United States: Expecting The "Unexpected": Asserted Claims Found Invalid After Allegedly "Unexpected Results" Suggested In Prior Art References

Holding

In Vanda Pharmaceuticals, Inc. v. Teva Pharmaceuticals USA, Inc., 2022 WL 17593282 (D. Del. Dec. 13, 2022) the district court held that all patent claims asserted against defendants Teva and Apotex were invalid for obviousness.

Background

Vanda Pharmaceuticals, Inc. ("Vanda") is the holder of several patents related to its Hetlioz® drug product, which is the only FDA-approved drug indicated for the treatment of Non-24-Hour Sleep-Wake Disorder. Teva Pharmaceuticals USA ("Teva") and Apotex Inc. ("Apotex") each submitted an ANDA seeking approval to market a generic version of Hetlioz®. In response, Vanda asserted four patents, U.S. Patent No. RE46,604 ("RE604"), U.S. Patent No. 10,149,829 ("the '829 patent"), U.S. Patent No. 9,730,910 ("the '910 patent"), and U.S. Patent No. 10,376,487 ("the '487 patent"), that the ANDA filings allegedly infringe.

Opinion

The district court held in favor of Teva and Apotex (collectively, "Defendants"), finding all asserted patent claims invalid for obviousness.

Defendants alleged that the asserted patent claims were invalid in view of various combinations of Hack, Lankford, Hardeland, Pandi-Perumal, and the '244 publication. Notably, Vanda argued in its post-trial brief that Lankford "'is not even prior art' 'because it represents Vanda's own work and was published in May of 2011, less than a year before the priority date of the RE604 patent.'" Id. at 30. The court noted that this was the first time that Vanda presented this argument. Vanda had not objected to the introduction of and reliance on Lankford before and during the trial, and therefore forfeited the right to argue that Lankford is not prior art. Id.

RE46,604

Defendants first alleged that claim 3 of the RE604 patent was invalid. Claim 3 of the RE604 patent depends from claims 1 and 2.

Claims 1-3 recite:

1. A method of entraining a patient suffering from Non-24 to a 24-hour sleep-wake cycle in which the patient awakens at or near a target wake time following a daily sleep period of approximately 7 to 9 hours, and maintaining said 24 hour sleep-wake cycle said method comprising: treating the patient by orally administering to the patient 20 mg of tasimelteon once daily before a target bedtime.

2. The method of claim 1, wherein the patient is totally blind.

3. The method of claim 2, wherein the tasimelteon is administered 0.5 to 1.5 hours before the target bedtime.

Vanda argued that claim 3 of the RE604 was not obvious due to unexpected results relating to (1) the relatively long half-life of tasimelteon in view of the relatively short half-life of melatonin, (2) the efficacy of the 20 mg dose of tasimelteon, (3) the timing of tasimelteon administration, and (4) the phase-response curve. The court noted that although Lankford disclosed that there were differences in the half-life of melatonin and tasimelteon, Lankford concluded that "[t]he longer half-life could make tasimelteon more suitable for treating insomnias other than just the sleep onset type." Based on this disclosure, the court found that a skilled artisan would have "understood Lankford as teaching or suggesting that tasimelteon could likely entrain blind patients with Non-24." Id. at 49. The court also noted that the references cited by the defendant additionally disclose the 20 mg dosage of tasimelteon, which would suggest that the dosage was not unexpected, and that tasimelteon could be administered approximately a half-hour before bedtime. Id. at 50-51.

Relying on the testimony of Defendant's expert witness, who Judge Connolly noted as being very credible, the court found that a skilled artisan would have had a motivation to combine the cited prior art references and would have had a reasonable expectation of success in entraining a totally blind patient with Non-24. Id. at 40-42. Judge Connolly specifically referenced the disclosure of Vanda's Phase III trial in Lankford as a contributing factor to a skilled artisan's expectation of success. Id. at 41. In his reasoning, Judge Connolly quoted the Defendant's expert witness, who said "[I]f someone is going to be spending the time and money to do a big Phase 3 trial, all that effort, as well as money, then that would say to me, and to a person of ordinary skill in the art, that clearly there was a reasonable expectation that they were going to succeed." Id. at 42. Therefore, the court held that claim 3 of RE604 was obvious in view of the cited prior art.

The '829 Patent

Defendants additionally alleged that claim 14 of the '829 patent is invalid. Claim 14 depends from claim 13.

Claims 13 and 14 recite:

13. A method of treating a patient for a circadian rhythm disorder or for a sleep disorder wherein the patient is being treated for a sleep disorder wherein the patient is being treated with a strong CYP1A2 inhibitor selected from a group consisting of fluvoxamine, ciprofloxacin, and verapamil, the method comprising: (A) discontinuing treatment with the strong CYP1A2 inhibitor and then (B) treating the patient with 20 mg of tasimelteon once daily.

14. The method of claim 13, that comprises treating the patient for Non-24-Hour Sleep-Wake Disorder.

Defendants argued many of the same reasons for obviousness as the RE604 patent, noting that the additional cited references teach against administration of tasimelteon with a CYP1A2 inhibitor.

Vanda argued that although the cited prior art taught that "CYP1A2 was one of the four enzymes 'primarily' responsible for tasimelteon in an in vitro laboratory test," without in vivo tests, a skilled artisan would not have known that tasimelteon and strong CYP1A2 inhibitors should be avoided. Id. at 53-54.

Relying on the determinations made in the analysis of the RE604 Patent, the court noted that the cited references teach the treatment of patients with 20 mg of tasimelteon and that a skilled artisan would have had a motivation to combine the references with a reasonable expectation of success that the treatment would succeed in treating a patient with Non-24. The court additionally described how Hardeland discloses that tasimelteon is metabolized by CYP1A2 and "expressly cautions against the administration of any drug with tasimelteon that inhibits CYP1A2." Id. at 43. Thus, the court found that claim 14 of the '829 patent was obvious in view of the cited prior art and therefore invalid.

The '910 Patent

Defendants also alleged that claim 4 of the '910 patent is invalid. Claim 4 of the '910 patent depends from claims 1, 2, and 3.

Claims 1-4 read:

1. A method of treating a patient for a circadian rhythm disorder wherein the patient is being treated with rifampicin, the method comprising: (A) discontinuing the rifampicin treatment and then (B) treating the patient with tasimelteon, thereby avoiding the use of tasimelteon in combination with rifampicin and also thereby avoiding reduced exposure to tasimelteon caused by induction of CYP3A4 by rifampicin.

2. The method of claim 1 that comprising treating the patient for Non-24-Hour Sleep-Wake Disorder.

3. The method of claim 2 wherein the patient is light perception impaired (LPI).

4. The method of claim 3 wherein treating the patient with tasimelteon comprises orally administering to the patient 20 mg of tasimelteon once daily before a target bedtime.

Defendants argued that claim 4 of the '910 patent is obvious for many of the reasons already described, noting that the additional cited reference teaches that ramelteon, a related melatonin agonist, is metabolized by CYP3A4.

Again, Vanda alleged that the asserted claim was not obvious due to unexpected results. Vanda alleged that it would have been unexpected that tasimelteon should not be co-administered with rifampicin, a strong CYP3A4 inducer, because data had shown that "[n]o metabolism of [tasimelteon] was observed following incubation with ... [CYP]3A4." Id. at 52. Addressing this argument, the court turned to Defendant's expert witness who opined that, "a skilled artisan aware of this data would not have 'excluded a major role of CYP3A4 in the induced state' because 'induction causes a massive increase in the amount of enzymes,' meaning 'you can't exclude a major role of CYP3A4 in the induced state even if you can't detect it in the uninduced state." Id. The court additionally found that "the artisan would have looked to ramelteon to predict tasimelteon drug-drug interactions because of the many known similarities between ramelteon and tasimelteon, including the fact that ramelteon and tasimelteon have similar structures, half-life durations, and affinitions for melatonin receptors (MT1 and MT2)." Id. at 45.

Similar to the analysis for the '829 patent, the court noted that the cited references taught the other elements of the claimed method of treatment. Therefore, the court found that claim 4 of the '910 patent was invalid for obviousness.

The '487 Patent

Lastly, Defendants alleged that claim 5 of the '487 patent is invalid under obviousness grounds under the arguments already presented. Claim 5 of the '487 patent depends from claims 1 and 4.

Claims 1, 4, and 5 recite:

1. A method of treating a human patient suffering from a circadian rhythm disorder or a sleep disorder that comprises orally administering to the patient an effective dose of tasimelteon without food, wherein the effective dose is 20 mg/d.

4. The method of claim 1, wherein the patient is suffering from a circadian rhythm disorder.

5. The method of claim 4, wherein the circadian rhythm disorder is Non-24 Disorder.

In response to Defendant's allegations, Vanda argued that "it would have been unexpected that administration of tasimelteon with food would decrease its efficacy in treating Non-24." Id. at 51. However, the court found that Vanda failed to provide any evidence as to what a skilled artisan would have expected when tasimelteon was administered with or without food, and therefore quickly dismissed this argument for nonobviousness. Id. at 51-52. The court also noted that "[w]hether to administer tasimelteon with food is a binary choice. A drug is administered with or without food. 'When two equally viable options are available, as here, then, without more, either one would seem to have been obvious." Id. at 70, citing C.R. Bard, Inc. v. Medline Indus., Inc., 2021 WL 3574043, at *4 (Fed. Cir. Aug. 13, 2021).

Similar to the analysis for the other asserted patents, the court indicated that the cited references teach the method of treating a patient with Non-24 with 20 mg of tasimelteon once daily, and that a skilled artisan would have had a motivation to combine the references with a reasonable expectation of success that the treatment would succeed. Id. at 47. The court therefore held that claim 5 of the '487 patent was obvious and therefore invalid.

Vanda's Other Objective Evidence of Nonobviousness

Vanda additionally argued that the asserted claims were not obvious due to (1) the long-felt need of the claimed Non-24 treatment, (2) industry praise for the claimed Non-24 treatment, (3) failure of others to develop the claimed Non-24 treatment, and (4) failure to recognize CYP3A4 metabolism.

Although Vanda alleged that there was a long-felt need for the claimed Non-24 treatment, the court noted that the evidence cited by Vanda did not demonstrate a long-felt need for the treatment. The evidence cited included a story of a single patient who was successfully treated after melatonin treatment had not succeeded, and other evidence that was "cursory at best and suggests at most that there was some need among Non-24 patients for whom melatonin had not worked for another drug; it does not suggest that there was a need for a specific method of using that drug." Id. at 55. The court also noted that while Vanda cited industry praise, it failed to cite evidence that the praise was directed at the treatment method, the subject of the asserted patents. Vanda's alleged claims of the failure of others were also seen as unpersuasive by the court because Vanda provided no evidence that others had tried to develop tasimelteon to treat Non-24.

Note: Vanda appealed, also motioning for a temporary injunction enjoining Teva and Apotex from commercially marketing generic versions of Hetlioz". On Dec. 28, 2022, the Federal Circuit denied the motion. The Federal Circuit did agree, however, to expedite the appeal; Vanda's opening brief is due no later than January 23, 2023; the appellees' response briefs are due no later than February 27, 2023; and Vanda's reply brief and the joint appendix are due no later than March 9, 2023.

Takeaways

In prosecution, objective evidence serves to rebut a prima facie case of obviousness. If an applicant presents evidence to rebut a prima facie case of obviousness, the examiner must reevaluate entirely the merits of the matter, taking into account the newly submitted evidence. See In re Hedges, 783 F.2d 1038, 1039 (Fed. Cir. 1986); In re Rinehart, 531 F.2d 1048, 1052 (CCPA 1976). Even in litigation, evaluating the obviousness of the subject matter as a whole also requires considering the objective evidence of nonobviousness along with the other Graham factual inquiries. If present, this evidence cannot be disregarded. See Apple Inc. v. International Trade Com'n, 725 F.3d 1356, 1365 (Fed. Cir. 2013).

Presenting comparative test data showing that the claimed invention possesses unexpectedly improved properties or properties that the prior art does not have is a form of objective evidence. If a person of ordinary skill in the art would have been surprised by applicant's results, then the invention could not have been obvious. As noted by the court in this case, "'by definition, any superior property must be unexpected to be considered as evidence of non-obviousness' and that unexpected results 'evidence must fail [if] the record is devoid of any evidence of what the skilled artisan would have expected.'" Id. at 52, citing Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007). Thus, if a practitioner is making an argument for unexpected results, it must truly be unexpected—not already disclosed in the prior art—and be supported by factual evidence. See also, Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1306 (Fed. Cir. 2015)("We also conclude that the district court did not clearly err in finding that the claimed formulation exhibited 'unexpected results,' which differed in kind, not just in degree, from the prior art."). In other words, the unexpectedness must be sufficient "to secure the validity of the claims in suit." Syntex (U.S.A.) LLC v. Apotex, Inc., 407 F.3d 1371, 1381 (Fed. Cir. 2005).

In order for an examiner, PTAB, or a court to credit objective evidence, the applicant must establish a nexus between the evidence and the merits of the invention. This "nexus" between the evidence and the claimed invention "is a legally and factually sufficient connection." Henny Penny Corp. v. Frymaster LLC, 938 F.3d 1324, 1332 (Fed. Cir. 2019). If the court finds that the objective evidence is attributable to something other than the invention, such as marketing and/or non-invention features, there is no nexus to the claimed invention and the objective evidence will fail to rebut a prima facie case of obviousness.

This decision also reminds practitioners to ensure that alleged prior art actually is prior art when it is being asserted. Failure to argue against a reference being characterized as prior art can estop a party from making the argument later on, as happened in this case. While it is uncertain if the asserted claims would have been nonobvious in view of the prior art without the Lankford reference, removing Lankford as a prior art reference would have only benefitted Vanda in its claims against Defendants. It would serve practitioners well to carefully scrutinize prior art to make sure that it actually is prior art.

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