Erlotinib - USA

On Oct 04, 2019, Federal Circuit reversed PTAB’s decision & found method of treatment claims valid in Tarceva® case.

This appeal concerns OSI’s patents, U.S6,900,221. Specifically Claims 44–46 and 53 are at issue.

44. A method for the treatment of NSCLC (non small cell lung cancer), pediatric malignancies, cervical and other tumors caused or promoted by human papilloma virus (H[P]V), Barrett's esophagus (pre-malignant syndrome), or neoplastic cutaneous diseases in a mammal comprising administering to said mammal a therapeutically effective amount of a pharmaceutical composition comprised of at least one of N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, or pharmaceutically acceptable salts thereof in anhydrous or hydrate forms, and a carrier.

45. The method of claim 44, wherein the treatment further comprises a palliative or neo-adjuvant/adjuvant monotherapy.

46. The method of claim 44, wherein the treatment further comprises blocking epidermal growth factor receptors (EGFR).

53. The method of claim 44 for the treatment of non-small cell lung cancer (NSCLC).

PTAB determined that  these claims would have been obvious over Schnur in view of Gibbs or OSI’s 10-K.

Schnur – relates to compound family where erlotinib is listed as preferred compound. It also discloses that these compounds inhibits EGFR receptors & therefore useful for treatment of various cancers including lung cancer.

Gibbs  - is review article & discusse s various signaling mechanisms in the cell and how they are associated with tumor malignancy. This article discusses generally EGFR as one of the target & erlotinib is one of those compounds. Cross reference 13 refers to Moyer, which discloses how erlotinib inhibits EGFR in mouse liver tumors and in human HN5 tumors. Moyer however, does not discuss NSCLC.

OSI’s 10-K  - states that erlotinib has entered phase II trials & is potent inhibitor of EGFR receptor. OSI’s 10-K discloses no data regarding erlotinib’s effect on NSCLC.

The Board found that the disclosures in OSI’s 10-K that erlotinib targeted a variety of cancers including NSCLC, and that erlotinib had entered Phase II clinical trials, would have provided a person of ordinary skill with a reasonable expectation of success in light of Schnur’s teachings. Although nothing in the record indicated that any preclinical data related to NSCLC existed, the Board concluded that an ordinary artisan would understand from the commencement of Phase I studies that “preclinical animal efficacy data” had been submitted to the FDA. It found similarly with regard to Gibbs, focusing on Gibbs’s disclosure that “[ZD-1839 and erlotinib] appear to have good anti-cancer activity in preclinical models, with an acceptable therapeutic index particularly in patients with non-small cell lung cancer.”

Federal Circuit on appeal said that as an initial matter, in reaching its conclusion, the Board misinterpreted the asserted references to teach more than substantial evidence supports. When the references are properly read, the Board’s finding that the asserted references provide a reasonable expectation of success also is not supported by substantial evidence. To be clear, the claims require only treatment of a mammal with erlotinib—efficacy in humans is not required. But the asserted references do not disclose any data or other information about erlotinib’s efficacy in treating NSCLC. The record does not contain any clinical (human) data or preclinical (animal) data. It does not even include in vitro (test tube) data regarding erlotinib’s effect on NSCLC. At the same time, it is undisputed that NSCLC treatment was highly unpredictable with an over 99.5% rate of failure for drugs entering Phase II clinical studies. On this record, we are not persuaded that a reasonable factfinder could conclude that a person of ordinary skill would have reasonably expected success based on the combination of Schnur and Gibbs or Schnur and OSI’s 10-K.

PTAB’s reading of Gibbs is erroneous because cross reference, Moyer discloses erlotinib but it does not disclose NSCLC. Instead other cross reference, Woodburn mentions NSCLC but it does not mention erlotinib at all. Thus, Board’s finding that there is a “clear inference” in Gibbs that “erlotinib has anti-cancer activity against non-small cell lung cancer” is thus not supported by substantial evidence.

With respect to reasonable expectation of success,CAFC concluded that, properly read, these combinations do not provide substantial evidence supporting the Board’s findings of reasonable expectation of success. Schnur in view of Gibbs, the asserted references do not disclose any information about erlotinib’s efficacy in treating NSCLC in a mammal. There is no dispute that Schnur fails to disclose any in vitro or in vivo efficacy data for erlotinib for NSCLC. The lack of erlotinib-NSCLC efficacy data or other indication of success here is significant because of the highly unpredictable nature of treating NSCLC, which is illustrated by the over 99.5% failure rate of drugs entering Phase II. Moreover, EGFR is involved in many types of cancers & therefore drug’s success in treating one type of cancer does not necessarily translate to success in treating a different type of cancer.

Federal Circuit, however cautioned & said that-

“To be clear, we do not hold today that efficacy data is always required for a reasonable expectation of success. Nor are we requiring “absolute predictability of success.” We conclude only that, on these particular facts, a reasonable fact finder could not find a reasonable expectation of success. The Board’s finding is thus not supported by substantial evidence, and accordingly we reverse its obviousness determination.”