Tavaborole – USA

On Aug. 27, 2020, Federal Circuit affirmed PTAB’s decision which found antifungal MoU/composition patents invalid as obvious.

Flatwing pharmaceuticals filed IPRs on US 9,549,938, US 9,566,289, US 9,566,290, and US 9,572,823 patents. These patents are listed in orange book for KERYDIN® (Tavaborole) topical solution, which is marketed by Anacor pharmaceuticals. KERYDIN® is indicated for the treatment of onychomycosis, or fungal infection, of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. Claim 2 of the ’823 patent is representative and it is dependent upon claim 1.

1. A method of delivering a compound, in a human, from a dorsal layer of a nail plate to a nail bed to treat onychomycosis caused by Trichophyton rubrum or Trichophyton mentagrophytes, the method comprising: contacting the dorsal layer of the nail plate with a pharmaceutical composition comprising a compound that penetrates the nail plate, the compound being [tavaborole] or a pharmaceutically acceptable salt thereof, thereby treating onychomycosis due to Trichophyton rubrum or Trichophyton mentagrophytes.

2. The method of claim 1, wherein the pharmaceutical composition is in the form of a topical solution comprising 5% w/w of [tavaborole], and wherein the pharmaceutical composition further comprises ethanol and propylene glycol.

The Board issued final written decisions concluding that the challenged claims would have been obvious over a combination of WO1995/033754 (Austin),US 2002/0165121 (Brehove), and US 6,224,887 (Samour). Austin discloses tavaborole as fungicides which shows antifungal activity against several fungi. Brehove discloses topical compositions of organoboron compounds and results showing nail penetration and antifungal activity for compositions of organoboron compounds formulated in petroleum jelly or mineral oil at 10% or 25% concentration. Samour discloses topical formulations of other antifungal compounds, such as econazole, at concentrations of 5% by weight. The Board found that Austin, Brehove, and Samour each teach antifungal compositions at concentration ranges that overlap 5%, that a skilled artisan would have been able to make the claimed composition of tavaborole using known techniques, and that formulation of tavaborole, even as a boron-containing compound, would not have been unpredictable.

Court’s analysis:

During appeal, Anacor argued that the Board erred in determining that the claimed composition would have been obvious as the product of routine optimization. Specifically, Anacor argued that it would not have been obvious to formulate the claimed composition, as organoborons are quite reactive compounds. Second, Samour teaches away from a 5%-econazole composition in favor of a 10%-econazole composition.

Federal Circuit with respect to teaching away argument said that Samour discloses several small experiments to determine the effect of econazole concentration on nail penetration. The results indicate that 10%-econazole compositions provide greater nail penetration than the 5%-econazole compositions, but the effect is modest overall and depends on other variables, such as excipients. Samour ultimately claims compositions with concentrations of 1 to 10% econazole. Court said that Samour’s teachings barely even suggest a “preference for an alternative” approach—let alone discourage a skilled artisan from pursuing a 5%-antifungal composition, as is required for a reference to teach away.

With respect to special technical challenges in formulating organoborons compounds, court found Anacor’s arguments unpersuasive. Flatwing’s expert said that the claimed composition could have been made according to well-known formulation techniques, and tavaborole’s potential reactivity as an organoboron compound would not have been an important consideration.  Moreover, the inventors evidently did not consider formulating organoborons a great challenge, as the specification does not offer any guidance beyond citation of well-known guides to pharmaceutical formulation.  Furthermore, there is no dispute that a skilled artisan would have appreciated that concentration is a result-effective variable, such that one could optimize nail penetration by routine experimentation within a predictable range of concentrations. Therefore, the selection of 5% as the concentration of a tavaborole composition would have been obvious to a skilled artisan.

Thus, the Board did not err in determining that creating a tavaborole topical composition would have been obvious.

Fingolimod - USA

On Aug. 10, 2020, Delaware Court found multiple sclerosis method of use patent valid & infringed by ANDA filer.

Novartis (Plaintiff) sued many ANDA filers (25 FTF) under Hatch-Waxman Act as Defendants filed ANDAs to market generic version of Gilenya® (0.5 mg capsule) before expiration of US 9,187,405 patent. All of them settled except HEC pharma. US’405 patent claims methods to treat Relapsing-Remitting multiple sclerosis ("RRMS") using  fingolimod at a daily dosage of 0.5 mg, absent an immediately preceding loading dose. Plaintiff asserted that defendant infringed the claims under induced & contributory infringement. Defendant counterclaimed that patent-in-suit is invalid under anticipation & lack of written description support. Delaware court held four-day bench trial from March 2-5, 2020.

Infringement:

1. Induced infringement:

Defendant argued that its label does not instruct physicians to omit a loading dose from the dosing regimen, so it is not practicing one of the elements of the patent claims in suit. Lable does not mention anywhere administration of loading dose. Court, however, said that HEC’s label induces infringement. Nothing in HEC's proposed label says to prescribe anything more or less than 0.5 mg. The label also provides a caution that there is "a greater incidence of adverse reactions without additional benefit" for doses over 0.5 mg. Experts also testified that they have never administered dose greater than 0.5 mg to patients. Court said that the prescribing physician would understand the label to contain the complete dosing information, and the instructions dictate the dose of the drug in question exactly as in the Patent- 0.5 mg daily without a loading dose. If a user follows the instructions, there will be direct infringement. Instructing use that will infringe is an active step that demonstrates a specific intent to infringe.

2. Contributory infringement:

Court said that contributory infringement is found where: ( 1) there is direct infringement; (2) the accused infringer had knowledge of the patent at issue; and (3) the product has no substantial non-infringing uses. HEC is liable for contributory infringement. HEC knew of the '405 Patent and the treatment method it sets forth. Because the only uses for HEC's generic fingolimod product are those identified in the clinical trial section of the proposed label, there is no substantial non-infringing use for which the product is indicated.  If a user follows the instructions on the label, there will be direct infringement.

Invalidity:

1. Anticipation:

HEC argued that the '405 Patent is anticipated by an abstract (Kappos 2006) published in the Journal of Neurology and presented at the European Neurologic Society Meeting in 2006. Kappos 2006 announces an upcoming Phase III trial of 1.25 mg and 0.5 mg doses of fingolimod daily compared to a placebo. Court, however, said that there is insufficient evidence to establish Kappos 2006 as prior art, as it has not been shown to have been available before June 27, 2006 (priority date). A copy of Kappos 2006 with a declaration from an employee from the British Library was offered but not admitted into evidence. The declaration is inadmissible hearsay and, in any event, is internally inconsistent regarding the location and availability of the document. It does not provide any information on the procedures for cataloging, indexing, or shelving of the Kappos 2006. So, it was not publicly available as on priority date.

If Kappos 2006 is considered admissible then also this abstract offers no evidence of effectiveness, which a person of skill would look for as an indication of a treatment purpose. It does not mention a loading dose. Unlike a patent, which is presumed complete, an abstract of an academic paper is not presumed to contain all of the necessary information about the study. Kappos 2006 does not enable the use of 0. 5 mg daily to treat RRMS because it would require undue experimentation.  HEC has failed to prove by clear and convincing evidence that Kappos 2006 anticipates each and every limitation of claims.

2. Lack of written description support:

HEC argued that the ‘405 has no written description support for the negative limitation "absent an immediately preceding loading dose" or for the claimed “0.5mg daily dose”. Court, however, said that examples mentioned in the specification discloses 0.5 mg dose and therefore POSA upon reading the specification would have known that 0.5 mg dose is effective in treating RRMS. With respect to loading dose court said that the absence of an immediately preceding loading dose from the specification, and example, would tell a person of skill that loading doses are excluded from the invention. If a loading dose were directed, the patent would say that a loading dose should be administered initially." But this is not the case here as patent in silent on loading dose. A person of skill in 2006 would not expect a loading dose to be used to treat RRMS with fingolimod. The patent here provides a sufficient written description of the invention such that a person of ordinary skill would know that loading dose is not required in treating RRMS. Thus, the inventors were in possession of the invention.

Naloxone hydrochloride (NARCAN) - USA

 

IPR decision: Aug. 21, 2020

AIA Review #	Filing Date	Institution Date	Petitioner	Patent	Respondent	Final Written Decision
IPR2019-00685	02/19/2019	08/27/2019	Nalox-1 Pharmaceuticals, LLC	9,211,253	Opiant Pharmaceuticals, Inc.	No Challenged Claims Unpatentable
IPR2019-00688	02/19/2019	09/09/2019	Nalox-1 Pharmaceuticals, LLC	9,468,747	Opiant Pharmaceuticals, Inc.	No Challenged Claims Unpatentable
IPR2019-00694	02/19/2019	09/11/2019	Nalox-1 Pharmaceuticals, LLC	9,629,965	Opiant Pharmaceuticals, Inc.	No Challenged Claims Unpatentable

On US’253, Nalox-1 Pharmaceuticals filed IPRs (IPR2019-00686 & IPR2019-00687) which were denied by PTAB.

On US’747, Nalox-1 Pharmaceuticals filed IPRs (IPR2019-00689 & IPR2019-00690) which were denied by PTAB.

On US’965, Nalox-1 Pharmaceuticals filed IPRs (IPR2019-00695 & IPR2019-00696) which were denied by PTAB.

US  9,211,253 (Lightlake Therapeutics Inc.; Exp: 03/16/2035):

1. A single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 .mu.L comprising: about 4 mg naloxone hydrochloride or a hydrate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of a preservative; about 0.2 mg of a stabilizing agent; an amount of an acid sufficient to achieve a pH or 3.5-5.5.

US  9,468,747 (Lightlake Therapeutics Inc / Opiant pharma.; Exp: 03/16/2035):

1. A method of treatment of opioid overdose or a symptom thereof, comprising nasally administering to a patient in need thereof a dose of naloxone hydrochloride using a single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which is an aqueous solution of about 100 .mu.L comprising: about 4 mg naloxone hydrochloride or a hydrate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer; between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of an acid sufficient to achieve a pH of 3.5-5.5.

30. A pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 .mu.L: about 4 mg naloxone hydrochloride or a hydrate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of a compound which is at least one of a preservative, a cationic surfactant, and a permeation enhancer; between about 0.1 mg and about 0.5 mg of a stabilizing agent; an amount of an acid sufficient to achieve a pH of 3.5-5.5.

US  9,629,965 (Opiant  pharma; Exp: 03/16/2035):

1. A pharmaceutical formulation for intranasal administration comprising, in an aqueous solution of not more than about 140 .mu.L: about 4 mg naloxone hydrochloride; about 0.74 mg NaCl; about 0.01 mg benzalkonium chloride; about 0.2 mg disodium edetate; and an amount of hydrochloric acid sufficient to achieve a pH of 3.5-5.5.

20. A single-use, pre-primed device adapted for nasal delivery of a pharmaceutical composition to a patient by one actuation of said device into one nostril of said patient, having a single reservoir comprising a pharmaceutical composition which comprises per 100 .mu.L of aqueous solution: about 4 mg naloxone hydrochloride or a hydrate thereof; between about 0.2 mg and about 1.2 mg of an isotonicity agent; between about 0.005 mg and about 0.015 mg of a preservative; between about 0.1 mg and about 0.5 mg of a stabilizing agent; and an amount of an acid sufficient to achieve a pH of 3.5-5.5.

Famotidine & Ibuprofen – USA

Claim construction (US 8,067,451)

Plaintiff: Horizon Medicines LLC

Defendant: Alkem Laboratories Ltd.

Case No.: 18-1014

Court: District of Delaware

Date: August 7, 2020 

Claim 1 of the ’451 patent is representative:

An oral dosage in tablet form comprising a first portion that comprises 800 mg ibuprofen and a second portion that comprises 26.6 mg famotidine, wherein a barrier layer comprising hydroxyl propyl methyl cellulose 2910, polyoxyethylene glycol 400, polysorbate 80, and titanium dioxide surrounds the second portion completely separating it from the first portion, wherein upon storage of the oral dosage in tablet form at 40° C. and 75% humidity for one month, no more than about 0.5% total famotidine impurities is present in the oral dosage in tablet form; wherein the oral dosage in tablet form is formulated so that release of both the ibuprofen and the famotidine occurs rapidly at about the same time, wherein none of the oral dosage in tablet form, the famotidine, and the ibuprofen is enterically coated or formulated for sustained or delayed release, wherein the oral dosage in tablet form is for use according to a TID (three times per day) administration schedule for reducing the risk of developing ibuprofen-induced ulcers in a human patient requiring ibuprofen for an ibuprofen-responsive condition selected from the group consisting of rheumatoid arthritis, osteoarthritis, and pain from a condition other than rheumatoid arthritis and osteoarthritis wherein the human patient does not suffer at the times of administering from a condition characterized by hypersecretion of gastric acid and/or from active severe oesophagitis and/or Barrett's ulceration, and/or from gastroesophageal reflux disease.

Construction of disputed term:

“a barrier layer comprising hydroxyl propyl methyl cellulose 2910, polyoxyethylene glycol 400, polysorbate 80, and titanium dioxide surrounds the second portion completely separating it from the first portion” (claims 1, 10)

a. Plaintiff's proposed construction: no construction needed

b. Defendant's proposed construction: a single barrier layer consisting essentially of hydroxyl propyl methyl cellulose 2910, polyoxyethylene glycol 400, polysorbate 80, and titanium dioxide surrounds the famotidine portion completely separating it from the ibuprofen portion.

c. Court’s construction: a barrier layer consisting essentially of hydroxyl propyl methyl cellulose 2910, polyoxyethylene glycol 400, polysorbate 80, and titanium dioxide surrounds the famotidine portion completely separating it from the ibuprofen portion.

Apixaban - USA

On Aug. 05, 2020, Delaware Court found compound and composition patents valid & infringed by ANDA filers.

Bristol-Myers Squibb / Pfizer Inc. (Plaintiffs) sued Sigmapharm Laboratories, Sunshine Lake Pharma and Unichem Laboratories (Defendants) under Hatch-Waxman Act as Defendants filed ANDAs to market generic version of Eliquis® [All other, at least 22 Defendants resolved their disputes before trial]. Plaintiffs sued Defendants for infringement of US 6,967,208 (compound patent – expiring on 11/21/2026) and US 9,326,945 (composition patent – expiring on 02/24/2031). Defendants brought counterclaims alleging that the asserted claims of both the '208 (claims 13 and 104) and '945 (claims 21 and 22) patents are not infringed and invalid. The Court held a nine-day bench trial between October 23 and November 13, 2019.

Asserted claims (US’208): Claim 13 which is a dependent claim recites apixaban or a pharmaceutically acceptable salt form of apixaban. Claim 104 which is dependent on claim 13 recites crystalline apixaban.

Asserted claims (US’945): Claims 21 and 22 (recites dose of apixaban as 2.5 mg & 5 mg respectively) depend on claim 12 which is:

12. A solid pharmaceutical composition comprising a therapeutically effective amount of apixaban and a pharmaceutically acceptable diluent or carrier, wherein apixaban comprises crystalline apixaban particles, wherein the crystalline apixaban particles have a D.sub.90 equal to or less than about 89 µm, and wherein, as measured using a USP Apparatus 2 at a paddle rotation speed of 75 rpm in 900 mL, of a dissolution medium at 37.degree. C., at least 77 wt % of apixaban in the pharmaceutical composition dissolves within 30 minutes in the dissolution medium, and the dissolution medium is 0.05 M sodium phosphate at a pH 6.8 containing 0.05% sodium lauryl sulfate.

Infringement:

1. Sigmapharm’s ANDA:

Sigmapharm used crystalline Form I of apixaban as the starting material for manufacturing of apixaban tablet. It used process where crystalline Form I was dissolved in solution with povidone & then it was sprayed, dried to make amorphous solid dispersion.  

With respect to US’208 patent, Sigmapharm argued that claim 1 of the patent on which claim 13 & claim 104 depend does not cover apixaban. Claim 1 requires that particular rings are “substituted with” certain number of R groups. Sigmapharm contended that each of these limitations specifies how many hydrogen atom “substituents” can be included in each ring.  BMS countered that it requires only how many R groups can be replaced in the rings. Court rejected Sigmapharm’s theory & agreed with BMS. Court said that accepting Sigmapharm’s theory would be in tension with well-established case laws because it results in preferred embodiments being excluded from the scope of the claims. Sigmapharm’s expert agreed that under this interpretation, none of the compounds disclosed in US’208 patent would fall within scope of claim 1. Thus, court found that claim 1 covers apixaban & therefore Sigmapharm’s ANDA infringes dependent claim 13.

With respect to US’945 patent, Sigmapharm argued that BMS failed to prove that its ANDA product contain crystalline apixaban & crystalline apixaban having claimed particle size. But court said that BMS expert, Dr Atwood identified four characteristic crystalline apixaban peaks at 12.3, 12.9, 27.1 & 22.1. In defense, Sigmapharm contended that its expert, Dr. Zaworotko’s XRPD testing revealed no evidence of crystalline apixaban. Court, however, said that Dr. Atwood’s method was more sensitive than Dr. Zaworotko because Dr. Atwood used count times of between 30 and 100 seconds. Sigmapharm non-infringement defense was largly relied on attacking the evidences developed by BMS experts. But court did not find Sigmapharm’s argument persuasive enough to discredit BMS expert. Sigmapharma finally argued that even if some of the apixaban in its ANDA prodcuct is crystallized, there is no “apixaban particle” as required by claims but rather “composite particles consisting of PVP-apixaban bonded together”.  Court, however, said that Sigmapharma has not shown that such composite particles do not contain crystalline apixaban particles. Thus, court concluded that any crystalline apixaban in Sigmapharma’s ANDA product consist of crystalline apixaban particles.

With respect to particle size limitation (D₉₀ less than 89 µm), Sigmapharm argued that BMS has not met its burden of proof because it did not measure any crystalline apixaban particles in tablet. BMS countered that it did not need to measure or calculate precise D₉₀ value because Sigmapharm’s manufacturing process makes it impossible for any crystalline apixaban particles to have D₉₀ greater than 89 µm. Court agreed with BMS & said that there is no general rule requiring to perform actual tests or experiments  on the accused product to prove infringement. Therefore, BMS has proved that Sigmapharm’s ANDA has crystalline apixaban particles with D₉₀ equal or less than 89 µm & thus it infringed US’945 patent.

2. Sunshine’s ANDA:

Sunshine also used similar process where amorphous dispersion was formed using crystalline apixaban & povidone. Court here also said that BMS has proved by preponderance of the evidence that Sunshine’s ANDA product contains crystalline apixaban particles. Dr. Atwood identified crystalline apixaban peaks at 12.3 & 27.1 which are listed in the US’945 patent as characteristics peaks. Sunshine’s expert, Dr. Brittain did not find evidence of  crystalline apixaban in its XRPD testing. Bur court said that Dr. Brittain testing was less sensitive than Dr. Atwood because Dr. Brittain used scan times of 1.75 seconds per step, whereas Dr. Atwood used scan times of upto 1000 seconds per step. With respect to particle size limitation (D₉₀ less than 89 µm), court here also agreed with BMS & said that it has proven that Sunshine’s ANDA meets this limitation. Court said that crystalline apixaban in ANDA product can not exceed 89 µm because apixaban was rapidly dried & used in very small quantity relative to the excipients during manufacturing. Therefore, BMS has proved that Sunshine’s ANDA has crystalline apixaban particles with D₉₀ equal or less than 89 µm & thus it infringes US’945 patent.

3. Unichem’s ANDA:

Unichem manufactured its ANDA product by Fluidized bed process. First dry excipients were fed into fluidized bed granulator. In parallel, starting apixabam API was dissolved in volatile solvents such as methylene chloride & isopropyl alcohol. Then this solution was sprayed onto surface of excipient particles floating in the fluidized bed granulator. Thus, volatile solvents evaporated leaving behind small apixaban particles deposited on excipient particles. After granulation, subsequent steps were undertaken to form tablet. The only limitation Unichem disputed was paticle size limitation.

BMS expert, Dr. Berkland analysed ANDA product using SEM-EDS technique. After observing 68 granules containing thousands of apixaban particles, he determined that all of the particles were 1 µm in size. Therefore, crystalline apixaban in Unichem’s ANDA product had D₉₀ equal or less than 89 µm. Dr. Berkland opined that his conclusions were consistent with Unichem’s manufacturing process which causes evaporation of volatile solvents leaving behind small apixaban particles. Unichem attemped to defeat BMS infringement case but it failed. Court was also not persuaded by Unichem’s affirmative evidence that it’s apixaban API has D₉₀ value between 150 – 1000 µm. Court said that this evidence is based on starting apixaban API, not the apixaban in Unichem’s ANDA product which has different form. Thus, court found that BMS has proven that Unichem’s ANDA product infringes the asserted claims of US’945 patent.

Invalidation:

With respect to invalidation, Defendants put forth various attacks such as improper dependency, lack of enablement, lack of written description and obviousness.  But, court found that Defendants failed to prove that asserted claims are invalid.

Bictegravir – USA

On Aug. 03, 2020, Delaware district court denied Gilead's Motion for Summary Judgment of non-infringement.

ViiV Healthcare / Shionogi & Co., Ltd. (Plaintiffs) filed lawsuit accusing Gilead Sciences, Inc. (Defendant) of infringement of US 8,129,385 patent. The US’385 patent covers pharmaceutical compounds for treating the human immunodeficiency virus (HIV). ViiV alleged that Gilead's HIV drug product, Bictegravir infringes claim 6 of the US’385 patent under the doctrine of equivalents. Bictegravir has a benzyl ring with three fluorines. 

Claim 6 of the US’385 patent claims four compounds, and pharmaceutically acceptable salts thereof, each with a benzyl ring that has two fluorines. Gilead moved for summary judgment of noninfringement based on the argument that two-fluorines limitation in claim 6 specifically excludes compounds with three fluorines.

Court said that the implicit disclaimer-known as the “specific exclusion principle” precludes a finding of equivalency infringement when a feature of the accused product is "the opposite of, or inconsistent with, [a] recited limitation" of the asserted claim. Here it is undisputed that a difluoro benzyl ring is not the same thing as a trifluoro benzyl ring. But it is not clear from the claims or written description of the US’385 patent that a difluoro benzyl ring necessarily excludes a trifluoro benzyl ring. Gilead has neither alleged nor submitted record evidence such as an expert affidavit to establish that a difluoro benzyl ring is the opposite of or incompatible with a trifluoro benzyl ring. ViiV, on the other hand, has alleged, and has submitted an expert affidavit to establish, that a trifluoro benzyl ring is not the opposite of and not incompatible with a difluoro benzyl ring. Accordingly, the specific exclusion principle does not bar ViiV from alleging that Bictegravir infringes claim 6 under the doctrine of equivalents.

Colchicine – USA

On Jul. 31, 2020, Federal Circuit affirmed district court’s decision in denying a preliminary injunction because Plaintiff failed to show that it was likely to succeed on the merits or that it would be irreparably harmed absent a preliminary injunction.

Background:

Takeda (Plaintiff) held NDA for Colcrys® (colchicine) tablet.  Mylan (Defendant) filed ANDA with USFDA to market generic version of Colcrys®. Plaintiff sued defendant in 2016 for infringement of orange book patents. The parties ultimately resolved the litigation through a Settlement Agreement. The Agreement allowed Mylan to sell a generic colchicine product on a specified date, or in the event of certain circumstances defined in Section 1.2, on an earlier date. According to another Section 1.10 of the Agreement, if Mylan breaches Section 1.2, the parties stipulate that such breach “would cause Takeda irreparable harm.” Concurrent with its litigation against Mylan, Takeda also pursued patent infringement claims against Hikma for its 505(b)2 product, Mitigare®. Initially, Takeda asserted eight of the Licensed Patents against Hikma in the West-Ward Litigation. But after the parties voluntarily dismissed with prejudice five of those patents, only three patents remained at issue in the case. Ultimately, in December 2018, the district court granted summary judgment in favor of Hikma, holding that Hikma did not infringe any asserted claim of the three remaining Licensed Patents. The court entered its final judgment of noninfringement the same day. Takeda did not appeal.

In October 2019, Mylan notified Takeda that it planned to “immediately start selling” a generic colchicine product pursuant to Section 1.2(d) of the Agreement. Mylan asserted that the provision had been triggered by a “judgment of noninfringement” in favor of West Ward/Hikma. Shortly after Mylan launched its product, on December 2, 2019, Takeda filed a complaint in Delaware court, alleging breach of contract and aksed for preliminary injunction. After full briefing and oral argument, the district court issued an order denying Takeda’s motion for preliminary injunction. You can read the decision summary “here” on this blog. Takeda appealed.

Section 1.2(d) states that Mylan is entitled to launch a generic at:

“The date that is [a specified time period] after the date of a Final Court Decision (as defined in Exhibit A) holding that all unexpired claims of the Licensed Patents that were asserted and adjudicated against a Third Party are either (i) not infringed, or (ii) any combination of not infringed and invalid or unenforceable”

Court’s analysis:

On appeal Takeda argued that the district court ignored the term “all” in Section 1.2(d), and by giving effect only to the word “adjudicated,” the court “read out the requirement that Section 1.2(d) is triggered only when ‘all’ asserted patents are adjudicated.” Takeda, therefore, argued that the West-Ward Litigation—which did not include a holding of noninfringement, invalidity, or unenforceability for five of the Licensed Patents—does not trigger Section 1.2(d) because “not all the claims that were asserted in that case were held to be not infringed . . . by a Final Court Decision.” Federal Circuit, however, disagreed with Takeda’s reading of the Agreement and said that plain language of Section 1.2(d), does not support Takeda’s interpretation.  Section 1.2(d) clearly states that Mylan may launch its generic colchicine product following “a Final Court Decision . . . holding that all unexpired claims of the Licensed Patents that were asserted and adjudicated against a Third Party are . . . not infringed.” Section 1.2(d) does not require, as Takeda suggests, a Final Court Decision for all claims that have merely been asserted during the course of the litigation. Instead, the plain language of the clause requires a Final Court Decision for all claims that are both asserted and adjudicated.

Takeda further argued that the district court’s interpretation of the Agreement is counter to the parties’ intent to limit Section 1.2(d) to changes in status quo with respect to generic colchicine products, which do not include Hikma’s Mitigare® product at the center of the West-Ward Litigation. Federal Circuit again disagreed with Takeda’s interpretation. Court said that the parties’ “intent” to limit Mylan’s market entrance under Section 1.2(d) based on changes in the generic Colcrys® market is absent from the language of the provision. Section 1.2(d) makes no mention of generic Colcrys® products. Indeed, Takeda admited that Section 1.2(d) “does not expressly exclude a litigation that does not involve a generic Colcrys® product.” Furthermore, the West-Ward Litigation, which resulted in a change in the status quo of three Licensed Patents, is exactly a circumstance Takeda asserts Section 1.2(d) was intended to cover. Accordingly, even to the extent it is proper to allow the subjective intent of the parties to control interpretation of the License Agreement, Takeda has not shown that the parties intended to exclude the West-Ward Litigation from Section 1.2(d). The parties further agreed that all unexpired claims of the remaining three Licensed Patents were adjudicated when the district court entered summary judgment of noninfringement for those claims. Thus, the West-Ward Litigation triggered Section 1.2(d) because all unexpired claims of the three Licensed Patents that were “asserted and adjudicated” against a Third Party were held to be not infringed in a Final Court Decision. Thus, Federal Circuit held that Takeda is unlikely to succeed on the merits.

With respect to irreparable harm, Takeda primarily relied on Section 1.10 of the License Agreement to prove irreparable harm. By its terms, Section 1.10 only offers Takeda a basis for establishing irreparable harm in the event Mylan breached Section 1.2. Federal Circuit said that it is unlikely Takeda can show that Mylan breached the License Agreement, as discussed above. Therefore,  Section 1.10 is not useful for establishing irreparable harm in this case. Without the stipulation of irreparable harm, Takeda made no credible assertion that it cannot be compensated by monetary damages. Takeda’s nonspecific and unsupported assertion that Mylan’s sales “likely will cause” irreparable harm falls far short of establishing that irreparable harm has occurred, or will likely occur, absent a preliminary injunction. Federal Circuit, thus, agreed with the district court that Takeda has not shown that it would be irreparably harmed absent a preliminary injunction.

Thus, district court’s denial of Takeda’s request for a preliminary injunction was affirmed.

Levothyroxine – USA

On Jul. 31, 2020, Federal Circuit affirmed district court’s decision which found levothyroxine composition patent invalid as indefinite under 35 U.S.C. § 112.

Background:

IBSA Institut Biochimique / IBSA Pharma Inc. (Plaintiffs) held NDA for Tirosint®(levothyroxine sodium) soft gel capsule.  Teva (Defendant) filed ANDA with USFDA to market generic version of Tirosint®.  Plaintiffs sued defendant for infringement of US 7,723,390 patent. The ’390 patent, entitled “Pharmaceutical Formulations for Thyroid Hormones,” provides pharmaceutical formulations based on thyroid hormones enabling a safe and stable oral administration for thyroid disorders. After trial, the district court held claims 1, 2, 4, and 7–9 invalid as indefinite.

Central issue is the parties’ dispute over the construction of “half-liquid,” which appears in independent claim 1.

1. A pharmaceutical composition comprising thyroid hormones or their sodium salts in the form of either: a) a soft elastic capsule consisting of a shell of gelatin material containing a liquid or half-liquid inner phase comprising said thyroid hormones or their salts in a range between 0.001 and 1% by weight of said inner phase, dissolved in gelatin and/or glycerol, and optionally ethanol, said liquid or half-liquid inner phase being in direct contact with said shell without any interposed layers, or b) a swallowable uniform soft-gel matrix comprising glycerol and said thyroid hormones or their salts in a range between 0.001 and 1% by weight of said matrix.

IBSA proposed that the term “half-liquid” should be construed to mean “semi-liquid, i.e., having a thick consistency between solid and liquid.” Teva argued that the term “half-liquid” is indefinite or should be construed as “a non-solid, non-paste, non-gel, non-slurry, nongas substance.”

Court’s analysis:

Federal Circuit first looked at the claim & said that the claim language of the ’390 patent does not make the meaning of “half-liquid” reasonably clear. The term “half-liquid” is merely used alongside “liquid” to describe the inner phase of a soft elastic capsule. Next looking at the specification, Federal Circuit said that the paragraphs in the specification designate a “half-liquid” is an alternative to the other members of the list, including pastes and gels which can be considered a phase between solid & liquid. Therefore, it is distinct from the “semi-liquid” as suggested by plaintiffs. Plaintiffs argued that priority (Italian) application is the best source to understand because the term “semiliquido” appears in the Italian Application as the same number of times, in the same places, to describe the same things” as “half-liquid” does in the ’390 patent. A POSA would therefore equate “semiliquido” with “half-liquid.” But Federal Circuit said that there are substantial differences between priority aplplication & ‘390 patent.  Therefore, POSA would likely consider the discrepant usage of “half-liquid” and “semiliquido” between the ’390 patent and the Italian Application to be intentional, implying that the different word choice has a different scope. In addition to the Italian Application, another portion of the prosecution history reinforces conclusion that the applicant intentionally used “half-liquid” instead of “semiliquid.” During the prosecution of the ’390 patent the applicant had a pending claim using “half-liquid” and another claim, depending from that claim, using the term “semi-liquid.” This is additional evidence that the applicant knew the term “semi-liquid” & “half-liquid” are mean to something different. Thus, the intrinsic evidence failed to establish the boundaries of a “half-liquid.”

Turning to the extrinsic evidence, Federal Circuit said that district court correctly held that dictionary definitions and four patents that predated the ’390 patent are not related to the ’390 patent and therefore do not provide context for what “half-liquid” means. In addition, the court found that Dr. Chyall was unable to articulate a boundary for what constitutes a “half-liquid” and could not tell how a skilled artisan would know when matter is not a “half-liquid” inner phase. Dr. Chyall was also unsure whether his construction of “half-liquid” would exclude the types of gel and slurry distinguished during prosecution.

Federal Circuit thus held that the intrinsic and extrinsic evidence failed to inform, with reasonable certainty, those skilled in the art about the scope of the invention. Therefore, claims are invalid as indefinite.