Fesoterodine – USA

On Aug. 09, 2017 Judge Sleet of District of Delaware upheld the validity of Toviaz (fesoterodine fumarate) patents challenged by Mylan.

Pfizer Inc. holds an approved New Drug Application ("NDA") No. 02-2030 for fesoterodine fumarate extended-release tablets, in 4 and 8 mg dosage strengths, which Pfizer sells under the trade name Toviaz®. Toviaz® was approved by the United States Food and Drug Administration ("FDA") in October 2008 for the treatment of overactive bladder with symptoms of urge urinary incontinence, urgency, and urinary frequency. Pursuant to 21 U.S.C. § 355(b)(l), and attendant FDA regulations, U.S. Patent Nos. 6,858,650 (the '"650 patent"), 7,384,980 (the '"980 patent"), 7,855,230 (the '"230 patent"), 7,985,772 (the "'772 patent), and 8,338,478 (the '"478 patent") (collectively, the "patents-in-suit") are listed in Orange Book (OB). Collectively, the '980, '230, '772, and '478 patents may be referred to as the "Compound Patents" & the ‘650 patent as “salt patent”.

Mylan filed Abbreviated New Drug Application No. 20-6701 to the FDA seeking approval to market a generic version of Toviaz. On December 11, 2014, Mylan sent Notice of its Paragraph IV certifications & on January 23, 2015, Plaintiffs sued Mylan for patent infringement. The court held a bench trial on January 23, January 25, and January 26, 2017. Mylan argued that all asserted claims are invalid as obvious under 35 U.S.C. § 103. Mylan stipulated to infringement on all asserted claims of all asserted patents.

During trial Mylan argued that a POSA would have found it obvious to synthesize fesoterodine as an improved overactive bladder treatment. Mylan bases its theory on the prior art molecule tolterodine and its metabolite, 5-Hydroxymethyl Tolterodine ("5-HMT"). Mylan argues a POSA would have selected 5-HMT as a lead compound for an improved overactive bladder treatment. As of the May 12, 1998 priority date, overactive bladder treatments included negative limitations such as urinary retention, dry mouth, constipation, and central nervous system effects.  According to Mylan, a POSA seeking to create an improved overactive bladder drug would have focused on antimuscarinic compounds. Both parties agree that antimuscarinics were a popular treatment for overactive bladder at that time. Oxybutynin and tolterodine were the primary antimuscarinic compounds approved to treat overactive bladder in the United States. Lead compound analysis "requires the challenger to demonstrate .. . that one of ordinary skill in the art would have had a reason to select a proposed lead compound or compounds over other compounds in the prior art." Daiichi Sankyo Co. v. Matrix Labs., Ltd, 619 F.3d 1346, 1354 (Fed. Cir. 2010).

(1) Lead compound analysis: Court said that Mylan's lead compound theory is flawed for several reasons. First, Mylan failed to justify its expert's narrow focus on tolterodine and 5-HMT. Pfizer's expert, Dr. Maag, testified that researchers eschewed nonselective antimuscarinic compounds and were actively pursuing a number of different strategies in search of improved overactive bladder treatments. In contrast, Mylan's expert, Dr. Carson, posited that 5-HMT seemed to be "at the forefront" of overactive bladder compounds, which made it prime for further investigation. Dr. Carson acknowledged that nothing in the prior art suggested administering 5-HMT to patients, which contradicts focusing on 5-HMT as a lead compound. The court finds Dr. Maag's testimony more persuasive because it is consistent with the field of overactive bladder treatment as of the priority date. The court therefore concludes that a POSA would have considered tolterodine and 5-HMT in addition to several other lead compound.

Second, even if a person of skill in the art would have focused on tolterodine and 5-HMT, tolterodine did not have problems that would have caused a POSA to develop 5-HMT. Mylan contends that the metabolism of tolterodine to arrive at 5-HMT presented a concern. In response, Pfizer argues that a POSA would not have ignored the prior art references that taught polymorphism was not a problem for tolterodine because poor and extensive metabolizers experienced nearly identical effects from the drug. Mylan's expert, Dr. Janero, supported the conclusion that there is no evidence that any POSA would have disregarded these conclusions, undermining the weight of Mylan's assertions. The court believes that a POSA would not have disregarded these conclusions. Thus, the court concludes that polymorphism would not have motivated a POSA to shift focus from tolterodine to its metabolite, 5-HMT.

Third, Mylan argues that a POSA would have focused on 5-HMT instead of tolterodine because tolterodine was associated with certain side effects not attributable to 5-HMT.  The court is not persuaded. Dr. Carson's testimony undermines the credibility of Mylan's assertions. Dr. Carson admitted that the clinical data considered tolterodine and 5-HMT together and, as a clinician, he knew of no differences between the two compounds. Moreover, Dr. Maag testified that a POSA would have expected the benefits and limitations associated with tolterodine to also be associated with 5-HMT. At minimum, given the state of the art, a POSA could not have drawn inferences about whether tolterodine or 5-HMT was driving any one of the side effects.

Finally, Mylan suggests that tolterodine's metabolism via the CYP3A4 pathway in poor metabolizers was a potential problem to solve. In light of the prior art, Mylan asserts that a POSA would have been motivated to eliminate dosing a compound such as tolterodine from the metabolic pathway responsible for delivering 5-HMTto the body. Mylan:'s own experts concede, however, that if CYP3A4 metabolism had been a real concern, a POSA would have also rejected 5-HMT since 5-HMT is also metabolized via the CYP3A4 pathway. Put simply, if 3A4 metabolism was a concern.for tolterodine, it also would have been for 5-HMT. Mylan's argument is to the contrary is unconvincing. Thus, the court rejects Mylan's arguments as to the selection of a lead compound, and concludes that Mylan has failed to meet its burden in this regard.

(2) Modification of 5-HMT:  Even accepting Mylan's selection of 5-HMT as lead compound, the court finds that Mylan has not established by clear and convincing evidence that modifying the lead to yield fesoterodine would have been obvious to a POSA. See Daiichi, 619 F.3d 1346 at1352 ("Proof of obviousness based on structural similarity requires clear and convincing evidence that a medicinal chemist of ordinary skill would have been motivated to select and then to modify a prior art compound (e.g., a lead compound) to arrive at a claimed compound with a reasonable expectation that the new compound would have similar or improved properties compared with the old"). Mylan argues that a POSA would have sought to develop a new prodrug5 of 5-HMT that would have similar absorption to tolterodine, but that had less CNS penetration, and did not exhibit variable bioavailability. 

In contrast, Pfizer offered evidence that 5-HMT's oral absorption properties were, and still are, unknown. Nonetheless, Pfizer contends that, based on 5-HMT's properties, a POSA would have expected 5-HMT to be well absorbed. Pfizer also adduced evidence that POSAs viewed prodrug design as a complex "last resort" approach to drug development. Lastly, Pfizer contends that a POSA would have first pursued non-prodrug development approaches, such as performing structural modifications to create an analog of tolterodine, or experimenting with the formulation of 5-HMT. The court agrees with Pfizer. The dearth of information about 5-HMT's properties, the inherent risk associated with prodrug development, and the existence of more straightforward optimization techniques all suggest that a prodrug approach would not have been obvious.

(3) Chemical Structure of Fesoterodine: Even accepting Mylan's proposal that it would have been obvious to create a new 5-HMT prodrug, the court does not find it would have been obvious to obtain the final chemical structure of fesoterodine. To prevail, Mylan must prove that a person of ordinary skill would have known to (1) use an ester prodrug, (2) add the substituent to only the phenolic hydroxyl, and (3) use an isobutyryl substituent, and ( 4) that a person of ordinary skill would have had a reasonable expectation of success regarding the resulting compound's properties. Mylan argues that a POSA would have chosen to develop an alkyl ester prodrug because esters were among the most commonly used prodrug moieties. Mylan's analysis is unavailing for several reasons. First, Mylan improperly narrows the field to ester prodrugs. A POSA would have considered a variety of prodrug types in the prior art. Second, while Mylan contends that a POSA would have to modify only one of the hydroxyl groups, Pfizer points out that 5-HMT contains four possible substitutions. Third, Mylan provided no evidence specifically teaching towards a phenolic isobutyryl ester of 5-HMT. Pfizer observes, however, that even limiting potential options to those presented by Mylan---esters with two to six carbons a POSA would have had over 7,000 options for modifying the 5-HMT molecule. The prior art does not provide any suggestion or teaching that the isobutyrl prodrug group would be compatible with 5-HMT, and Mylan identified no reference that disclosed an isobutyryl derivative.

Finally, the process engaged by the inventors' demonstrates the highly unpredictable nature of the prodrug development approach. The inventors prepared 20 prodrug candidates and evaluated their conversion rates and absorption rates. Pfizer submitted evidence that their experiments yielded unpredictable results. The inventors' results, and Dr. Janero's ultimate admission that prodrugs are complicated, are powerful evidence of the unpredictability inherent in prodrug design, a factor that weighs strongly against an obviousness finding. Procter & Gamble Co. v. Teva Pharm USA, Inc., 566 F.3d 989, 996 (Fed. Cir. 2009).

(4) Salt Forms of Fesoterodine: Mylan argues it would have been obvious to make salt forms of fesoterodine as claimed in the '650 patent. As fesoterodine is not prior art to the '650 patent, Mylan must prove fesoterodine would have been obvious to invalidate its claims. Mylan has failed to do so. Preparation of salt forms of a compound, like prodrugs, is a highly unpredictable exercise. The court finds that the asserted claims of the '650 patent are not obvious.

CONCLUSION: For the reasons stated above, the court concludes that none of the asserted claims of the patents-in-suit are invalid due to obviousness.