On Jan 11, 2019, Federal Circuit affirmed PTAB’s decision
of upholding the compound patent on Pfizer Inc.’s Toviaz® drug in an IPR challenge
from Amerigen Pharmaceuticals Ltd.
UCB Pharma owns
U.S.
Patent 6,858,650 (expiring on 07/03/2022) patent, which covers certain
chemical derivatives of 3,3- diphenylpropylamines, including a compound called
fesoterodine. Fesoterodine is an antimuscarinic drug marketed as Toviaz® to
treat urinary incontinence. Fesoterodine is a prodrug of the active compound
5-hydroxymethyl tolterodine ("5-HMT"). 5-HMT is a metabolite of the
compound tolterodine, an older antimusarinic drug sold under the trade name
Detrol® to treat overactive bladder. Fesoterodine differ s from 5- HMT at the
2-position : 5-HMT has a hydroxy group, while fesoterodine has an isobutyryl
ester. The issue before federal circuit was whether it would have been obvious
to modify the 2-position hydroxy group of 5-HMT to an alkyl ester of six
carbons or less as in fesoterodine.
Fesoterodine 5-hydroxymethyl tolterodine
("5-HMT")
Mylan Pharmaceuticals Inc. petitioned for IPR of the ’650
patent, and the Board instituted review of claims 1–5 and 21–24 on two grounds:
(1) obviousness over the Detrol Label, Postlind, Bundgaard, Bundgaard PCT, and
Berge; and (2) obviousness over Brynne, Bundgaard, Bundgaard PCT, and
Johansson. The references fall into three general categories. First, the
Detrol Label, Postlind, and Brynne discuss tolterodine and its metabolism
and pharmacokinetics. Second, Bundgaard and Bundgaard PCT focus on prodrug
design principles. Third, Berge and Johansson relate to pharmaceutical
salts. After institution, Amerigen and two other companies were joined as
parties to the proceeding. In its obviousness analysis, the Board accepted that
a person of ordinary skill would have chosen 5-HMT as a lead compound for
development in order to reduce the number of potential metabolic steps and to
avoid CYP2D6-related drug-drug interactions. However, after considering expert
testimony from both the petitioners and UCB, the Board found that a person of
ordinary skill would not have been motivated to modify 5-HMT to make a prodrug
by replacing the 2- position hydroxy group with an alkyl ester of six or fewer
carbons. Specifically, the Board found that a person of ordinary skill would
not have been motivated to modify 5-HMT to improve its bioavailability.
Petitioners’ expert, Dr. Patterson, testified that 5-HMT was insufficiently
lipophilic because of its two hydroxy groups, and that its lipophilicity would
cause bioavailability problems. UCB responded that no prior art reference
suggested that 5-HMT would not be well-absorbed, and that the lipophilicity of
5-HMT relative to tolterodine, a known, well absorbed drug, did not show that
5-HMT had a bioavailability problem. Furthermore, UCB’s expert, Dr. Roush,
conducted an analysis of 5-HMT using the “Rule of 5” discussed in a research
article on drug delivery by Lipinski and concluded that none of them indicated
that 5-HMT had a bioavailability problem. Dr. Patterson did not rebut this
analysis. The Board thus credited Dr. Roush and determined that a person of
ordinary skill would not have been motivated to modify 5-HMT because of
bioavailability concerns.
Next, Board said that designing a prodrug was a complex
endeavor, as toxicity, bioavailability, and other drug characteristics must be
monitored for two compounds rather than just one. The Board also found that
Bundgaard defined the prodrug form of a compound as inactive, but the
petitioners did not demonstrate that esters of 5-HMT would be inactive.
Moreover, the petitioners did not point to any prodrugs analogous to
fesoterodine, for example, prodrugs in the same chemical class, with the same
mechanism of action, or in the same field of treatment. The Board thus found
that a person of ordinary skill would not have been motivated to develop a
prodrug of 5-HMT. Even assuming that a person of ordinary skill would have
been motivated to modify 5-HMT, the Board found that producing the specific
claimed compounds would not have been a matter of routine optimization.
Considering competing expert testimony, the Board determined that there were
many possible molecular modifications of 5-HMT consistent with a prodrug
design. For example, Bundgaard explained that diesters could be used in a
prodrug. The Board credited Dr. Roush’s testimony that a person of ordinary
skill would have considered esterifying the hydroxy groups at both the 2- and
5-positions. And even if a person of ordinary skill only considered
esterifying the 2-position hydroxy group, the Board credited Dr. Roush’s
testimony that there was no scientific justification to limit the ester to
six carbons or fewer. Finally, even if the universe of possible esters was
limited to alkyl esters of six carbons or fewer at the 2-position, that still
left 86 possible monoesters. The Board found that it would not have been
routine to test each one. Altogether, the Board held that the prior art did not
suggest modifying 5-HMT to make the specific claimed compounds.
Amerigen appealed. During appeal Amerigen argued that the
Board did not properly consider the evidence in support of obviousness. In
particular, Amerigen alleges that: (1) the Board misunderstood Amerigen’s
arguments concerning lipophilicity, and it should have recognized that a person
of ordinary skill would have increased the lipophilicity of 5-HMT for its own
sake; (2) the Board placed an excessive burden on Amerigen to show a motivation
to make a 5-HMT prodrug; and (3) the Board failed to recognize that arriving at
the specific claimed compounds would have been routine optimization.
On first issue, Federal Circuit held that Board correctly
found that Dr. Roush better addressed the bioavailability issue and that the
lipophilicity of 5-HMT relative to tolterodine did not demonstrate a
bioavailability problem. Federal Circuit therefore agreed with UCB that a
reasonable fact finder could have weighed Dr. Roush’s testimony over Dr.
Patterson’s & concluded that substantial evidence supports the Board’s
finding that a person of ordinary skill would not have been motivated to modify
5- HMT to increase its lipophilicity. Moreover, Amerigen does not point to a
specific error in the Board’s findings, but generally argues that “there need
not be a specific problem with bioavailability of 5-HMT for one of ordinary
skill in the art to be motivated to modify 5-HMT to further improve its
bioavailability. That may be true in some cases, but Amerigen’s conclusory
argument is not sufficient to overcome the substantial evidence to the contrary
underpinning the Board’s analysis.
On second issue, Amerigen argued that the Board imposed an
“insurmountable burden” on petitioners. But Federal Circuit said that the Board
sensibly found that a skilled artisan would “seek some degree of certainty that
a prodrug of a particular molecule would be inactive before embarking on the
process of attempting to create the prodrug,” and the petitioners failed to
provide any such certainty. This deficiency is compounded by the Board’s second
finding that the petitioners did not point to any prodrugs analogous to
5-HMT. Specifically, the Board found no evidence of prodrugs in the same
chemical class, with the same mechanism of action, or in the same field of
treatment. Therefore, Board just found that the absence of such evidence
supported UCB’s argument that at the time of the invention skilled artisans
had not considered “a prodrug of an antimuscarinic drug or any sort of
overactive bladder drug.”
On third issue, Amerigen argued that Bundgaard disclosed
esters as prototypical prodrug moieties and that modifying the 2-position alone
would have been the most obvious choice. Federal Circuit said that while the
Board considered Bundgaard’s disclosure of ester prodrugs, the Board also
observed, citing Dr. Roush, that Bundgaard taught many other prodrug
substitutions that a person of ordinary skill would have considered. Dr.
Roush testified that these additional substitutions included ethers,
carbamates, carbonates, phosphate esters, Mannich bases, and macromolecular
prodrugs. Moreover, the Board also found that a person of ordinary skill
would have considered modifications at the 5-position because the prior art did
not indicate a preference for either the 2- or 5-position, and the
inventors themselves considered modifying the 5-position. Moreover, Amerigen
has demonstrated no discernible error in the Board’s technical analysis. Thus
Federal Circuit concluded that substantial evidence supports the Board’s
determination that the prior art did not suggest making the claimed monoester
substitutions solely at the 2-position.
Altogether, the Board found that the petitioners neither
established a general motivation to make a 5-HMT prodrug nor proved that the
specific claimed modifications would have been obvious. Federal Circuit thus
concluded that Amerigen’s factual challenges to the Board’s decision are
without merit and that substantial evidence supports the Board’s findings.
Federal Circuit also touched upon issue related to standing to appeal. UCB argued that
Amerigen lacks standing to appeal from the Board’s decision because USFDA will
not approve Amerigen’s ANDA until the expiration of the ’650 patent, previously
upheld in a separate suit in the District of Delaware, in 2022. Accordingly, UCB
contends that Amerigen is foreclosed from infringing the ’650 patent, and
without a possibility of infringement there can be no justiciable dispute. But Federal
Circuit said that this case does not arise under the Hatch-Waxman Act, and the
causes of action available under that Act do not necessarily control the
standing inquiry in an appeal from an IPR decision. They do not control here
because Amerigen does not rely on a risk of infringement liability as a basis
for injury in fact; rather, it contends that the mere listing of the ’650 patent
in the Orange Book inflicts a concrete commercial injury redressable by this
court. And this court has previously recognized that listing a patent in the
Orange Book may create a cognizable injury independent of the prospect of
infringement liability. Moreover, The America Invents Act (“AIA”) and its
provisions governing IPRs do not support an analogous statutory implication.
Congress granted parties broad access to challenge patents through the IPR
procedure. Any “party dissatisfied with the final written decision of the
[Board] . . . may appeal the decision . . . .” The AIA thus provides no
basis for us to premise standing in an appeal from an IPR decision on the
availability of particular causes of action under the Hatch-Waxman Act. Rather,
an appellant must demonstrate an injury consistent with the generally
applicable requirements of Article III, i.e., a controversy “of sufficient
immediacy and reality” to warrant the requested judicial relief. Federal
Circuit further held that because Amerigen has demonstrated such a controversy
traceable to UCB’s ’650 patent and redressable by this court, it has standing
to appeal from the Board’s decision even though it may be incapable (as a
Paragraph III filer) of maintaining a parallel Hatch-Waxman suit.
