On Aug. 19, 2021, Delaware Court found Imbruvica® patents valid and infringed by ANDA filer in a Hatch-Waxman litigation.

 

Plaintiffs (Pharmacyclics and Janssen Biotech) sued Defendants (Alvogen Pine Brook and Natco pharma) for infringement of four patents: US 8,008,309 (compound patent expiring on Nov. 13, 2027), US 8,754,090 (method of use patent expiring on Jun. 03, 2031), US 9,725,455 (polymorph patent expiring on Jun. 03, 2033) and US 9,655,857 (composition patent expiring on Mar. 03, 2036). All these patents are listed in Orange Book for Imbruvica® (Ibrutinib) tablets. Imbruvica® is used to treat patients with small cell lymphomas in adults. Defendants submitted ANDA with P-IV certification and thus plaintiffs initiated lawsuit. Plaintiffs asserted claim 10 of the #309 patent, claim 2 of the #090 patent, claim 5 of the #455 patent, and claims 30 and 37 of the #857 patent. Defendants stipulated that its ANDA product infringes the asserted claims of the #309 patent, #090 patent, and #455 patent. Court ruled at trial that defendants infringed the asserted claims of the #857 also. Defendants thus relied on invalidation aspect.

 

1. US 8,008,309 (compound patent):

Defendants argued that claim 10 of the #309 patent is anticipated. Claim 10 of the #309 patent claims ibrutinib compound. Defendants argued that claim 10 is invalid because it was anticipated by Pan article, which was published on Dec. 12, 2006. Filing date of #309 patent is Dec. 28, 2006 and it claims priority to 2 provisional applications filed on Sep. 22, 2006 and Oct. 6, 2006. Defendants argued that the provisional applications fail to satisfy written description and enablement requirements, and therefore, Pharmacyclics is not entitled to priority. Court, however said that both the provisional applications disclose the structure of ibrutinib and refer to it as Compound 13. POSA would have understood from the provisional applications’ disclosure of ibrutinib’s structure that the inventors possessed ibrutinib as of the date each application was filed. Moreover, the provisional applications also described biological data obtained from experiments using ibrutinib. With respect to synthesis of ibrutinib, the provisional applications disclosed a mixture of ibrutinib and ibrutinib’s chiral counterpart refereed as Compound 4. POSA would have been able to isolate ibrutinib from its chiral counterpart using known methods. The parties dispute was whether the provisional applications enabled the starting material (intermediate 2) for synthesis of Compound 4. Court said that provisional application incorporated by reference, WO 2001019829. This WO’829 explain how to synthesize Intermediate 2. Therefore, POSA would have followed WO’829’s instructions to synthesize Intermediate 2. Moreover, Pan article discloses verbatim the Compound 4 Scheme disclosed in provisional applications. Both Alvogen and Pharmacyclics also agreed that Pan enables and describes claim 10 of the #309 patent.  Therefore, provisional applications contain written descriptions as well as enablement. Thus, #309 patent is entitled to earlier priority dates and cannot be anticipated by Pan.

 

2. US 8,754,090 (method of use – Mantle cell lymphoma):

Claim 2 of the #090 patent claims a method of treating relapsed or refractory mantle cell lymphoma (MCL) with a once-daily oral dose of about 560 mg of ibrutinib. Defendants argued that claim 2 is invalid because it is not adequately described or enabled, is obvious in light of four prior art references, and constitutes obviousness-type double patenting.

With respect to written description and enablement, Court said that Example 13 of #090 patent provides a protocol to evaluate the efficacy of treating R/R MCL with a BTK inhibitor. The protocol instructs that the BTK inhibitor should be administered at a dose of 560 mg per day. POSA would have understood from reading the patent that ibrutinib is to be used as the “BTK inhibitor”. Defendants have therefore failed to establish by clear and convincing evidence that claim 2 is not adequately described or not enabled.

With respect to obviousness, Defendants argued that POSA would have been motivated to use ibrutinib to treat R/R MCL because the Phase I dose escalation study disclosed in Pollyea and the December 2009 Press Release shows “that ibrutinib is efficacious in treating R/R MCL.” But Court said that, given the unpredictable nature of oncology and the fact that only two of the study’s patients had R/R MCL, POSA would have not interpreted these results as showing that ibrutinib could be used as a treatment for R/R MCL. The mere fact that ibrutinib was being studied in a Phase I trial does not speak to ibrutinib’s efficacy. Indeed, less than five percent of oncology drugs that enter a Phase I trial ultimately receive FDA approval. Thus, reading these references would not have motivated POSA to use ibrutinib to treat R/R MCL. Additionally, none of Defendant’s references alone or in combination would have motivated POSA to use a once-daily dose of about 560 mg. Finally, safety concerns about ibrutinib would have discouraged an artisan of ordinary skill from treating R/R MCL with ibrutinib. Specifically, POSA would have been concerned that treating a patient with a BTK inhibitor could cause life-threatening infections similar to those experienced by patients suffering from Bruton’s disease who are born without BTK. Court said that as a factual matter, Defendants did not prove by clear and convincing evidence that POSA would have been motivated to combine with a reasonable expectation of success the teachings of the prior art to achieve the claimed method of treating R/R MCL with a once-daily dose of about 560 mg of ibrutinib. Secondary considerations are also against a finding of obviousness. Specially, existence of a long-felt but unmet need and commercial success were probative.

With respect to OTDP, Court said that Claim 20 of the #015 patent and claim 2 of the #090 patent differ in numerous ways. Claim 20 claims a method of treating any often lymphomas including MCL, but not R/R MCL. Claim 20 generally claims administration of “a therapeutically effective amount” of ibrutinib, whereas claim 2 recites a fixed dose of about 560 mg of ibrutinib per day. Claim 20 does not recite the spacing of the doses every other day, once-daily, twice daily, etc.), whereas claim 2 requires a single dose administered each day. Defendants argued that claim 2 of the #090 patent is invalid because “the US 8,952,015 patent describes a ‘therapeutically effective amount’ as between 1 and 1500 mg ibrutinib, which includes the ‘about 560 mg’ ibrutinib” through routine experimentation. Court said that these arguments conflate single-reference obviousness with OTDP and improperly use the #015 patent’s written description as prior art in an OTDP analysis. OTDP “is altogether a matter of what is claimed,” and Federal Circuit “precedent makes clear that the disclosure of a patent cited in support of a double patenting rejection cannot be used as though it were prior art.”

 

3. US 9,725,455 (polymorph patent):

Claim 5 of the #455 patent is directed to a crystalline form of ibrutinib with certain 2-Theta peaks. Defendants argued that claim 5 is invalid because (1) it is inherently anticipated by Pollyea and Fowler; and (2) it is obvious in light of Honigberg, Miller/Bauer, and US 7,514,444.

Court said that discovering new crystalline forms is challenging and unpredictable. Pollyea discloses interim results of a dose escalation study conducted by Pharmacyclics of PCI-32765 (Ibrutinib), an orally administered covalent inhibitor of BTK. Fowler discloses updated results of the study. But PCI-32765 does not refer to a particular form (e.g., amorphous or crystalline) of ibrutinib. It can be present in any amorphous or crystalline forms. Therefore, neither Pollyea nor Fowler inherently disclose crystalline Form A of ibrutinib.

With respect to obviousness, Court said that the #444 patent disclosed that the BTK inhibitors “may be in various forms,” including in different crystalline forms. But the patent does not disclose that any crystalline forms of ibrutinib actually exist. Honigberg disclosed ibrutinib as potent, selective and irreversible BTK inhibitor. Miller/Bauer is a general reference on polymorphism and does not mention ibrutinib. Court said that POSA would have been motivated to develop a crystalline form of ibrutinib because of advantages over amorphous form. But the inquiry is not whether an artisan would have been motivated to develop a crystalline form of ibrutinib; the inquiry is whether an artisan would have been motivated to develop crystalline ibrutinib having 2-Theta peaks as claimed. None of Defendant’s cited references disclosed a crystalline form with any of the six claimed 2-Theta peaks, let alone suggested that a crystalline form with the six claimed 2-Theta peaks would be more desirable than any other crystalline form. Thus, none of these references would have motivated an artisan to develop a crystalline form of ibrutinib with the claimed 2-Theta peaks. Moreover, as the prior art did not teach how to make any crystalline form of ibrutinib, POSA in June 2012 could not reasonably have expected to make a crystalline form of ibrutinib with the six claimed 2-Theta peaks.

 

4. US 9,655,857 (composition patent):

Claims 30 and 37 claim high-load solid tablet formulations consisting essentially of ibrutinib and other ingredients at specific weight concentrations and ranges of weight concentrations. Defendants argued that claims 30 and 37 are invalid for lack of adequate written description and for obviousness in light of the following prior art references: Imbruvica® Capsule Label; US 2013/0338172; Goldstein PCT application and the Handbook of Pharmaceutical Excipients (HPE).

With respect to written description, Court said that the written description of the patent recites verbatim the formulations claimed in claims 30 and 37, describes them as being for high-load solid tablets. It then goes on to state that in some of those embodiments, the ibrutinib dosage can be between 35 mg and 840 mg. POSA would have also understood that the formulations in the #857 patent could have been scaled to make a tablet with the full range of claimed ibrutinib amounts. Thus, the written description would have conveyed to POSA that the inventor had possession of the claimed subject matter.

With respect to obviousness, Court said that none of the prior art references teach the claimed amounts of ibrutinib; nor do any of the references disclose an ibrutinib formulation that uses polyvinylpyrrolidone. Moreover, there are differences in amounts of some excipients recited therein. Defendants argued that POSA would have pursued tablet dosage form compared to capsule because of disadvantages of formulating ibrutinib in a capsule dosage form. But Court said that Defendants have not produced any evidence of inconvenience caused by taking 4 capsules (140 mg each) to obtain the recommended 560 mg dose. Moreover, Defendants offered at trial no evidence that Imbruvica® capsules exhibited any instability or moisture loss. And the record evidence of humidity and moisture stability testing adduced by Pharmacyclics showed that the Imbruvica® capsule’s stability was not affected by heat, humidity, or moisture. Considered alone or in combination, the references do not teach the ingredients and amounts recited in claims 30 and 37. A skilled artisan who studied the references as of the priority date would have been faced with a hodgepodge of teachings of capsules and tablets, with different excipients and different amounts, and no reason to pursue a formulation with the specific ingredients recited in the asserted claims. Moreover, secondary consideration of skepticism and commercial success favor non-obviousness. Therefore, Defendants have failed to establish that claims 30 and 37 of the #857 patent are invalid as obvious under § 103.