Saturday, March 25, 2017

Two different PTAB IPR requests on US 8,399,514 (Tecfidera/multiple sclerosis) yield different reasoning by PTAB

Back in September 2016, IPBiz had a post PTAB declines to institute IPR against Biogen's US 8,399,514 related to the MS drug Tecfidera which, among other things, questioned the logic of PTAB in asserting that evidence of decline in MRI-measured lesions did NOT establish therapeutic effectiveness:

One notes that if a study showed a product containing a mixture of fumaric acid
esters reduced the number of gadolinium-enhancing (Gd+) lesions in
patients with RRMS , then therapeutic effectiveness
has been established. The Kappos people had already found --a therapeutically effective amount--.
Optimizing amounts when the effect is demonstrated is usually considered "obvious."
MRI measurements are standards used by the FDA to judge effectiveness for many
disease-modifying MS drugs. [note: the "gadolinum" refers to an MRI scan technique,
including paramagnetic gadolinium, which is sensitive to newly-formed lesions;
this is related to the NMR relaxation time T1, and is distinct from MRI measures
related to T2, which are not necessarily solely related to "newly-formed" lesions]

When the asserted prior art showed the drug to diminish Gd-T1 lesions, therapeutic effectiveness,
as accepted by the FDA, was established, and the PTAB reasoning was problematic.

Flash forward to a different IPR against US 8,399,514 brought by Kyle Bass and others.

From Paper 63 of IPR2015-01993:

Kappos 2006 teaches both the effectiveness of the 720 mg/day dose
and that DMF is a result-effective variable:
[DMF] significantly reduces brain lesion activity, in a
dose-dependent manner, as measured by MRI in patients with
RRMS over 24 weeks of treatment.
Ex. 1003A, p. 2 (emphasis added).

Because of the reported side-effects from the treatment of with fumarates,
(Joshi ‘999, Ex. 1030, 5:29-42; Press Release, Ex. 2057, p. 1),
those working in the art would have had sufficent reason to investigate doses between 720 mg/day and 360 mg/day
in hopes of identifying effective dose with fewer side-effects.
Those working in the art would also have had
a reasonable expectation of success in determining additional therapeutically effective doses.

Suddenly, the Kappos work is recognized to establish the therapeutic effectiveness of fumarates in treating
relapsing remitting multiple sclerosis [RRMS] BECAUSE OF the MRI results.

Biogen's [prevailing] argument to PTAB in 01993 was about "unexpected results," with therapeutic effectiveness
of the drug (at the higher does) a given fact:

Biogen argues, inter alia, that “[t]he magnitude of the clinical efficacy exhibited by administering the 480 mg/day dose was unexpected.” Biogen Res., Paper 38, pp. 43-49. (...) [Studies] establish “surprisingly—that a 480 mg/day dose of DMF proved to have similar efficacy” to the 720 mg/day taught by Kappos 2006 for almost every end point measured.

The "unexpected" aspect was established by the testimony of experts

Biogen’s evidence of unexpected results includes the testimony of Ronald A. Thisted, Ph.D (Thisted Test., Ex. 2038); Richard C. Brundage, Pharm. D., Ph.D (Brundage Test., Ex. 2042) and Richard A. Rudick, M.D. (Rudick Test., Ex. 2044).


It is known to those developing new drugs or treatments that there may be a plateau in the dose-response curve in which the increase in the dose does not significantly change the effect of the drug. ICH, p. 10. However, Drs. Thisted, Brundage and Rudick, testify to the effect that one having ordinary skill in the art would not have expected the 480 and 720 mg/day doses to be on such a plateau. All three experts testify that one skilled in the art would have expected the efficacy of 480 mg/day to be closer to that of 360 mg/day, a dose which did not have a statistically significant effect, than to 720 mg/day dose described in Kappos 2006.


Consistently with the other two experts, Dr. Rudick’s testifies that one skilled in the art would have expected the efficacy of 480 mg/day to be similar to that of 360 mg/days:

based on the Phase 2 results, a person of ordinary skill would have at most expected that the efficacy of a 480 mg/day dose would be more like that of the 360 mg/day dose (which was not effective) than that of the 720 mg/day dose (which was effective). This is because a 480 mg/day dose is closer to a 360
mg/day dose than a 720 mg/day dose.


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