo’s commercial product, Aveed, requires two initial treatments, after which only 5 treatments per year are needed. Aveed also works for nearly all patients, does not require the previously required personalized adjustment, and furthermore avoids fluctuations in testosterone levels. The representative claims are as follows, with key limitations bolded:
‘640 patent:
1. A composition formulated for intramuscular injection in a form for single injection which contains 250 mg/ml testosterone undecanoate in a vehicle containing a mixture of castor oil and benzyl benzoate wherein the vehicle contains castor oil in a concentration of 40 to 42 vol %.
2. A composition formulated for intramuscular injection in a form for single injection according to claim 1, which contains 750 mg testosterone undecanoate.
‘395 patent:
14. A method of treating a disease or symptom associated with deficient endogenous levels of testosterone in a man, comprising administering by intramuscular injection a composition comprising testosterone undecanoate (TU) and a vehicle consisting essentially of castor oil and a co-solvent, the castor oil being present in the vehicle at a concentration of 42 percent or less by volume, the method further comprising:
(i) an initial phase comprising 2 initial intramuscular injections of a dose of TU at an interval of 4 weeks between injections, each dose including 500 mg to 1000 mg of TU, followed by,
(ii) a maintenance phase comprising subsequent intramuscular injections of a dose of TU at an interval of 10 weeks between injections, each dose including 500 mg to 1000 mg of TU.
18. The method of claim 14, in which each dose contains 750 mg of TU.
Custopharm argued that the patents were obvious in view of the cited art, including three non-patent literature references (collectively referred to as the “Articles”). The Articles teach clinical studies using 1000 mg TU injections, at a concentration of 250 mg/ml in castor oil. Although not stated in the actual Articles, which were all published prior to the 2003 priority date, a 2007 article revealed that the vehicle used in the studies included benzyl benzoate as a co-solvent, and had a mixture of 40% castor oil and 60% benzyl benzoate. Custopharm also relied on two additional references, Pushpalatha and Riffkin. Pushpalatha describes a drug administered in a mixture of 40% castor oil and 60% benzyl benzoate. Riffkin disclosed, in the context of administration of steroids, that the combination of castor oil and benzyl benzoate improved the solvent abilities compared to castor oil alone.
The district court concluded that the prior art did not disclose the 750 mg dosage, and that it would not have been obvious to lower the dosage from 1000 mg to 750 mg. The district court also concluded that the Articles did not inherently disclose the mixture of castor oil and benzyl benzoate or the recited percentage, because other alternative vehicles could have been used. Additionally, the district court concluded that the administration schedule was not disclosed and was not obvious.
CAFC Decision
The CAFC addressed each of these points one-by-one and found that the claims are not invalid. First, as to dosage, it was agreed by both parties that the prior art does not disclose the precise dosage of 750 mg. However, Custopharm argued that this would have been obvious at least because, according to guidelines by the American Association of Clinical Endocrinologists (AACE), a dosage of 1000 mg would result in testosterone levels above the normal range.
However, the CAFC found no reason why one skilled in the art would follow the AACE guidelines, since FDA guidelines were commonly applied in clinical use. According to FDA guidelines, all but one of the patients in the study of one of the Articles would have a testosterone level in the normal range. As such, the CAFC found no reason to lower the dosage.
Additionally, the CAFC explained that Custopharm needed to demonstrate not only that the cited art does not preclude lowering the dosage, but rather that one skilled in the art would have had a motivation to lower the dosage. Finally, the CAFC stated that even if testosterone levels in patients were too high, the skilled artisan also had the option of changing the administration schedule, in addition to changing the dosage. Thus, the subject matter of the claimed dosage was not obvious.
Next, the CAFC rejected Custopharm’s arguments that the vehicle formulation was either inherent in the cited art, or would have been obvious. Custopharm argued that the formulation in the pre-2003 Articles was inherently in the claimed range based on a 2007 disclosure of the content of the formulation. The court did not agree, for several reasons.
First, the CAFC indicated that Custopharm did not show that the results in the Articles were only due to the vehicle formulation, and could not have resulted from other formulations. In putting forth this argument, Custopharm improperly shifted the burden to Endo to show that it was possible to have the same result with two different formulations.
Next, the CAFC stated that, due to many other co-solvents being in common usage, one skilled in the art would not have concluded for certain that benzyl benzoate was the co-solvent in the Articles. Further, even if the skilled artisan knew the co-solvent, they would not necessarily know the mixture. Riffkin, for example, showed a range of 50% to 98% castor oil. In dismissing Custopharm’s argument, the CAFC stressed that it has not been shown that the results of the Articles could only be obtained with the formulation of 40% castor oil and 60% benzyl benzoate.
Next, the CAFC addressed the Custopharm’s alternative argument that it would have been obvious to combine Pushpalatha with the Articles to arrive at the claimed formulation. Pushpalatha disclosed weekly administration of a steroid drug to prevent miscarriages, using a vehicle of 40% castor oil and 60% benzyl benzoate. Custopharm argued that this would have been obvious to combine this teaching with the Articles because both relate to hormones, and also because Riffkin previously disclosed such a vehicle.
However, the CAFC rejected this argument on the grounds that there is no reason in the combination of references for the co-solvent to necessarily be benzyl benzoate. Additionally, the court noted that the Articles relate to a hormone for men, while Pushpalatha relates to a hormone for women. Furthermore, the CAFC pointed out that there is no reason why one skilled in the art would apply the vehicle from a short-lived hormone treatment to a long-acting hormone treatment.
Finally, the CAFC addressed the argument that it would have been obvious to arrive at the claimed injection schedule. On this point, Custopharm’s argument was based on the idea that at least one patient in the Articles was being overdosed, and that it would have been routine to optimize the treatment for an individual patient. Custopharm relied in part on an interpretation of claim 18 as being infringed by administration to a single patient.
Custopharm pointed out that two of the Articles had a protocol that resulted in drug accumulation, thereby permitting extending the dosing interval. Custopharm argued that this suggested a two-phase dosing regimen. The first article (Nieschlag) taught four doses at a six week interval that could be extended to ten weeks, while the second article (von Eckardstein) taught an interval of up to twelve weeks. Custopharm interpreted Nieschlag as teaching a first dosing stage and von Eckardstein as teaching a second dosing phase. Since Custopharm also argued that it was obvious to reduce dosage from 1000 mg to 750 mg, Custopharm argued that it would be obvious to reduce the intervals from six weeks to four weeks and from twelve weeks to ten weeks.
However, the CAFC indicated that the Articles do not clearly teach a two stage dosing regimen. Rather, the Articles only teach increasing the intervals between doses, not to have a four week interval followed by a ten week interval. Additionally, the evidence showed that dosage and regimen changes would require more than routine experimentation due to unpredictability, because the Articles do not show a linear relationship between dose amount and TU in the body. Custopharm acknowledged this point, but argued that the claims should be interpreted from the perspective of an individual patient. However, the CAFC disagreed and stated that there was no claim construction argument in support of this position, as opposed to a population dose argument.
Thus, for the above reasons, the CAFC held that the claims were not invalid, and Custopharm’s ANDA application amounts to infringement.
Takeaway
Inherency requires than an element is necessarily present in a cited art reference. In the rare event that an ambiguous point is clarified by a later reference, this cannot be relied upon to show inherency. Rather, inherency must be taken from the point of view of the actual disclosure of a reference, and what can be gleaned from the public disclosure.
If the invalidity argument was based on a public use theory, then inherency may not have been an issue. In such a case, it is possible that the analysis would focus on what was actually in the vehicle, rather than what a public statement about the vehicle disclosed. However, it appears that the clinical trials described in the Articles were performed under a confidentiality agreement, so this theory could not be used.
