Reliance on Inherently Disclosed Embodiments in Prior Art is Dangerous

Originally published by Haynes and Boone Benefits Group.

Andrew Cohn
Associate
Haynes and Boone, LLP

Prior art disclosures, and particularly non-patent literature, can be relied on for more than what they explicitly disclose.  For example, many prior art references may be interpreted as including inherent disclosures. However, reliance on inherent disclosures does not come without a large amount of risk, requiring a careful analysis of the inherent yet undisclosed characteristics of the reference. The strict test for inherent disclosures was apparent in Endo Pharmaceuticals Solutions, Inc. et al., v. Custopharm Inc., (Appeal Number 2017-1719, Fed. Cir. July 13, 2018) (“Endo Pharms.”), where a showing that an undisclosed (but actually used) formulation in the prior art was insufficient to find an inherent disclosure.

In Endo Pharms., Endo Pharmaceuticals Solutions, Inc., Bayer Intellectual Property GHBM, and Bayer Pharma AG(“Endo”) sued Custopharm Inc. (“Custopharm”) over infringement of U.S. Patent No. 7,718,640 (“the ‘640 patent”) and U.S. Patent No. 8,338,395 (“the ‘395 patent”). The ‘640 and ‘395 patents cover Endo’s medication Aveed®, a formulation of testosterone undecanoate (TU) that addresses shortcomings in the administration of TU to patients. The Federal Circuit noted that, prior to the 2003 priority date of the patents, administration of testosterone to treat hypogonadism suffered from three notable defects: first, injectable therapies required visiting a doctor every two to three weeks to receive an injection and topical therapies required daily application; second, the therapies required constant maintenance and monitoring to adjust administration levels based on varying testosterone levels during therapy; and third, the therapies caused instability in testosterone levels that could cause those levels to fall below the proper physiological range. Endo Pharms. at 2-3.

Aveed® provides a “long-acting injectable testosterone replacement therapy for men suffering from physiologically low levels of testosterone.” Endo Pharms. at 2. In particular, the ‘640 and ‘395 patents cover a specific vehicle formulation and administration of TU formulation, with the ‘640 patent specifically covering a formulation for administration of a 750mg dosage of 250mg/ml TU in a claimed mixture of 40-42% castor oil and 58-60% benzyl benzoate, and the ‘395 patent directed to the administration of TU in the same mixture according to a schedule that includes two initial injections followed by a “maintenance phase” of subsequent injections every ten weeks. Representative claims 1 and 2 in the ‘640 patent, and claims 14 and 18 in the ‘395 patent, are reproduced below.

Claims 1 and 2 of the ‘640 patent read:

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.

Claims 14 and 18 of the ‘395 patent read:

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.

The key elements of dispute between Endo and Custopharm were “(1) 750 mg TU, (2) vehicle consisting of castor oil and a co-solvent (benzyl – benzoate 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).” Endo Pharms. at 4-5. During trial, the sole issues became whether claim 2 of the ‘640 patent and claim 18 of the ‘395 patent were obvious. Id. at 5. In particular, three scientific articles describing “small clinical studies involving 1000 mg TU injections” were introduced as prior art. Id. at pages 5-6. The three scientific articles[1] (collectively “the Articles”) explicitly disclose a composition of 250mg/ml of TU in castor oil, but the parties agreed that the Articles did not disclose use of a co-solvent, much less benzyl benzoate. Id. at 6. However, it was later revealed in 2007 (after the 2003 priority date of the patents at issue) that the actual formulation used in the studies was 40% castor oil and 60% benzyl benzoate. Id.

Two additional prior art articles were also introduced. The first article[2] (“Pushpalatha”) describes Proluton Depot (“Proluton”), an injectable form of hydroxyprogesterone that is given to pregnant women, and that includes 40% castor oil and 60% benzyl benzoate. Endo Pharms. at 6. The second article[3] (“Riffkin”) discloses that benzyl benzoate may be used during administration of steroids to improve the solvent abilities of castor oil. Id.

In a bench trial, the District Court found that Custopharm had not met its burden of proving the claims would have been obvious because (1) Custopharm had not shown by clear and convincing evidence that a skilled artisan would lower the dosage from 1000mg to 750mg due to overdosing concerns, and (2) the Articles do not inherently disclose benzyl benzoate as a co-solvent, much less the particular ratio of castor oil to benzyl benzoate. Endo Pharms. at 6-7. The second point was concluded after the District Court noted that “inherency may only supply a missing claim limitation if the limitation at issue is the ‘natural result’ of the combination of prior art elements or a ‘necessarily present’ limitation.” Id. at 7. In particular, the District Court found that Custopharm had failed to establish that the Articles could not have used other vehicle formulations for the administration of TU. Additionally, the District Court found that the prior art did not disclose the injection schedule of the ‘395 patent, and it would not have been obvious to a skilled artisan in light of the prior art.

Custopharm appealed, and the Federal Circuit agreed with the District Court’s decision. Endo Pharms. at 7. The Federal Circuit reviewed the three previous issues: the testosterone dose, the vehicle formulation for the administration of TU, and the injection schedule. First, the Federal Circuit noted that the parties did not contest that the prior art did not disclose the 750mg dose. Id. at 8. However, the Federal Circuit did not find a motivation for one of skill in the art to lower the dose of TU in the Articles from 1000mg to 750mg, as in the ‘640 patent. Id. Custopharm argued that American Association of Clinical Endocrinologists (“AACE”) Guidelines set normal testosterone levels that would have resulted in an injection of 1000mg of TU that would have overdosed patients. Id. at 9. The Federal Circuit noted that this argument relies “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.” Id. Custopharm’s own expert edited a textbook that confirmed that the clinical practice was to use the FDA Guidelines, which would have resulted in normal to underdosing of patients when administering 1000mg TU (measured at specific test intervals after administration). Id. Custopharm argued that a “best” motivation is not required to lower the dose to 750mg, only a “suitable” motivation, but the Federal Circuit found that unpersuasive because “Custopharm needed to affirmatively demonstrate that a skilled artisan would have been motivated to lower the dose of TU despite no clear evidence of overdosing under the FDA Guidelines.” Id. at 10. Finally, the Federal Circuit saw no reason for a skilled artisan to lower the dose when a plausible alternative practice in light of the prior art would instead be to extend the injection schedule and administer TU less frequently.

The Federal Circuit next moved to the vehicle formulation for administering TU using 40% castor oil and 60% benzyl benzoate. Endo Pharms. at 11. Custopharm’s relied on two theories as to why the vehicle formulation was unpatentable in light of the prior art. First, Custopharm argued that the vehicle formulation was inherently described in the Articles because it was later revealed that the vehicle formulation was the actual formulation used by the authors of the Articles when performing clinical studies. Id. at 11-12. Second, Custopharm argued that there was a motivation to combine the Articles with Proluton to achieve a 40% castor oil and 60% benzyl benzoate formulation. Id. at 11 and 16.

Regarding inherency within prior art, the Federal Circuit did not find that the vehicle formulation was “necessarily present” in the prior art even if not explicitly disclosed. Endo Pharms. at 11-16.In particular, the Federal Circuit noted that the proper test for inherency is whether the limitation at issue is “necessarily present” in the prior art, and not that the element might be present in, or could result from, the prior art. Id. at 11-12. Although the authors of the Articles actually used the co-solvent and ratio claimed in the ‘640 patent, Custopharm’s evidence did not support that one of skill in the art would have arrived at this vehicle formulation based on the pharmacokinetic properties and results disclosed in the Articles. Id. at 12-14. For example, the Articles did not necessarily indicate the claimed formulation based on the reported results, and the prior art was replete with other co-solvents. Id. at 12-14. The Federal Circuit also failed to find a motivation to combine the described Proluton vehicle formulation in Pushpalatha with the Articles and Riffkin to arrive at the vehicle formulation of TU in the ‘640 patent. Id. at 16. The Federal Circuit agreed with the District Court that Custopharm failed to meet its burden because, “while Proluton and Riffkin do suggest the use of a co-solvent, they do not suggest that the co-solvent necessarily be benzyl benzoate as opposed to other co-solvents known in the art.” Id. at 17. Moreover, Proluton was administered to pregnant women to prevent miscarriage, which is not an injectable steroid product with prolonged activity for men. Id.

The Federal Circuit also found that the District Court did not err in rejecting Custopharm’s argument that the injection schedule would have been obvious for a skilled artisan to arrive at when adjusting the prior art for each individual patient. Endo Pharms. at 18. Custopharm’s argument relied on the overdose theory using 1000mg TU injections, which was already rejected. Id. at 19. The Articles further taught an initial injection schedule of four injections at six week intervals, and then increasing the interval between subsequent injections. Id. This did not reasonably teach shortening the schedule to four weeks and then increasing to ten weeks, as required in the ‘395 patent. Id. Moreover, Endo provided evidence that TU injections can behave in unpredictable ways so that “dose and regimen changes would require more than routine experimentation. Id. The ‘395 patent aimed to “achieve a commercially viable testosterone therapy,” and regardless of experimentation from the perspective of an individual patient, a skilled artisan would have been confronted by this same issue. Id. at 19-20. Thus, Custopharm failed to properly show that a skilled artisan would combine a lowered dose with an injection schedule based on the prior art.

Obviousness and Inherency – Unrecognized or Unappreciated but Necessarily Inherent Characteristics

Inherency may be utilized to provide a missing claim limitation only when the limitation is necessarily present or a natural result of the elements that are explicitly within the prior art. This strict test means that “probabilities or possibilities” within the prior art are insufficient to show a limitation, such as the “mere fact that a certain thing may result from a given set of circumstances.” Endo Pharms. at 12 citing In re Rijckaert, 9 F.3d 1531 at 1533-4 (Fed. Cir. (1993). Instead, the rule requires that “the limitation at issue necessarily must be present [even if unrecognized or unappreciated], or [is] the natural result of the combination of elements explicitly disclosed by the prior at.” Id. at 11-12 citing Par Pharmaceutical v. TWI Pharmaceuticals, Inc., 773 F.3d 1186 at 1196 (Fed. Cir. 2014).

The District Court found that the Articles did not bar other possible vehicle formulations from being used in the prior art formulations. Endo Pharms. at 12. The Federal Circuit agreed that Custopharm had not shown that one of skill in the art could determine that the formulation actually used during the clinical trials in the Articles would only cause the reported results disclosed in the Articles. Id. at 12-13. Nothing in the Articles showed that the pharmacokinetic performance of the administered TU vehicle could only be attributed to the vehicle formulation in the ’640 patent.  Id. Instead, Custopharm was required to show that the Articles necessarily disclosed this formulation based on the pharmacokinetic performance, and had failed to do so. Id. Moreover, the prior art utilized many different co-solvents so that a skilled artisan would not have recognized that benzyl benzoate was actually used. Id. at 13. Custopharm own expert stated that even knowing benzyl benzoate was used would not lead to the proper ratio. Id. at 13-14.

Custopharm’s cited cases include an inherent property that was actually present in a known prior art product. Endo Pharms. at 14. Custopharm’s arguments were predicated on In re Omeprazole Patent Litigation (“Omeprazole”) and In re Crish (“Crish”). Id. at 14-15 citing Omeprazole 483 F. 3d 1364 (Fed. Cir. 2007) and Crish 393 F. 3d 1253 (Fed. Cir. 2004). In Omeprazole, claim 1 at issue was invalidated by a Chong Kun Dan Corporation (CKD) patent application because claim 1 was directed to a process for making a pharmaceutical composition “which included an in situ separating layer or subcoating.” Id. at 14. In the CKD patent application, even though the application “expressly disavowed the presence of a separating layer, the record showed that the in situ separating layer was, in fact, the natural result of using the ingredients outlined in the CKD application.” Id. Thus, this in situ separating layer was inherent in the CKD patent application because “it would result each and every time a skill artisan followed the prior art process.” Id. In Crish, a prior publication disclosed the structure of a HiNV gene, as well as the approximate size of its promoter region, but not the sequence of the promoter. Id. at 14-15. However, this was enough to disclose the HiNV promoter in the claimed invention because “the record was clear that the known HiNV promoter region necessarily contained the sequence that the inventor tried to patent.” Id. That is, the prior publication necessarily disclosed that HiNV promoter region even if it was not specifically recognized by the disclosure.

Custopharm’s did not provide evidence that the vehicle formulation in the Articles would be derived by a skilled artisan based on the Articles’ disclosure. For example, the record did not present any evidence that only the claimed vehicle formulation in the ‘640 patent can be used to achieve the particular pharmacokinetic performance that was disclosed within the Articles. Endo Pharms. at 15. This is likely the main problem with Custopharm’s reliance on inherency – the evidence and experts provided by Custopharm did not provide proof that the pharmacokinetic performance was due to the actually used formulation by the Articles’ authors (i.e., the claimed formulation in the ‘640 patent). Without showing that the author’s results were due to the claimed formulation, and only due to the claimed formulation, Custopharm’s argument failed. In contrast to Custopharm’s interpretation of inherency, the lack of evidence supporting a direct and singular tie between the claimed formulation in the ‘640 patent and the reported results in the Articles ultimately doomed Custopharm.

At the outset, it is noteworthy that the vehicle formulation from the ‘640 patent was actually used during clinical testing. That means that the claimed vehicle formulation was actually present in the prior art and used to obtain those results. Of course, if the researchers had recorded the proper mixtures and combinations in their studies and research papers, there would be no question as to the explicit disclosure of the claimed limitations within the prior art. However, Custopharm failed to provide enough evidence to persuasively link the claimed formulation (although unrecognized, unappreciated, and unrecorded in the prior art) to the pharmacokinetic properties reported in the Articles. Utilizing the reported properties and results in the Articles, Custopharm could have utilized an expert, test results, or other evidence that the claimed vehicle formulation necessarily provides the results disclosed in the Articles. This may have been available since the claimed vehicle formulation was actually present in the Articles. If this was available or could have been obtained, it appears that this type of evidence would have swayed the Federal Circuit. However, without connecting the reported results of the clinical trials in the Articles to the claims of the ‘640 patent, the Federal Circuit was unwilling to find an inherent disclosure within the prior art.

Moreover, it appears that the wide number of available co-solvents further convinced the Federal Circuit that the prior art failed to teach one of skill in the art of the claimed vehicle formulation. While Proluton used a 40% castor oil and 60% benzyl benzoate combination, and Riffkin discusses use of benzyl benzoate with castor oil for the administration of steroids, the prior art included numerous other types of co-solvents. There were numerous other vehicle formulations for administration of intramuscular medications and the high degree of variance that required experimentation to arrive at appropriate vehicle delivery formulations. Further, the Federal Circuit acknowledges the disparities between the administration of TU, a steroid required by men suffering from low testosterone, and hydroxyprogesterone, which assists in preventing miscarriages, and felt that these differences would make it unlikely that one of skill in the art would apply such the formulation in administration of hydroxyprogesterone to a steroid administration. Although Riffkin suggests the benzyl benzoate and castor oil combination, it seems the Federal Circuit was unwilling to combine that with Proluton due to the difference between the drug types.

Custopharm likely believed that they had strong arguments based on the vehicle formulation being actually present when performing the clinical trials. Unfortunately, the failure to provide evidence that only the particular vehicle formulation could have resulted in the reported results in the Articles caused this argument to fail. It is interesting to consider whether it would have been important if the exemplary studies had been sold instead of merely used during clinical trials. Since these were clinical trials, the utilized formulation in the Articles is likely covered as an experimental use. However, a sale would appear to qualify as public use or on sale bar. Without this, Custopharm was forced to rely on inherency, as the clinical trials did not qualify elsewhere as prior art.

 

[1] (1) H. M. Behre et al., Intramuscular injection of testosterone undecanoate for the treatment of male hypogonadism: phase I studies , 140 Eur. J. Endocrinol. 414 (1999), (2) E. Nieschlag et al., Repeated intramuscular injections of testosterone undecanoate for substitution therapy in hypogonadal men , 51 Clin. Endocrinol. 757 (1999), and (3) S. von Eckardstein & E. Nieschlag, Treatment of Male Hypogonadism with Testosterone Undecanoate Injected at Extended Intervals of 12 Weeks: A Phase II Study , 23(3) J. Androl. 419 (2002).

[2] Pushpalatha, et al., Effect of prenatal exposure to hydroxyprogesterone on steroidgenic enzymes in male rats , 90 Naturwissenschaften 40 (2003).

[3] C. Riffkin, et al., Castor Oil as A Vehicle for Parenteral Administration of Steroid Hormones , 53(8) J. Pharm. Sci. 891 (1964).

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