Tenofovir & Emtricitabine – UK

On Apr. 25, 2018, in a request for a preliminary ruling, Advocate General Wathelet delivered judgment in SPC case involving Gilead’s Truvada (Tenofovir + Emtricitabine) product.

The High Court of Justice, Chancery Division (Patents Court), lodged this request for a preliminary ruling with the Court Registry on 8 March 2017. It concerned the interpretation of Article 3(a) of Regulation (EC) No 469/2009 concerning the supplementary protection certificate for medicinal products. This request was made in proceedings brought by Teva UK Ltd, Accord Healthcare Ltd, Lupin Ltd, Lupin (Europe) Ltd and Generics (UK), trading as ‘Mylan’, against Gilead Sciences Inc. (‘Gilead’) contending that the SPC does not comply with Article 3(a) of that regulation. In the main proceedings, the applicants are challenging the validity of Gilead’s supplementary protection certificate (‘SPC’) SPC/GB05/041 for a product described in the SPC as a ‘composition containing both Tenofovir disoproxil (TD), optionally in the form of a pharmaceutically acceptable salt, hydrate, tautomer or solvate, together with Emtricitabine’. The product covered by the SPC is an anti-retroviral medication used in the treatment of human immunodeficiency virus (HIV) and is marketed by Gilead under the trade mark Truvada.

Gilead holds European patent No EP 0 915 894 (‘the basic patent’). This patent was expired on 24 July 2017. It covers, in general terms, a series of molecules, which are helpful in the therapeutic treatment of a number of viral infections in humans and animals, in particular HIV. Claim 27, which is important here, reads as:

 ‘A pharmaceutical composition comprising a compound according to any one of claims 1 to 25 together with a pharmaceutically acceptable carrier and optionally other therapeutic ingredients’.

The applicants in the main proceedings contended that claim 27 does not require the presence of any ‘other therapeutic ingredients’ since such ingredients are only ‘optionally’ present. Gilead asserted that in order for Article 3(a) of Regulation No 469/2009 to be satisfied, it is necessary and sufficient that the product in question falls within the scope of protection of at least one claim of the basic patent applying the Extent of Protection Rules. It takes the view that the combination of TD and emtricitabine does fall within the scope of protection of claim 27 of the patent under Article 69 of the EPC and under the Protocol on interpretation.

Court said the fact that a substance or combination of substances falls within the scope of protection of the basic patent is a necessary, but not sufficient, requirement for it to constitute a product protected by a patent within the meaning of Article 3(a) of Regulation No 469/2009. Court specifically held that the active ingredient emtricitabine is claimed solely through the use of completely indeterminate expressions such as ‘comprising’ and ‘optionally other therapeutic ingredients’, terms which may cover multiple substances that are not specifically and precisely identifiable on the priority date of the patent. Therefore, the combination containing the active ingredients TD and emtricitabine, that is to say, the medicinal product marketed under the name Truvada, is not protected by the basic patent within the meaning of Article 3(a) of Regulation No 469/2009, even though that combination may fall within the protection of claim 27 of the patent at issue in the main proceedings under Article 69 of the EPC. 

Sofosbuvir – USA

On Apr. 25, 2018, Court of Appeals for the Federal Circuit (CAFC) affirmed unenforceability of both the Merck’s patents based on unclean hands.

This case involves two patents relating to treatments for Hepatitis C. Merck & Co., Inc. and Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) collaborated on research in the area and eventually obtained U.S. Patent Nos. 7,105,499 and 8,481,712. The patents, whose specifications are materially the same for present purposes, describe and claim classes of compounds, identified by structural formulas, and the administration of therapeutically effective amounts of such compounds. Gilead Sciences, Inc., developed its own Hepatitis C treatments—marketed now as Solvadi® and Harvoni®, both based on the compound sofosbuvir.

Previously, Gilead filed action against Merck & sought a declaratory judgment that Merck’s ’499 and ’712 patents are invalid and that Gilead is not infringing by its activities involving its sofosbuvir products. Merck counterclaimed for infringement. Gilead eventually stipulated to infringement based on the district court’s claim construction, which was not challenged on appeal. A jury trial was held on Gilead’s challenges to the patents as invalid for lack of both an adequate written description and enablement. The jury ruled for Merck and awarded damages. The district court then held a bench trial on Gilead’s equitable defenses, including unenforceability against Gilead based on the allegation that Merck had unclean hands regarding the patents. The district court ruled for Gilead, finding both pre-litigation business misconduct and litigation misconduct attributable to Merck, and it barred Merck from asserting the patents against Gilead. The court also awarded attorney’s fees, relying on the finding of unclean hands.

Merck appealed the unenforceability judgment based on unclean hands. Gilead cross-appealed the denial of judgment as a matter of law of invalidity, but it asked to reach that issue only if court set aside the unenforceability judgment.

CAFC agreeing with the district court found, with adequate evidentiary support, two related forms of pre-litigation business misconduct attributable to Merck. First, Dr. Durette learned of Pharmasset’s PSI-6130 structure by participating, at Merck’s behest, in a conference call with Pharmasset representatives, violating a clear “firewall” understanding between Pharmasset and Merck that call participants not be involved in related Merck patent prosecutions. Second, Merck continued to use Dr. Durette in the related patent prosecutions even after the call. The district court also found, with adequate evidentiary support, a direct connection to the ultimate patent litigation involving sofosbuvir. Thus, Dr. Durette’s knowledge of PSI-6130, acquired improperly, influenced Merck’s filing of narrowed claims, a filing that held the potential for expediting patent issuance and for lowering certain invalidity risks. Those findings establish serious misconduct.

The district court also found, with adequate evidentiary support, essentially two forms of litigation misconduct involving Dr. Durette as a witness and attributable to Merck. First, in his deposition, where he appeared partly as Merck’s corporate witness on issues to which the March 2004 call was relevant, Dr. Durette gave testimony that he did not participate in the March 2004 call— testimony that was later conceded to be false and that the court found to be intentionally so. Second, both in the deposition and then at trial, Dr. Durette, in support of Merck’s validity positions, gave testimony about the role the January 2005 Clark Application played in Dr. Durette’s filing of the February 2005 amendment that the court found so incredible as to be intentionally false. CAFC said that the intentional testimonial falsehoods qualify as the kind of misconduct that can, in these circumstances, support a determination of unclean hands.

CAFC saw no reversible error in the district court’s balancing of the equities. As to the ’499 patent, the equity balance follows directly from the determinations already described: the misconduct leading to the February 2005 amendment and the misconduct involved in the litigation defense of the resulting patent claims. CAFC also saw no abuse of discretion in the district court’s conclusion that the unclean hands defense extends to the ‘712 patent as well. More importantly, the district court, turning from the business misconduct to the litigation misconduct, reasonably concluded that “Merck’s litigation misconduct infects the entire lawsuit, including the enforceability of the ’712 Patent.” “[T]he untruthful testimony offered by Dr. Durette in his deposition and at trial was not incidental, but rather was directed at and supported Merck’s validity arguments, and went to the heart of significant issues in this case.” Thus, the litigation misconduct “infected this entire case, covering both patents-in-suit.”

Therefore, finally CAFC concluded that district court did not abuse its discretion in applying the doctrine of unclean hands & affirmed the unenforceability judgment.

Ezetimibe & Rosuvastatin – Netherlands

On Apr. 10, 2018, District Court The Hague handed down its decision in combo SPC case & denied appeal filed by Merck against patent office’s decision that rejected the SPC application.

By decision of May 03, 2016, the Dutch patent office (Respondent) rejected the Merck’s (Plaintiff) application for a supplementary protection certificate for ezetimibe & rosuvastatin. By a decision of Apr 28, 2017, the respondent declared the plaintiff's objection to the primary decision unfounded. Merck (Plaintiff) appealed against the contested decision.

On Sep 08, 2014, the plaintiff filed an application for the issue of an SPC for a product described as ezetimibe, optionally in the form of a pharmaceutically acceptable salt, and rosuvastatin. Plaintiff based its application on European Patent 0720599 B1 entitled Hydroxy-substituted azetidinone compounds useful as hypocholesterolemic agents (Hydroxysubstituted azetidinone compounds, useful as hypocholesterolemic agents). This patent expired on Sep 14, 2014. Ezetimibe satisfies the Markush formula of claim 1 of EP 599 patent and, more specifically, corresponds to the compound in claim 8. Combinations of ezetimibe with a cholesterol biosynthesis inhibitors were claimed in claim 17, where a number of biosynthesis inhibitors were specifically mentioned. Based on the basic patent, plaintiff has previously obtained an SPC for the monoproduct 'ezetimibe, if desired in the form of a pharmaceutically acceptable salt'. This SPC expires on 16 April 2018.

The dispute was whether Article 3 (a and / or c) of the Regulation precludes Plaintiff from obtaining an SPC for the combination product ezetimibe and rosuvastatin, in addition to an SPC for the monoproduct ezetimibe. The basic patent in this case refers to a new group of azetidinone compounds that can be used for the prevention of arteriosclerosis and / or as cholesterol-lowering agents. This matter can be regarded in the terminology of Actavis / Sanofi as the 'core inventive advance' of the patent. Ezetimibe is one of those new compounds and thus as an innovative active ingredient ('innovative active ingredient'), which is protected as such ('as such') by EP 599. Cholesterol biosynthesis inhibitors are not protected as such in EP 599. Cholesterol biosynthesis inhibitors are therefore not an 'innovative active ingredient' in the context of EP 599 and as such are not the object (matter) of EP 599. A number of biosynthesis inhibitors have been specified in claim 17 but rosuvastatin is not mentioned.

Court thus held that from the explanation given by the CJEU to article 3 in Actavis / Sanofi and Actavis / Boeringer, it follows that in this situation, where the combination product consists of an active substance that is protected as such ('as such') by the basic patent and the object (subject matter) of the patented invention and on the other hand of an active substance - forming part of a non-limited group of biosynthesis inhibitors - which is not protected as such by the same basic patent and is not the object of the invention, no place for granting of SPC for the combination product, now that SPC based on the same basic patent has already been granted for the first active substance on the basis of a previous marketing authorization.

Levodopa & Carbidopa – USA

On Apr. 18, 2018, U.S. District Judge STANLEY R. CHESLER, of District of New Jersey granted in part & denied in part Actavis’ motion for summary judgment of non-infringement in Rytary®(carbidopa and levodopa) Extended-release Capsules.

This matter came before this Court on the motion for summary judgment, pursuant to Federal Rule of Civil Procedure 56, by Defendants Actavis Laboratories FL, Inc. and Actavis Pharma Inc. (collectively, “Actavis”). Plaintiff Impax Laboratories, Inc. (“Impax”) has opposed the motion. The Court heard oral argument on this motion on February 27, 2018. This is a Hatch-Waxman case involving a patent dispute regarding pharmaceuticals: the Complaint alleges that Actavis seeks to make and sell a generic version of Plaintiff’s Rytary® (levodopa/carbidopa) capsules prior to the expiration of the relevant patents. This consolidated case now involves four patents. Actavis moves for summary judgment that its proposed generic product will not infringe 37 claims in U.S. Patent Nos. 8,557,283 (“the ’283 patent”), 9,089,608 (“the ’608 patent”), 9,463,246 (“the ’246 patent”), and 9,533,046 (“the ’046 patent”).

I. Infringement of claims requiring a particular formulation structure:

For purposes of this motion, the parties have grouped together claims in the ’283 and ’608 patents that contain this phrase: “(a) levodopa; (b) a decarboxylase inhibitor; and (c) a carboxylic acid that is not (a) or (b); wherein the carboxylic acid of (c) is in a distinct bead from (a) or (b).” While Actavis makes a number of arguments, the heart of its non-infringement case for these claims is the contention that its proposed product does not meet this limitation, and thus cannot literally infringe. Specifically, Actavis contends that, the bead with tartaric acid, a carboxylic acid, also contains levodopa (“LD”) and a decarboxylase inhibitor (“CD.”). As a result, the proposed product does not contain the claim limitation at issue: the carboxylic acid is not in a distinct bead from the levodopa and decarboxylase inhibitor.

Court after hearing both the parties held that Impax has failed to defeat Actavis’ motion as to these claims, and thus granted motion for summary judgment of non-infringement, as to literal infringement of the Formulation Structure Claims.

II. Infringement of claims requiring a particular PK profile:

For purposes of this motion, the parties have grouped together method of use claims in the ’246, ’046, and ’608 patents that require pharmacokinetic profiles with certain characteristics. In brief, one subset of claims contains claim limitations involving “maximum concentration” (“the ‘maximum concentration’ claims”) while the other subset of claims contains claim limitations with the term, “the levodopa blood plasma levels do not fluctuate more than 40% between 0.5 hours and six hours after administration” (“the ‘40% fluctuation’ claims). Actavis moved for summary judgment of literal non-infringement on all such claims on the ground that its proposed product does not meet these limitations.

Court held that Impax has failed to defeat the motion for summary judgment of non-infringement on the method of use claims that contain “maximum concentration” limitations. As to the issue of literal infringement, in regard to the counts based on the method of use claims that contain “maximum concentration” limitations, the motion for summary judgment will be granted. See Intellectual Ventures I LLC v. Motorola Mobility LLC, 870 F.3d 1320, 1331 (Fed. Cir. 2017) (“a finding of direct infringement is predicate to any finding of indirect infringement”).

Court thus granted Actavis’ motion for summary judgment of non-infringement under literal theory & denied motion for summary judgment of non-infringement under DOE theory.

Tadalafil – USA

On Apr. 18, 2018, Court of appeal for the federal circuit affirmed PTAB’s decision & found patents covering tadalafil formulation obvious over certain prior arts.

ICOS Corporation appealed the PTAB’s inter partes review (“IPR”) decisions holding claims 1–32 of U.S. Patent No. 7,182,958 and claims 1–11 of U.S. Patent No. 6,821,975 would have been obvious over PCT Application WO 97/03675 (“Daugan”), PCT Application WO 96/38131 (“Butler”), U.S. Patent No. 4,721,709 (“Seth”), and Wadke, et al. The ’958 patent is directed to pharmaceutical formulations containing micronized tadalafil. The ’975 patent is directed to micronized tadalafil in a free-drug particulate form. Actelion Pharmaceuticals Ltd. (“Actelion”) filed two petitions for inter partes review. The first, IPR2015- 00561, alleged claims 1–32 of the ’958 patent would have been obvious & second, IPR2015-00562, alleged claims 1–11 of the ’975 patent would have been obvious.

In the ’958 IPR, the Board found a motivation to combine Butler’s teaching that tadalafil has poor solubility with Seth’s teaching that compounds with low solubility generally also have a slow dissolution rate, and with Seth and Wadke’s teachings that reducing particle size through micronization can increase dissolution rate. It found there was a reasonable expectation of success in combining the teachings of these references, and rejected ICOS’ claim of unexpected results. In the ’975 IPR, the Board found Daugan, Butler, Seth, and Wadke disclose every limitation of the challenged claims. It found the general knowledge that tadalafil is poorly water soluble would have motivated an ordinarily skilled artisan to micronize it to improve its absorption and an ordinarily skilled artisan would have had a reasonable expectation of success in doing so. Based on these facts, in each instance, the Board concluded that the claims would have been obvious. ICOS appealed.

On appeal, ICOS challenged the Board’s findings that there was a motivation to micronize tadalafil, that a skilled artisan would have had a reasonable expectation of success in doing so, and that Daugan teaches the claimed combination of excipients. Federal circuit however, said that substantial evidence supports the Board’s findings that the prior art discloses the compound tadalafil, the micronization of drugs to less than about 40 microns, and a motivation to combine these teachings. Actelion’s expert testified that even if tadalafil’s absorption was solubility-limited, a skilled artisan would still have considered particle size reduction useful for increasing dissolution rate and improving absorption. Court further said that substantial evidence also supports the Board’s finding that an ordinarily skilled artisan would have combined the claimed excipients recited in claims.

Federal circuit finally rejecting ICOS challenges held that the prior arts provided a motivation to combine the elements in the manner claimed, and there was a reasonable expectation of success & found no error in the Board’s conclusions of obviousness. Federal circuit therefore affirmed the Board’s conclusion that claims 1–32 of the ’958 patent and claims 1–11 of the ’975 patent would have been obvious. 

Lurasidone – USA

On Apr. 16, 2018, Court of appeal for the federal circuit affirmed New Jersey district court’s claim construction in LATUDA® & found patent infringed by ANDA filers in Hatch-Waxman litigation.

This Hatch-Waxman appeal required federal circuit to construe the scope of a claim depicting a compound’s chemical structure. Although the compound can exist in two different three-dimensional orientations that are mirror images of each other, only one is portrayed in the claim. The district court construed the claim to cover the two three-dimensional orientations in isolation—both the one shown in the claim and its mirror image—as well as mixtures of the two in any ratio.

Sumitomo Dainippon Pharma Co. and Sunovion Pharmaceuticals Inc. own U.S. Patent No. 5,532,372. The ’372 patent relates generally to “novel imide compounds and their acid addition salts” that are useful as antipsychotic agents. Lurasidone, the (–)-enantiomer of an imide compound covered by the ’372 patent, is the active ingredient in Sunovion’s schizophrenia and bipolar depression drug LATUDA®. After Emcure Pharmaceuticals Ltd., Heritage Pharma Labs Inc., InvaGen Pharmaceuticals, Inc., Teva Pharmaceuticals USA, Inc., and Teva Pharmaceutical Industries, Ltd. (collectively, “Appellants”) filed ANDA seeking approval to market generic versions of LATUDA®, Sumitomo and Sunovion sued the Appellants for infringing claim 14 of the ’372 patent.

The claim construction question for the district court centered on what combination of enantiomers claim 14 encompassed. Appellants sought to limit claim 14 to “a racemic mixture of two enantiomers of which the structural formula is representative.” For support, Appellants relied on the claimed structure’s similarities to Compound No. 101, which Appellants contend is a racemic mixture, organic chemistry textbooks suggesting that ordinarily skilled artisans draw a single enantiomer as a shorthand representation for a racemic mixture, and the ’372 patent’s prosecution history. The district court rejected Appellants’ narrow construction, which would have excluded the specific enantiomer depicted in claim 14. The court adopted Sunovion’s proposal to construe claim 14 as covering “lurasidone, lurasidone’s enantiomer, as well as mixtures of these enantiomers.” Following the district court’s claim construction order, Appellants stipulated to infringement of claim 14 and the entry of permanent injunctions. Appellants then filed this appeal.

On appeal, federal circuit said that the plain claim language and specification demonstrate that, at a minimum, claim 14 covers what it depicts: the (–)-enantiomer. Of equal importance is the lack of anything in the claim language limiting its scope to a “racemate” or “racemic mixture.” Absent some indication in the specification or prosecution history to the contrary, it follows that the plain and ordinary meaning of claim 14 covers at least the specific enantiomer depicted in the claim itself. Federal circuit further said that Appellants’ claim construction arguments conflict with Pfizer and other precedent because they seek to import limitations from the specification into the claim. Even if Compound No. 101 is a racemic mixture, the specification neither defines claim 14’s structure as Compound No. 101 nor disclaims scope in a way that confines claim 14 to a racemic mixture. Claim 14 does not refer to Compound No. 101, and nothing in the specification links the two structures together.

Federal circuit further said that, Appellants’ organic chemistry textbooks and expert testimony do not compel a different result. Extrinsic evidence is, in general, “less significant than the intrinsic record in determining ‘the legally operative meaning of claim language.’” Phillips, 415 F.3d at 1317 (quoting C.R. Bard, Inc. v. U.S. Surgical Corp., 388 F.3d 858, 862 (Fed. Cir. 2004)). This is particularly so here, where the intrinsic record demonstrates that claim 14’s structure covers at least the (–)-enantiomer. Federal circuit thus did not see clear error in the district court’s rejection of the organic chemistry textbooks as irrelevant or contradictory to Appellants’ construction.

Thus, finally federal circuit held that district court did not err in construing claim 14 to cover the (–)-enantiomer. The judgment of the district court therefore affirmed.

Fulvestrant - Netherlands

On Apr. 11, 2018, District Court The Hague handed down its decision in FASLODEX® & revoked formulation patents for lack of inventive step in a revocation proceeding initiated by Sandoz.

AstraZeneca is the holder of the European patents EP 1250138 B2 and EP 2266573 B1. The patents belong to the same patent family, both bear the title " Fulvestrant formulation." Court considered “Howell” as closest prior art, which shows results from Phase II clinical studies with fulvestrant for the treatment of estrogen-dependent breast cancer. It discloses formulation of fulvestrant in castor oil containing 250 mg / ml fulvestrant is administered intramuscularly to patients with breast cancer. It is also shown in Howell that the blood plasma concentration of fulvestrant remains at a therapeutically relevant value for a month.

Based on the foregoing, the objective technical problem can, in the opinion of the District Court, be further specified as follows: “the provision of a fulvestrant formulation in which 250 mg of fulvestrant is dissolved in 5 ml of castor oil and the formulation (i) is suitable for treatment. of breast cancer, (ii) does not precipitate and (iii) with sustained release, in that a therapeutically significant plasma concentration is obtained for at least two weeks after administration 5 ml by intramuscular injection”.

Court further said that in the search for a solution to the problem, the person skilled in the art would primarily look for known castor oil formulations of fulvestrant. Applying a previously disclosed formulation is after all the simplest solution to the problem. The court agreed with Sandoz that the expert will encounter “McLeskey” in the same field - research into the treatment of breast cancer - and was public. In McLeskey, moreover, reference is made to Howell. In McLeskey two different formulations of fulvestrant are disclosed, both with a concentration of 50 mg fulvestrant / ml, as shown by the description of the drugs used. In McLeskey, therefore, one skilled in the art will find a preformulated solution of fulvestrant in castor oil with exactly the target concentration (50 mg / ml corresponds to 250 mg in 5 ml, as used in Howell, sub-features 30.5 and 30.6).

The person skilled in the art knew that there had to be a formulation which showed the positive therapeutic effects, sustained release and few side effects disclosed in Howell, in which 250 mg of fulvestrant was dissolved in 5 ml of castor oil. He also knew by the clinical research published in Howell, but also by publications of (the predecessor of) AstraZeneca , that fulvestrant was promising for the second-line treatment (after tamoxifen) of (estrogen-dependent) breast cancer in humans. According to the person skilled in the art, it was not possible to dissolve 250 mg of fulvestrant without excipients in 5 ml of castor oil. This provides an important motivation to search for a formulation containing 5 ml (this is the maximum amount that can be comfortably injected intramuscularly). In McLeskey a formulation is disclosed with three excipients (15% w / v BzBz, 10% w / v BzOH and 10% w / v EtOH) where fulvestrant is dissolved in the desired concentration in castor oil. The excipients that are disclosed in McLeskey are therefore excipients that are suitable for and not unusual in medicines. This fact will put the person skilled in the art on the trail that there may be a suitable formulation, and in any case the used expedients will not prevent him from doing research.

Court further held that the relevant person skilled in the art, starting from the objective technical problem and encountering the castor oil formulation of McLeskey, will examine the suitability of that formulation with standard tests with a reasonable expectation of success. In doing so, he will find that the formulation in vivoanimal testing on rabbits is appropriate for the treatment of breast cancer, does not precipitate and that there with a therapeutically significant plasma concentration is obtained for at least two weeks after administration of 5 ml by intramuscular injection, at least for five days in rabbits. He thus comes to the invention claimed in claim 30 without creative thinking. This implies that conclusion 30 in combination with claims 1 and 29 of EP 138 is null and void due to lack of inventiveness.

EP 573 is a (small) daughter of EP 138. EP 573 discloses the specific formulation of (claim 30 of EP 138), which has previously been found invalid. Neither has it been established nor revealed that EP 573 discloses other sub-features which make it inventive. The same applies to the sub claims. All this implies that EP 573 on the same grounds as considered with regard to EP 138 is not inventive based on Howell in combination with general knowledge and McLeskey, so that the Dutch part of this patent will also be destroyed. 

Iloperidone – USA

On Apr. 13, 2018, Federal Circuit affirmed district court’s decision in Fanapt® finding patent valid & infringed by ANDA filer in Hatch-Waxman litigation.

Vanda owns New Drug Application for Fanapt® (iloperidone), an atypical antipsychotic approved by the USFDA in 2009 for the treatment of patients with schizophrenia. Vanda owns US 8,586,610 patent, which will expire on November 2, 2027. The ’610 patent relates to a method of treating schizophrenia patients with iloperidone wherein the dosage range is based on the patient’s genotype. The ’610 patent teaches “that treatment of a patient, who has lower CYP2D6 activity than a normal person, with a drug [such as iloperidone] that is pre-disposed to cause QT2 prolongation and is metabolized by the CYP2D6 enzyme, can be accomplished more safely by administering a lower dose of the drug than would be administered to a person who has normal CYP2D6 enzyme activity.”

Claim 1 of the ’610 patent is representative and reads as follows:

A method for treating a patient with iloperidone, wherein the patient is suffering from schizophrenia, the method comprising the steps of:

determining whether the patient is a CYP2D6 poor metabolizer by: obtaining or having obtained a biological sample from the patient; and performing or having performed a genotyping assay on the biological sample to determine if the patient has a CYP2D6 poor metabolizer genotype; and if the patient has a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount of 12 mg/day or less, and if the patient does not have a CYP2D6 poor metabolizer genotype, then internally administering iloperidone to the patient in an amount that is greater than 12 mg/day, up to 24 mg/day, wherein a risk of QTc prolongation for a patient having a CYP2D6 poor metabolizer genotype is lower following the internal administration of 12 mg/day or less than it would be if the iloperidone were administered in an amount of greater than 12 mg/day, up to 24 mg/day.

In 2013, West-Ward filed Abbreviated New Drug Application (“ANDA”) seeking approval to commercially manufacture, use, offer to sell, and sell a generic version of Fanapt® in 1 mg, 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg strengths. The proposed ANDA label is substantially identical in all material respects to the Fanapt® label. The proposed label provides that the “[i]loperidone dose should be reduced by one-half for poor metabolizers of CYP2D6 [see Pharmacokinetics (12.3)].” Section 5.2, entitled “QT Prolongation,” explains: “iloperidone was associated with QTc prolongation of 9 msec at an iloperidone dose of 12 mg twice daily” and that “[c]aution is warranted when prescribing iloperidone . . . in patients with reduced activity of CYP2D6 [see Clinical Pharmacology (12.3)].” Following a bench trial, the district court found that West-Ward’s proposed products induce infringement of the asserted claims of the ’610 patent, but do not contributorily infringe them. The court found that the proposed ANDA label “recommends”: (1) “practitioners use iloperidone to treat patients suffering from schizophrenia”; (2) “oral administration of iloperidone tablets at 12 to 24 mg/day to nongenotypic CYP2D6 poor metabolizers and 12 mg/day or less to genotypic CYP2D6 poor metabolizers”; and (3) “practitioners perform or have performed a genotyping assay to determine whether patients are CYP2D6 poor metabolizers.”

The district court also held that the asserted claims were not invalid under § 101, § 103, or § 112 for lack of written description. The court did conclude that “the asserted claims depend upon laws of nature,” specifically, “the relationship between iloperidone, CYP2D6 metabolism, and QTc prolongation.” But the court explained that the ’610 patent “addresses natural relationships to which the claims add conducting CYP2D6 genotyping tests to determine the appropriate dose of iloperidone to reduce QTc-related risks.” “The court f[ound] that while it may have been conventional to investigate for side-effects, [West-Ward] has not proven by clear and convincing evidence that the precise test and the discovered results were routine or conventional.” West-Ward appealed from the district court’s final judgment.

Induced Infringement:

During appeal, West-Ward argued that the district court clearly erred in finding that it would induce infringement because Vanda failed to prove the requisite direct infringement and specific intent to induce infringement. Specifically West-Ward argued that the district court clearly erred in finding that its proposed label “satisfies” the asserted claims because the language of the label itself cannot constitute direct infringement of the asserted method claims. Turning to specific intent, West-Ward argued that Vanda failed to prove that its proposed label would “‘encourage’ or ‘recommend’ a direct infringer (a psychiatrist or other physician) to perform each step of the claimed methods.” West-Ward contended that the substantial number of noninfringing uses precludes a finding of specific intent as a matter of law.

Federal circuit, however agreed with Vanda that the district court did not clearly err in finding induced infringement of independent claims 1, 9, and 13.8.  Section 2.1 of label entitled, “Usual Dose,” states: Iloperidone must be titrated slowly from a low starting dose . . . . The recommended starting dose for iloperidone tablets is 1 mg twice daily. Dose increases to reach the target range of 6 to 12 mg twice daily (12 to 24 mg/day) may be made with daily dosage adjustments not to exceed 2 mg twice daily (4 mg/day). The maximum recommended dose is 12 mg twice daily (24 mg/day). . . . Prescribers should be mindful of the fact that patients need to be titrated to an effective dose of iloperidone”. Section 12.3 of the proposed label, entitled “Pharmacokinetics,” states: Approximately 7 to 10% of Caucasians and 3 to 8% of Black/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are intermediate, extensive or ultrarapid metabolizers. Co-administration of iloperidone with known strong inhibitors of CYP2D6 like fluoxetine results in a 2.3 fold increase in iloperidone plasma exposure, and therefore one-half of the iloperidone dose should be administered. Similarly, PMs of CYP2D6 have higher exposure to iloperidone compared with [extensive metabolizers] and PMs should have their dose reduced by one-half. Laboratory tests are available to identify CYP2D6 PMs.

Thus, the district court did not clearly err in finding that § 12.3 “recommends that practitioners perform or have performed a genotyping assay to determine whether patients are CYP2D6 poor metabolizers.” Experts for both parties testified that the referred-to “laboratory tests” are “genotyping tests.” The district court thus found that “when the label states that ‘laboratory tests’ are available to identify poor metabolizers, the label is referring to ‘genotyping tests.’” The label instructs practitioners that “PMs should have their dose reduced by one-half. [Genotyping tests] are available to identify CYP2D6 PMs.” The court did not clearly err in finding that this constitutes a recommendation to perform genotyping tests on iloperidone patients.

Court further held that if the proposed ANDA product has “substantial noninfringing uses,” West-Ward may still be held liable for induced infringement. “Section 271(b), on inducement, does not contain the ‘substantial noninfringing use’ restriction of section 271(c), on contributory infringement.” Sanofi, 875 F.3d at 646. Thus, “a person can be liable for inducing an infringing use of a product even if the product has substantial noninfringing uses . . . .”(citing Grokster, 545 U.S. at 934–37).

Patent Subject Matter Eligibility:

Court next addressed whether the asserted claims are directed to patent-eligible subject matter. West-Ward argued that the asserted claims are ineligible under § 101 because they are directed to a natural relationship between iloperidone, CYP2D6 metabolism, and QT prolongation, and add nothing inventive to those natural laws and phenomena. Vanda responded that the asserted claims are patent eligible under § 101 at both steps of Mayo/Alice. Consistent with Supreme Court precedent, federal circuit agreed with Vanda that the asserted claims are not directed to patent-ineligible subject matter. Court further said that, first the claims in Mayo were not directed to a novel method of treating a disease. Instead, the claims were directed to a diagnostic method based on the “relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.”

In this case, the ’610 patent claims are directed to a method of using iloperidone to treat schizophrenia. The inventors recognized the relationships between iloperidone, CYP2D6 metabolism, and QTc prolongation, but that is not what they claimed. They claimed an application of that relationship. Unlike the claim at issue in Mayo, the claims here require a treating doctor to administer iloperidone in the amount of either (1) 12 mg/day or less or (2) between 12 mg/day to 24 mg/day, depending on the result of a genotyping assay. The specification further highlights the significance of the specific dosages by explaining how certain ranges of administered iloperidone correlate with the risk of QTc prolongation. Thus, the ’610 patent claims are “a new way of using an existing drug” that is safer for patients because it reduces the risk of QTc prolongation. At bottom, the claims here are directed to a specific method of treatment for specific patients using a specific compound at specific doses to achieve a specific outcome. They are different from Mayo. They recite more than the natural relationship between CYP2D6 metabolizer genotype and the risk of QTc prolongation. Instead, they recite a method of treating patients based on this relationship that makes iloperidone safer by lowering the risk of QTc prolongation. Accordingly, the claims are patent eligible.

Written Description:

West-Ward’s argued that the district court erred in finding that the claims are not invalid for lack of adequate written description. Specifically, West-Ward argued that the asserted claims are invalid for lack of written description because nothing in the ’610 patent demonstrates possession of the claimed dosage ranges for poor and non-poor CYP2D6 metabolizer genotypes. West-Ward contended that the description does not contain experiments with doses of 12 mg/day or less given to poor metabolizers, and reports data that does not support the claimed poor-metabolizer dose range. However, Federal circuit agreed with Vanda that the district court did not clearly err in finding that the ’610 patent contains adequate written description for the claimed “12 mg/day or less” dosage range for poor metabolizers. The ’610 patent further explains that the reported results “show that patients can be more safely treated with iloperidone if the dose of iloperidone is adjusted based on the CYP2D6 genotype of each patient.”

Thus for the foregoing reasons, Federal circuit affirmed the district court’s decision.

Ferric Carboxymaltose – USA

On Apr. 12, 2018, in one liner decision, Federal Circuit affirmed Patent Trial and Appeal Board’s (PTAB) decision in two IPRs finding certain claims unpatentable.

Previously, PTAB in its decision related to IPR2015-01490 & IPR2015-01493 in Dec 2016 & Jan 2017 found claims of US 7,754,702 and US 8,431,549 unpatentable. These patents are related to administration of stable, high doses of iron. US’702 patent (Exp: 02/13/2027) is listed in Orange Book for INJECTAFER®.

Mesalamine – USA

On Apr. 06, 2018, in one liner decision, Federal Circuit affirmed Florida district court’s non-infringement finding in favor of Mylan in Lialda® Hatch-Waxman litigation.

Previously following a four-day bench trial, U.S. District Judge Charlene Edwards Honeywell in January 2017 concluded that the ANDA from Mylan infringes the US 6,773,720 patent. Mylan appealed but it was deactivated. Mylan then returned to the Florida Middle court & asked to re-consider its decision. The Court agreed, and in Jun 2017 it vacated the prior decision and entered non-infringement judgment in favor of Mylan. This judgment was appealed by Shire. Federal circuit then heard oral argument in Apr 2018 & affirmed the non-infringement decision of Florida court by way of Rule 36 judgment.