Vortioxetine – USA

Vortioxetine – USA

On Sep. 30, 2021, Delaware court found compound patent valid & infringed, whereas, other patents valid and not infringed in Trintellix® litigation.

 

Background:

Plaintiffs (Lundbeck / Takeda) sued 16 ANDA filers (defendants) in the consolidated action brought pursuant to the Hatch-Waxman Act. Plaintiffs market Trintellix® product in USA for the treatment of major depressive disorder (MDD). It is an immediate-release tablet for oral administration that contains the beta (β) polymorph of vortioxetine hydrobromide. Six defendants (Alembic, Lupin, Macleods, Sandoz, Sigmapharm & Zydus) proceeded to trial. Lundbeck is the assignee and owner of the 8 Patents-in-Suit as mentioned below:

(a) US 7,144,884 & US 8,476,279 are the “Compound Patents;”
(b) US 8,722,684 & US 9,861,630 are the “Crystalline Form Patents;”
(c) US 9,101,626 & US 9,090,575 are the “Process Patents;”
(d) US 9,278,096 is the “Sexual Dysfunction Patent;” and
(e) US 9,125,910 is the “Cognitive Impairment Patent.”

Not all of the Patents-in-Suit are asserted against all six defendants. Of those claims that are asserted, some defendants contest infringement while others concede infringement. One or more defendants challenge the validity of many asserted of the claims but not of all of them.

 

Compound patents:

Defendants sought to invalidate the asserted claims of the Compound Patents as obvious over certain prior arts. Defendants’ obviousness contention was not based on “lead compound” analysis. Rather, Defendants’ expert, Dr. Lepore, began his obviousness analysis with a “lead motif.” Dr. Lepore discerned in six pieces of prior arts (ES ’127, Planas, Pinder, Kopicová, Jílek, and WO ’678) – a common structure that, he asserts, would be the starting point for a POSA at the pertinent date seeking to develop an improved antidepressant. Court did not reject this “lead motif” theory and said that this analysis seems potentially compatible with the required lead compound analysis. However, Court found lack of clear and convincing evidence for the numerous modifications POSA would have been required to make to Dr. Lepore’s lead motif or lead compound. One reason Defendants have failed to persuade the Court is that Dr. Lepore did not adequately address the antidepressant landscape in 2001. Defendants have not presented clear and convincing evidence for why a POSA in 2001 would have preferred the ten-year-old venlafaxine path over the then-current state of the art at the time of the invention: SSRIs and SNRIs with high-selectivity and a superior side-effect profile. Defendants have not proven by clear and convincing evidence that prior art compounds exhibit the pertinent properties “such as activity and potency, adverse effects such as toxicity, and other relevant characteristics in evidence.” Moreover, far more modifications are necessary to move from the lead motif to vortioxetine than Defendants suggest. POSA would not have been motivated to make all of these modifications; nor would a POSA would have had a reasonable expectation of success in doing so. Therefore, Defendants have not proven that the Compound Patents are invalid due to obviousness.

 

Crystalline form patents:

The Crystalline Form Claims are directed to crystalline forms of vortioxetine hydrobromide with specific XRPD peaks and/or XRPD patterns, including the alpha (α) form, the beta (β) form, and the gamma (γ) form of vortioxetine hydrobromide. Defendants used amorphous form of vortioxetine in their ANDA products, except, Alembic which used benzyl alcohol hemi solvate (“Form C”).

Court said that Plaintiffs’ theory of infringement against Alembic and Zydus depends on the presence of, at most, just a single one of the multiple characteristic peaks the Crystalline Form Patents disclose. But Court was not persuaded by the testimony of Plaintiff’s expert (Dr. Myerson), who cited no literature to support his opinion that use of a single peak is a scientifically valid method of identifying a particular crystalline form. Court said that a single peak may provide a sufficient basis on which to ground a finding that crystallization is present. A single peak may also be indicative of the presence of a particular crystalline form so long as the weight of the XRPD images does not rule out the likely presence of other characteristic peaks of that form. Where, as here, however, the overwhelming abundance of careful XRPD images developed expressly for purposes of determining infringement detects no more than one of the multiple characteristic peaks – effectively ruling out the remaining peaks characteristic of the particular form – and particularly where the claims identify the particular crystalline form by the presence of multiple characteristic peaks, evidence of the presence of just a single (even discriminatory) peak is not sufficient to amount to proof by a preponderance of the evidence. [Cephalon, Inc. v. Sun Pharms., Ltd., 2012 WL 12904999 (D.N.J. Dec. 20, 2012) (rejecting infringement premised on single XRPD “diagnostic” peak that could not differentiate between multiple polymorphic forms)]

Second, Plaintiffs’ efforts to persuade the Court that Defendants’ ANDA Products that are manufactured using amorphous API will, in time, convert to crystalline forms, were generally unavailing. Frequently, Plaintiffs’ evidence involved testing that occurred under conditions – in terms of variables such as time, temperature, and pressure – that are unrealistic and/or that are well outside of what will be permitted with proper handling of the ANDA Products.

Third, Plaintiffs’ infringement case against Defendants Alembic, Macleods, and Zydus depends to a great extent on internal testing Defendants did themselves. However, without exception, this testing was performed on less sensitive XRPD instruments than the testing performed by the experts for this case. Plaintiffs identify no internal documents that compare any of the Asserted Claims to the proposed ANDA Products.

Fourth, with respect to Lupin and Zydus, part of Plaintiffs’ infringement case is based on Defendant internal testing of development batches. There was no persuasive evidence that development batches are representative of the ANDA Product Lupin or Zydus seeks approval to sell.

Finally, Plaintiffs’ handling of the samples of Defendants’ ANDA Products further undermines the Court’s confidence that the relatively paltry evidence of infringement they did produce adds up to proof by a preponderance of the evidence. In several instances, Defendants timely provided unexpired samples of their proposed products and Plaintiffs then waited to ask their experts to test those samples until after they expired.

 

Process patents:

US’575: Claim 3 of the ’575 Patent is directed to a novel process for preparing vortioxetine by reacting 2,4-dimethylphenylthiol aniline (compound of formula IVa) with a bis(chloro or bromo)ethyl amine. Zydus asserted that for the same reasons vortioxetine would have been obvious, Claim 3 of the ’575 Patent would have been obvious over same prior arts. The Court, however, concluded that Zydus has failed to prove obviousness of the ’575 Patent by the required clear and convincing evidence.

US’626: The ’626 Patent claims specify two different types of reactions: a one-pot process, in which all reactants are together from the start of the process (Claim 3), and a two-pot process, comprising a series of reactions in which the initial reaction product later reacts with other compounds to yield the final product (Claim 2). Court here adopted the Plaintiffs’ proposed construction of “reacting” and found that Lupin’s process infringes.

 

Sexual Dysfunction Patent:

Each Defendant’s proposed prescribing information contains only one indication, which is “the treatment of major depressive disorder (MDD) in adults.” Defendant’s label carves out two sets of information from Trintellix’s label, specifically in Sections 6.1 and 14. Those two sets of carve outs relate to: (1) cognitive impairment information in Section 14; and (2) TESD comparative information in Sections 6.1 and 14.

Court said that the disputes regarding infringement of Claim 7 of US’096 patent focus on the claim limitation relating to the use of vortioxetine in a patient who has “previously received medication or is still receiving medication for the treatment of [depression], the medication is ceased or reduced or has to be ceased or reduced due to sexually related adverse events, and the medication is selected from the group consisting of selective serotonin reuptake inhibitors, selective noradrenaline reuptake inhibitors, noradrenaline/serotonin reuptake inhibitors, and tri-cyclics,” which the Court will refer to hereinafter as the “TESD Limitation.”

Court said that Defendants’ labels, read as a whole will not encourage, recommend, or promote an infringing use. Defendants have “carved out” the TESD comparative information from their proposed prescribing information. Due to Defendants’ section VIII carve-outs, Defendants’ labeling will not encourage, recommend, or promote the practice of switching MDD patients, who have previously experienced adverse sexual side effects while taking one of the four classes of antidepressants, to vortioxetine. As a result of the carve-outs, the only information related to TESD in Defendants’ proposed Prescribing Information appears in the “Adverse Reactions” Section 6.1 of Defendants’ proposed labels. This information uses ASEX data to report the incidence of TESD that developed in patients without sexual dysfunction at baseline using vortioxetine doses compared with a placebo. Plaintiffs have failed to persuade the Court that clinicians would understand from the data in Section 6.1, that vortioxetine has placebo-like levels of sexually related adverse events and would, therefore, be encouraged to prescribe vortioxetine for use according to the claimed method. Instead, Defendants correctly state, “Defendants’ skinny labels leave nothing that ‘encourage[s], recommend[s], or promote[s]’ claim 1’s three key steps: (1) the patient must take a first antidepressant in one of the four recited classes; (2) the patient must cease or reduce or have to cease or reduce that antidepressant ‘due to’ TESD; and (3) the patient must then take vortioxetine.”Defendants’ Prescribing Information contains no reference in Section 6.1 to any other antidepressant, let alone a comparison between the rates of TESD for vortioxetine and other drugs. In fact, Defendants’ label expressly instructs against making such comparisons.

Moreover, Plaintiffs’ own actions provide further support for the Court’s conclusions. Plaintiffs did not submit the ’096 Patent within 30 days. Instead, Plaintiffs listed the ’096 Patent as covering Trintellix® in October 2018, only after the FDA approved a supplement to the NDA that added the TESD comparative information to the Trintellix® Prescribing Information. This comports with an understanding that the ’096 Patent does not cover products sold without the TESD comparative information. Accordingly, Plaintiffs have failed to prove induced infringement.

With respect to contributory infringement, Court said that it is persuaded not only that use of Trintellix as a first-line treatment of MDD is currently a substantial non-infringing use but, more importantly, that in a genericized market
Defendants’ ANDA Products will be prescribed as a first-line treatment in a not-insubstantial number of cases. The record also establishes that even for those MDD patients for whom vortioxetine is not their first antidepressant, a not-insubstantial number of them will have only used other ADs that do not fall into the categories required for meeting the TESD Limitation. The record establishes that the most common reason for discontinuing an antidepressant is lack of efficacy. Switching from an SSRI, SNRI, NRI, or TCA due to lack of efficacy, however, does not meet the TESD Limitation. The Court thus concluded that this is a substantial non-infringing use and Plaintiff failed to prove contributory infringement.

Court also held that Defendants failed to prove the ‘096 patent invalid.

 

Cognitive Impairment Patent:

Claim 6 of the ’910 Patent is directed to a method of treating cognitive impairment in a patient diagnosed with MDD wherein the method is comprised of administering a therapeutically effective amount of the hydrobromide salt of vortioxetine and the method alleviates a symptom or complication of cognitive impairment or delays the progression of cognitive impairment. A substantial non-infringing use is that clinicians will prescribe vortioxetine separate from combating cognitive impairment. Some patients will be prescribed Defendants’ ANDA Products for the purpose of treating MDD, not for the purpose of treating cognitive impairment, for reasons including that at least some MDD patients will not even have cognitive symptoms. Accordingly, Plaintiffs have failed to show that Defendants will contributorily infringe Claim 6 of the ’910 Patent.

Court also held that Defendants failed to prove the ‘910 patent invalid.

 

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