Aripiprazole Lauroxil - USA

On Aug. 29, 2017, a Court of appeal for the District of Columbia upheld the Food and Drug Administration’s approval of a competitor for a major drug Aripiprazole. The two drugs at issue in this case are antipsychotics primarily used to treat schizophrenia and bipolar disorder. The first drug, manufactured by Otsuka Pharmaceutical, is called Abilify Maintena (Aripiprazole) injection. The second, made by Alkermes, is named Aristada (Aripiprazole Lauroxil) injection.

On Aug. 22, 2014, Alkermes submitted 505 (b)(2) application for Aristada, another injectable antipsychotic. The company also sought to rely on prior studies conducted by Otsuka demonstrating the safety and efficacy of Abilify Tablets. Aristada shares certain chemical similarities with the Abilify line of products: Aristada’s active moiety, N-hydroxymethyl aripiprazole, is a “prodrug” of aripiprazole, meaning that it ultimately metabolizes into aripiprazole in the body.

When Alkermes sought FDA approval for Aristada, Otsuka opposed the application on the ground that Aristada’s approval would violate an ongoing period of marketing exclusivity enjoyed by Abilify Maintena. Otsuka emphasized that both drugs ultimately metabolize in the body into the same molecule & in light of the relationship between the two drugs, approving Aristada would infringe on Abilify Maintena’s exclusivity. The FDA rejected Otsuka’s arguments and granted approval to Aristada. The agency relied on the fact that the two products have different “active moieties”—roughly active ingredients. In approving Aristada, the FDA staked out the position that a drug’s active moiety not only determines its eligibility for marketing exclusivity, but also defines the field of drugs subject to that exclusivity. Otsuka sought judicial review, contending, among other things, that the agency’s same-moiety limitation on the scope of a drug’s marketing exclusivity conflicts with the FDCA. The district court granted summary judgment in favor of the FDA and Alkermes. The court concluded that the FDA’s same-moiety test is a reasonable construction of the statute and is consistent with the agency’s regulations.

During appeal Otsuka based its argument on “legal equivalence” theory & argued that Aristada and Abilify Maintena are legally equivalent. Aristada relied in its application on Abilify Tablets, which in turn is legally equivalent to Abilify Maintena because the two drugs share the same active moiety (aripiprazole), and also because Abilify Maintena itself relied on Abilify Tablets for approval.

Appeal court rejected Otsuka’s “legal equivalence” theory and affirmed FDA’s “same-moiety” theory. Court said that statute nowhere expressly set out any concept of legal equivalence in describing the scope of marketing exclusivity. Congress perhaps could have written a statute under which, if one drug relies on the safety or efficacy of a previously approved drug to obtain approval, the two drugs must be considered “legally equivalent” for purposes of defining the previously approved drug’s zone of exclusivity. Relying on its decision in Actavis Elizabeth LLC v. FDA, 625 F.3d 760 (D.C. Cir. 2010) which involved prodrugs (which, as noted, are drugs that eventually metabolize into a different chemical compound in the body) court said that we have previously upheld the FDA’s understanding that a prodrug of a previously approved drug, if it has a different active moiety, can qualify as a “major innovation” entitled to “‘[N]ew [C]hemical [E]ntity’ status and the resulting five-year exclusivity” . In the FDA’s view, ”prodrugs with previously unapproved active moieties “are ‘major innovations’ deserving five-year exclusivity,” even if they ultimately metabolize into a previously approved active moiety. We have no occasion to revisit our decision in Actavis, or to question the FDA’s expert judgment that “even minor covalent structural changes are capable of producing . . . major changes in the activity of a drug.”

Finally appeal court said that for these reasons, Otsuka fails to show that the language of the FDCA unambiguously compels its “legal-equivalence” interpretation of the scope of marketing exclusivity under the romanettes. Rather, the agency’s “same-moiety” interpretation is reasonable and warrants our deference.

Saxagliptin - USA

Decision on IPR:

AIA Review	Filing Date	Institution Date	Petitioner	US Patent	Respondent	Status
IPR2015-01340*	06/04/2015	05/02/2016	Mylan	RE44,186	AstraZeneca AB	Final Written Decision - Aug 18, 2017 (Claims are patentable)

*Wockhardt (IPR2016-01029), Teva (IPR2016-01122), Aurobindo (IPR2016-01117) and Sun/Amneal (IPR2016-01104) have each been joined as a Petitioner to this proceeding.

Mylan Pharmaceuticals Inc. (“Mylan”) filed a Petition to institute an inter partes review of claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42 of U.S. Patent No. US RE44,186 E. The ’186 patent is directed to “cyclopropyl-fused pyrrolidine-based inhibitors of dipeptidyl peptidase IV (DP-4) and to a method for treating diabetes.”

PTAB initially denied institution of an inter partes review of all the challenged claims. Mylan subsequently filed a Request for Rehearing. On May 2, 2016, PTAB granted the Request for Rehearing and concurrently instituted an inter partes review of all the challenged claims. An oral hearing for this proceeding was held on January 25, 2017.

PTAB issued its decision on Aug 18, 2017 & determined that Petitioners have not established, by a preponderance of the evidence, that claims 1, 2, 4, 6–22, 25–30, 32–37, and 39–42 of the ’186 patent are unpatentable. Specifically PTAB determined that Petitioners have not established that claim 25, a saxagliptin-specific claim, would have been obvious and that the secondary considerations weigh in favor of the patentability.

Guaifenesin / Guaifenesin & Pseudoephedrine – USA

On Aug. 22, 2017, United States District Court for the District of New Jersey issued an opinion ruling that Amneal Pharmaceuticals & DR Reddy’s did not infringe patents owned by Reckitt Benckiser by seeking permission from FDA to market a generic version of Mucinex® & Mucinex®D before the expiration of orange book patents.

Reckitt Benckiser holds an approved New Drug Application ("NDA") for Mucinex® (Guaifenesin) & Mucinex®D (Guaifenesin & Pseudoephedrine) extended-release tablets.  Mucinex®& Mucinex®D were approved by the United States Food and Drug Administration ("FDA") in Jul 12, 2002 & Jun 22, 2004 respectively. There are total 03 patents listed in orange book (OB) expiring on Apr 28, 2020.

Amneal Pharmaceuticals filed Abbreviated New Drug Application (ANDA) to the FDA seeking approval to market a generic version of Mucinex® & Dr Reddy’s filed ANDA for Mucinex®D.  Dr. Reddy's Mucinex®D case was consolidated with Amneal. New Jersey District Court held bench trial on May 18, 2017 & ruled that Amneal and Dr Reddy’s did not infringe U.S. Patent Nos. 6,372,252; 6,955,821 and 7,838,032. 

Oxcarbazepine – USA

On Aug. 15, 2017, Judge Renée Marie Bumb of the United States District Court for the District of New Jersey issued an opinion ruling that TWi Pharmaceuticals, Inc. infringed three patents owned by Supernus Pharmaceuticals, Inc. by seeking permission from FDA to market a generic version of Oxtellar XR® before the expiration of patents. U.S. District Judge also rejected all invalidity claims brought by TWi Pharmaceuticals.

Supernus Inc. holds an approved New Drug Application ("NDA") for Oxtellar XR® (Oxcarbazepine) extended-release tablets in 150, 300 & and 600 mg dosage strengths, Oxtellar XR® was approved by the United States Food and Drug Administration ("FDA") in October 2012 for the treatment of partial seizures in adults and children. There are total 07 patents listed in orange book (OB) expiring in Apr 2027.

TWi Pharmaceuticals filed Abbreviated New Drug Application (ANDA) to the FDA seeking approval to market a generic version of Oxtellar XR®.  On Jan 16, 2015 Supernus sued TWi in New Jersey District Court. Following a four-day bench trial on Apr 06, 2017, the New Jersey  district court ruled that TWi Pharmaceuticals, Inc. and its subsidiary infringed U.S. Patent Nos. 7,722,898, 7,910,131, and 8,821,930. In addition to the three patents that were the subject of the District Court’s decision, Oxtellar XR® is further protected by four other patents that are also listed in the Orange Book.

In another case with generic drug maker Actavis, the New Jersey district court issued its 136 page Opinion on February 5, 2016 concluding that Actavis product infringed two of the patents (7,722,898 and 7,910,131); it did not infringe the third (8,617,600). In addition, the Court concluded that all of the patents were valid, overcoming defenses of obviousness, written description, and indefiniteness. Actavis promptly appealed & in Dec 2016 the Court of Appeals affirmed without opinion.

Trastuzamab emtansine - Netherlands

On Aug. 02, 2017, the Hague court of Netherlands published its judgment in Trastuzamab emtansine Supplementary Protection Certificate (SPC) case & affirmed the Dutch patent office decision to refuse the SPC.

This is an appeal against the decision (10 March 2016) of the Dutch Patent Office to refuse to grant an SPC for trastuzamab emtansine. The plaintiff challenged the contested decision and requested the defendant (The Netherlands Patent Office) to conclude a direct appeal within the meaning of Article 7.

On 9 May 2014, plaintiff filed an application (registered under number 300665) to issue an SPC for the product trastuzumab emtansine registered under number EU / 1/13/885, on 15 November 2013. Furthermore, plaintiff has applied for its application based on European Patent 0 865 448 B2 entitled "Apoptosis induced by monoclonal antibody anti-her2" (Apoptosis induced by monoclonal antibody anti-Her2). The defendant based on the contested decision that trastuzumab emtansin is not protected by the basic patent so that Article 3, preamble and (a) of the Regulation is not fulfilled. The defendant has summarized in the contested decision that the active substance in the medicament according to claim 1 of EP 448 is a genus characterized by functional characteristics and that one skilled in the art, in the light of the description of The patent, on the priority date, will not have been able to realize that the thus-described antibody also relates to conjugates of antibodies with cytotoxic agents, not to mention the specific trastuzumab emtansin. Plaintiff claims that the term antibody as described in claim 1 of EP 448 does not in any way imply the exclusion of conjugates with other chemical groups, including cytotoxic agents. Furthermore, plaintiff claims that trastuzumab emtansin, although in the form of a conjugate, should be seen as an "antibody" which, as a whole, induces apoptosis. In view of the wording of the conclusion, it is irrelevant which part of this "antibody" leads to apoptosis.

In dispute, whether trastuzumab emtansin is protected by the basic patent within the meaning of Article 3, preamble and (a) of the Regulation, more specifically whether it is protected by claim 1 of that patent. Trastuzumab emtansin is not mentioned (as structural formula) in that conclusion. The question then is whether the active substance trastuzumab emtansin falls under the antibody described in claim 1 of EP 448, and that based on that conclusion, explained in particular in light of the description of the invention as required In Article 69 of the European Patent Convention and the Protocol on its interpretation, it can be concluded that this conclusion implicitly but necessarily and specifically relates to this active substance.

The Court agrees with the Dutch Patent Office that Article 3 first part and under SPC Regulation (EC) no. 469/2009 is not complied with. The anti-Her2 antibody of the invention may also be an anti-Her2 body which induces apoptosis as a result of a cytotoxic agent conjugated thereto, as claimed by the plaintiff, will be understood by one skilled in the art from claim 1 of EP 448 in the light of the foregoing Description, do not distract. In view of the foregoing, it cannot be concluded that conclusion 1 of EP 448 implicitly but necessarily and specifically relates to trastuzumab emtansin. 

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.