Endo Pharmaceuticals Solutions, Inc. v. Custopharm Inc. (Fed. Cir. 2018)

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Last month, in Endo Pharmaceuticals Solutions, Inc. v. Custopharm Inc., the Federal Circuit affirmed a decision by the U.S. District Court for the District of Delaware finding that Defendant-Appellant Custopharm Inc. had not proven that claim 2 of U.S. Patent No. 7,718,640 or claim 18 of U.S. Patent No. 8,338,395 were invalid as obvious under 35 U.S.C. § 103.  The '640 and '395 patents are owned by Plaintiffs-Appellees Bayer Intellectual Property GmbH and Bayer Pharma AG.

Seeking approval to market a generic version of Aveed®, a long-acting injectable testosterone replacement therapy for men suffering from physiologically low levels of testosterone, for which Plaintiff-Appellee Endo Pharmaceuticals Solutions, Inc. holds the approved New Drug Application, Paddock Laboratories, LLC (Custopharm's predecessor-in-interest) filed an Abbreviated New Drug Application (ANDA) with the FDA.  In response to that filing, Endo and Bayer brought an action for infringement of the '640 and '395 patents.  During the proceedings, Custopharm stipulated to infringement, and Endo and Bayer limited their asserted claims to claim 2 of the '640 patent and claim 18 of the '395 patent.

Claim 1 of the '640 patent recites (emphasis in the following claims from opinion):

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 %.

Asserted claim 2 of the '640 patent recites:

A composition formulated for intramuscular injection in a form for single injection according to claim 1, which contains 750 mg testosterone undecanoate.

Claim 14 of the '395 patent recites:

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 cosolvent, 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.

Asserted claim 18 of the '395 patent recites:

The method of claim 14, in which each dose contains 750 mg of TU.

As the opinion points out:

The key elements of both claims in dispute are: (1) 750 mg TU, (2) vehicle consisting of castor oil and a co-solvent (benzylbenzoate in the '640 patent) where the castor oil is 42% or less by volume, and (3) an injection schedule comprising two initial injections at an interval of four weeks followed by injections at ten week intervals ('395 patent only).

At trial, Custopharm argued that the claims-at-issue were obvious in view of three primary references:  Behre et al., 140 Eur. J. Endocrinol. 414 (1999); Nieschlag et al., 51 Clin. Endocrinol. 757 (1999); and von Eckardstein et al., 23(3) J. Androl. 419 (2002).  These references describe clinical studies using 1000 mg TU injections, wherein the administered composition comprises 250 mg/mL TU in castor oil.  The parties agreed that these references do not describe the use of a co-solvent.  Custopharm also relied on two additional references:  Pushpalatha et al., 90 Naturwissenschaften 40 (2003); and Riffkin et al., 53(8) J. Pharm. Sci. 891 (1964).  Pushpalatha describes the effects of an injectable composition of hydroxyprogesterone in a mixture of 40% castor oil and 60% benzyl benzoate (Proluton Depot), which is administered once a week to pregnant women to prevent miscarriage.  Riffkin describes the use of castor oil for the parenteral administration of steroids.

The District Court determined that Custopharm had not met its burden of proving that the claims-at-issue were obvious.  In particular, the District Court found that (a) the prior art did not disclose the 750 mg TU injection dosage, (b) Custopharm failed to show by clear and convincing evidence that a skilled artisan would have been motivated to lower the dosage of TU from 1000 mg to 750 mg due to concerns that patients were being overdosed, (c) the cited references do not inherently disclose benzyl benzoate as a co-solvent or the particular ratio of solvent to co-solvent recited in the claims-at-issue, and (d) the prior art did not disclose the specific injection schedule claimed in the '395 patent, and this specific schedule would not have been obvious to a skilled artisan.

The opinion begins its discussion by noting that:

The '640 and '395 patents disclose three primary elements in the composition and administration of Aveed®: (1) 750 mg TU in (2) a 40% castor oil and 60% benzyl benzoate vehicle (the benzyl benzoate element only applies to the '640 patent; the '395 patent only requires a cosolvent) (3) administered at an initial interval of two injections four weeks apart and maintenance injections at ten week intervals thereafter (’395 patent only).

Custopharm argued that a skilled artisan would have recognized that patients were being overdosed with 1000 mg TU injections at a concentration of 250 mg/ml, and therefore that it would have been obvious to a skilled artisan to reduce the amount of injected fluid to 3 ml while maintaining the same TU concentration for a total of 750 mg TU per injection.  Custopharm also argued that the cited references inherently describe the vehicle formulation (40% castor oil and 60% benzyl benzoate).  Cusotpharm further argued that such a dose adjustment would have made it obvious to adjust the injection interval to use a two-phase dosing regimen.  The Federal Circuit, however, disagreed with each of Custopharm's arguments, finding no clear error in the District Court's underlying factual findings.

With respect to Custopharm's argument that the District Court clearly erred in finding no motivation to lower the dose of TU from 1000 mg to 750 mg in view of the American Association of Clinical Endocrinologists (AACE) Guidelines (which Cusotpharm contended showed that patients were being overdosed in prior art clinical studies), the Federal Circuit noted that "Custopharm's overdose argument is predicated on the assumption that a skilled artisan would have applied the AACE Guidelines to the exclusion of other guidelines that existed at the time, including the FDA Guidelines."  The opinion also notes that the most prevalently applied guidelines in clinical practice and the guidelines cited in the patents-at-issue were, in fact, the FDA guidelines, which differed from the AACE guidelines.  The Federal Circuit therefore concluded that "the district court reasonably rejected Custopharm's argument that a skilled artisan would consider 1000 mg of TU to be an overdose and would have been motivated to lower the dosage to the patented 750 mg."

Custopharm next argued that the District Court erred in finding that the vehicle formulation (i.e., 40% castor oil and 60% benzyl benzoate) was not inherently described by the cited references, and that the District Court also erred in finding no motivation to combine the vehicle formulation of Proluton with the lowered dose and modified injection schedule.  Custopharm's inherency argument was based on the revelation that the actual vehicle formulation used in the cited references was that recited in the claims-at-issue.  Custopharm also contended that a skilled artisan could derive that the vehicle formulation consisted of 40% castor oil and 60% benzyl benzoate from the detailed recitation of the TU injection composition's pharmacokinetic performance in the cited references.  The Federal Circuit, however, disagreed with Custopharm's arguments, countering that Custopharm did not demonstrate that a skilled artisan could extrapolate the vehicle formulation used in the cited references from pharmacokinetic performance data.  The Federal Circuit also observed that Custopharm's expert conceded that even knowing the identity of the co-solvent would not necessarily lead a skilled artisan to the particular ratio claimed in the '650 and '395 patents.  The Court was therefore not persuaded by Custopharm's inherency argument, stating that the cases cited by Custopharm:

[W]ere about inherently present properties or characteristics for a "known" prior art product.  But here, the TU injection composition recounted in the Articles cannot be said to be "known" in the same way; the Articles failed to disclose that the composition's vehicle formulation included another, key ingredient, benzyl benzoate, let alone the ratio of benzyl benzoate to castor oil.  And there was no evidence in the record that a skilled artisan could determine the non-disclosed vehicle formulation based on the reported pharmacokinetic performance profile, or that the non-disclosed vehicle formulation was necessarily a feature of the TU injection studied in the Articles.  Under the circumstances of this case, the incomplete description of the TU injection composition elements denied skilled artisans from having access to that composition, thereby precluding use of the inherency doctrine to fill in disclosure about the product missing from the Articles.

Thus, the Court concluded that "the district court did not err in finding that Custopharm did not present clear and convincing evidence showing the 40% castor oil to 60% benzyl benzoate as claimed was necessarily present in the Articles."

As for Custopharm's argument that a skilled artisan would have been motivated to combine the vehicle formulation of Proluton with the lowered dose and modified injection schedule, the Federal Circuit again disagreed.  In particular, the Court noted that neither Pushpalatha nor Riffkin suggest the use of benzyl benzoate as a co-solvent, adding that Proluton is not a testosterone product for men, but rather is administered to pregnant women to prevent miscarriage, and further, that it is not an injectable steroid with prolonged activity.  The Federal Circuit therefore concluded that "the district court did not err in rejecting Custopharm's argument that the patented formulation for Aveed® was obvious over Proluton in view of the prior art."

The opinion turned next to Custopharm's final argument on appeal, that once a skilled artisan recognized that patients injected with 1000 mg TU were being overdosed, the specific injection schedule claimed in claim 18 of the '395 patent would be the result of routine treatment of individual patients and thus obvious.  The Federal Circuit, however, dismissed this argument as well, explaining that "this argument is predicated on Custopharm's overdose theory, which we have already rejected supra."  The Court also noted that the cited references do not explicitly teach the use of loading doses, and could be interpreted as reasonably teaching a skilled artisan to increase the intervals between doses, not to initially shorten them to four weeks and then to lengthen them to ten weeks.  The Federal Circuit therefore concluded that "the district court properly found that Custopharm failed to meet its burden of showing that a skilled artisan would combine the lowered dose with the injection schedule in the manner claimed."

Concluding that the District Court did not commit reversible error in finding that claim 2 of the '640 patent and claim 18 of the '395 patent were not proven to be obvious over the prior art, the Federal Circuit affirmed the District Court's decision that neither claim 2 of the '640 patent nor claim 18 of the '395 patent were invalid as obvious under 35 U.S.C. § 103.

Endo Pharmaceuticals Solutions, Inc. v. Custopharm Inc. (Fed. Cir. 2018)
Panel: Circuit Judges Moore, Linn, and Chen
Opinion by Circuit Judge Chen

DISCLAIMER: Because of the generality of this update, the information provided herein may not be applicable in all situations and should not be acted upon without specific legal advice based on particular situations.

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