Pegfilgrastim – USA

On Jul 29, 2019, Federal Circuit affirmed district court & found Coherus' biosimilar non-infringing under Doctrine of Equivalents (DOE) because of prosecution history estoppel (PHE).

Coherus filed aBLA with USFDA which sought approval of biosimilar version of Amgen’s pegfilgrastim product, Neulasta®. Amgen sued Coherus over US 8,273,707 which claims methods of purifying proteins using hydrophobic interaction chromatography (“HIC”). All of the ’707 claims require a salt combination chosen from one of three pairs: citrate and sulfate, citrate and acetate, or sulfate and acetate for effective purification.

Claim 1 recites:

1. A process for purifying a protein on a hydrophobic interaction chromatography column such that the dynamic capacity of the column is increased for the protein comprising

mixing a preparation containing the protein with a combination of a first salt and a second salt,

loading the mixture onto a hydrophobic interaction chromatography column, and eluting the protein,

wherein the first and second salts are selected from the group consisting of citrate and sulfate, citrate and acetate, and sulfate and acetate, respectively, and

wherein the concentration of each of the first salt and the second salt in the mixture is between about 0.1 M and about 1.0.

Amgen during prosecution argued that prior art did not teach or suggest the claimed particular combination of salts. It supported this arguments with Declaration from inventor.  Amgen further argued that the claimed invention is directed to increasing dynamic capacity of a HIC column and prior art does not teach dynamic capacity at all. Examiner first rejected the arguments but finally allowed the claims as Amgen pointed out that choosing a working salt combination was a “lengthy development path” and that “merely adding a second salt” would not result in the invention.

During litigation, Delaware Court dismissed Amgen's infringement claim under DOE for failure to state the claim based on PHE. Amgen appealed. During appeal Federal Circuit sided with district court & said that argument based prosecution history estoppel prohibits Amgen from asserting infringement under DOE. Amgen clearly and unmistakably surrendered salt combinations other than the particular combinations recited in the claims. Notably, Amgen’s response to the examiner’s office action quotes the Declaration’s conclusion that “use of this particular combination of salts greatly improves the cost-effectiveness of commercial manufacturing by reducing the number of cycles required for each harvest and reducing the processing time for each harvest.”

Amgen argued that its statement regarding the “particular combinations” of salts “simply observes (correctly) as a factual matter that prior art does not disclose using combinations of salts in the first instance,” and thus does not clearly and unmistakably surrender unclaimed salt pairs. Amgen argued that PHE does not apply because it made three bases/statements along with the one which states that prior art failed to teach particular salt combination. But Federal Circuit said that PHE can apply to single statement or base also unless the combine effect is argued. Amgen did not rely on the combination of its asserted grounds to distinguish prior art, so prosecution history estoppel applies to the “particular combinations” ground regardless of the other two arguments Amgen made. Therefore, single statement or base can give rise to estoppel.

Amgen next argued that the statements made during prosecution were not final ones which resulted in notice of allowance. Court again disregarded this & held that it is not necessary that to apply the PHE only final response is taken into consideration. Any response made against the rejection at any stage can give rise to estoppel. Federal Circuit thus held that the district court did not err in determining that prosecution history estoppel bars Amgen from succeeding on its infringement claim under the doctrine of equivalents.

Bevacizumab - USA

On Jul 19, 2019, Delaware court denied both motions filed by Genentech.

Genentech filed 2 motions which require Amgen to provide new 180-day commercial marketing notice & temporary restraining order (TRO). Amgen’s biosimilar (Mvasi : bevacizumab-awwb) product was approved in Sep 2017. In Oct. 2017, Amgen sent Genentech a Notice of Commercial Marketing Under§ 262(1)(8)(A). Amgen then filed supplements which FDA approved in Dec. 2018 & Jun. 2019 for change in drug substance manufacturing facility & change in labeling respectively. On July 10, 2019, Genentech filed above 2 motions.

Genentech argued that Mvasi product made pursuant to the specifications approved by the FDA in June 2019 is "a distinct 'product licensed under subsection (k)' requiring its own notice" because it is "a new product made by a new manufacturing process, accompanied by a new label, and the subject of separate applications, FDA reviews, and FDA approvals. But Court denied the motions & held that Amgen is not required to give new marketing notice because it is the same product. Though FDA approved the later supplements which require facility & labelling changes but it does change “biological product”. BPCIA's language makes clear that a biologic product is not defined by its manufacturing facilities or labeling. Court also said that nothing in the BPCIA states or even suggests that an applicant cannot file or the FDA cannot approve a supplement filed after the FDA approved the underlying application (or an earlier supplement).

With respect to TRO, court already found that Genentech cannot succeed on the merits because it has failed to establish a likelihood of success & thus denied this motion also.

Weekly Patent Round-up

Delhi court rejects Bayer injunction against Natco Pharma generic

India’s Delhi High Court has dismissed a petition for an injunction by German pharma company Bayer against an Indian competitor. In a judgment on Thursday July 11, the court said Bayer could not stop Natco Pharma from launching a generic used to treat colorectal cancer and advanced gastrointestinal tumours. The dismissal comes after an earlier July 5 ruling in which Bayer secured an injunction against Natco, but Natco appealed the decision….

https://www.lifesciencesipreview.com/news/delhi-court-rejects-bayer-injunction-against-natco-pharma-generic-3608

Inequitable Conduct Accusations Still Powerful Pharma Patent Litigation Tool Post-Therasense

When proven, accusations of fraud-like behavior in the Patent Office make patents unenforceable, but the Federal Circuit has called such accusations a “plague” on the system. Cooley’s Jason A. Lief takes a look at the law of inequitable conduct after the Federal Circuit’s Therasense opinion. Accusations are the currency of conflict. True accusations reveal wrongdoing; false accusations harm reputations, subject the accused to ordeal and waste resources….

https://biglawbusiness.com/insight-inequitable-conduct-accusations-still-powerful-pharma-patent-litigation-tool-post-therasense

Merck & Co., Mylan Settle Patent Suit on Noxafil Antifungal Copy

Merck and Mylan have settled a lawsuit in which Merck had accused Mylan’s proposed generic of the antifungal Noxafil of infringing two patents for the injectable version of the drug.

•             Mylan is blocked from making copies “unless otherwise specifically authorized pursuant to the settlement,” according to agreement approved Monday in federal court in Wilmington, Delaware

•             Patents expire in June and July 2031, according to filing

•             Merck previously had reached settlements with Actavis, Roxane, Par and Fresenius, allowing each to launch...

https://news.bloomberglaw.com/pharma-and-life-sciences/merck-co-mylan-settle-patent-suit-on-noxafil-antifungal-copy

The revised Rules of Procedure of the EPO Boards of Appeal

The Boards of Appeal of the European Patent Office (EPO) published on 3 July 2019 their revised Rules of Procedure, which will come into force on 1 January 2020 and will apply also to pending appeals (with some exceptions under Article 25, see below). The revision includes several changes, in particular the introduction of a so-called “convergent approach”, which comprises the following three levels…

http://www.sib.it/en/flash-news/the-revised-rules-of-procedure-of-the-epo-boards-of-appeal/

Endo Pharma To Pay $2.3M To 18 States In Lidoderm Deal

Endo Pharmaceuticals Inc. has agreed to pay $2.3 million to 18 states in a deal ... The states, including Illinois, Florida, Hawaii and Utah, claim Endo had an ... joint motion for a settlement agreement and stipulated order also filed Friday. ... due to concerns over drug prices and repeated antitrust allegations....

https://www.law360.com/articles/1180279/endo-pharma-to-pay-2-3m-to-18-states-in-lidoderm-deal

Methylnaltrexone - USA

On July 17, 2019, New Jersey court found formulation patent of Relistor® valid & infringed by Actavis.

Plaintiffs Bausch Health Companies Inc., Progenics Pharmaceuticals, Inc., Salix Pharmaceuticals, Inc., and Wyeth LLC (“Plaintiffs”) sued Defendant Actavis for infringement of U.S. Patent No. 8,524,276 under Hatch-Waxman Act. Patent in suit relates to tablet composition comprising methylnaltrexone & sodium lauryl sulphate which forms ion pair when goes into solution. Inventor found this method of ion pairing basically to increase the permeation & bioavailability of methylnaltrexone. Actavis contended that claims 2 & 5 are invalid as obvious & non-infringement of claim 2.

1. A pharmaceutical composition for oral administration comprising a solid dosage of (i) methylnaltrexone, or a pharmaceutically acceptable salt thereof, and (ii) sodium dodecyl sulfate (SDS), wherein the composition is a tablet, and wherein the composition comprises from about 7% to about 75% methylnaltrexone cation and dodecyl sulfate anion, based upon the total weight of the composition.

2. The pharmaceutical composition of claim 1, wherein the methylnaltrexone, or a pharmaceutically acceptable salt thereof, and sodium dodecyl sulfate (SDS) form an ion pair when dissolved in solution.

5. The pharmaceutical composition of claim 1, wherein at least 50% of the composition dissolves in a dissolution apparatus with paddles at 100 rpm in 900 mL of 0.1 N HCl at 37° C. within about 15 minutes.

Obviousness:

The central issue was whether there was motivation in the prior arts to combine methylnaltrexone & SLS in order to increase permeation & bioavailability. Actavis begins its argument with the proposition that methylnaltrexone was known to have poor permeability and poor bioavailability. Court noted that the choice of adjective here matters: “poor” implies deficiency and a problem to be solved, whereas “low” does not. If Actavis’ theory contends that a low or lower level of permeability would have motivated the POSA to improve the permeability, the evidence must support the inference that the POSA would have recognized the level of permeability as a problem to be solved.

District court however, concluded that Actavis failed to show that prior arts recognized the problem of permeation. According to court the evidence clearly shows that the POSA would have believed that increasing plasma levels was undesirable, but it does not show what effect this belief had on beliefs about increasing permeation. The Court’s uncertainty about what the prior art understood about whether permeation could be increased without a concomitant increase in bioavailability does not weaken Plaintiffs’ argument that there was no motivation to increase the permeability of methylnaltrexone in the prior art. Plaintiffs expert said that for the potent drug like methylnaltrexone it is not necessary to have good permeability because less amount of drugs which is available in the blood is sufficient to elicit response. Court thus said that Actavis' primary argument regarding question to solve failed as there is nothing in the prior art which showed that permeability is a problem.  Moreover, the prior arts cited by Actavis are all addressing different problem ie increasing the bioavailability of methylnaltrexone. Actavis' argued that as per the specification,  inventor solved the question of bioavailability and based their whole theory on "accordingly" word. But court said that this word is ambiguous and one can not say firmly that this was the problem that inventor wanted to solve. Even assuming that this was the problem patent addressed, still there was nothing in the prior art, which disclosed n number of ways & excipients to achieve the bioavailability problem. Actavis can not cherry pick SLS as the preferred one. There is no motivation to combine methylnaltrexone & SLS in order to come with the invention as claimed.

Court held that in conclusion, Defendant’s obviousness theory has at least two large holes. The first hole is the failure to establish the fundamental proposition that the prior art believed that methylnaltrexone had poor permeability such that it was a problem to be solved. The second hole is the failure to show how it would have been obvious to the POSA, following the teachings of prior arts, to select SLS to combine with methylnaltrexone in an oral formulation. Lastly, Plaintiffs have shown, and Actavis has not disproven, that the prior art taught away from the inventive formulation, and that the inventive formulation produced unexpected results, supporting a conclusion of nonobviousness.

Infringement:

The central issue was whether Actavis product forms an ion pair in the solution. Plaintiff's Expert used the experimentation such as shake-flask method to determine apparent octanol/water partition coefficient (APC). Actavis argued that the experiments do not prove infringement of claim 2 on several grounds. Actavis cited the testimony of various Experts in support of the proposition that an increase in APC does not demonstrate ion pairing. Actavis next argued that APCs cannot be determined for ingredients within tablets. Actavis next points to the fact that there is only one example of the shake-flask method in the ’276 patent, and that it was performed on a pure compound, not tablets. It was also argued by Actavis that it is incorrect method as it is difficult to predict the APC of a particular tablet. It can be measured for API or its salt only. Becuase other excipients in the tablet may interface in the analysis. But court credited testimony of Plaintiff’s Expert & said that through experimentation it was observed that APC was less when there was no SLS in tablet composition blend compared to the tablet containing SLS. Plaintiffs have presented unrebutted evidence that, when SLS is removed from the tablet blend, the measured APC drops substantially.  The Court determined that, in the context of this case, the only explanation for this change is the presence or absence of ion pairing. Plaintiffs have also presented unrebutted evidence that the methylnaltrexone and SLS in the ANDA tablet, dissolved in solution, appear in the octanol phase in a 1:1 molar ratio. This supports the inference that the methylnaltrexone and SLS have formed ion pairs. Actavis has presented no useful experimental evidence.

The Court thus concluded that Plaintiffs have proven, by a preponderance of the evidence, that the methylnaltrexone and SLS in the Actavis ANDA product form an ion pair when dissolved in solution. Plaintiffs have proven, by a preponderance of the evidence, that the proposed ANDA product will infringe claim 2. Actavis has failed to prove, by clear and convincing evidence, that claims 2 or 5 of the ’276 patent are invalid as obvious.

Vortioxetine - USA

Claim Construction (District of Delaware): July 16, 2019

Plaintiffs (Lundbeck) brought this suit against Defendants^* asserting infringement of U.S. Patent Nos. 8,772684 (the '"684 patent"), 8,969,355 (the '"355 patent"), 9,227,946 (the '"946 patent"), and 9,861,630 (the "'630 patent") (the "Crystalline Form Patents"), among others. The Court held a claim construction hearing on May 29, 2019, at which both sides presented oral argument.

Construction of Disputed Terms:

A. "characterized by an XRPD [pattern] as shown in [any of] FIG[S] ...

Plaintiffs: No construction necessary. Alternatively, "identifiable by reference to an x-ray powder diffraction pattern as shown in any of FIG[S] ...

Defendants: "having an XRPD pattern with all the peaks and corresponding relative intensities shown in the recited Figure[ s ]". Alternatively, the claim is indefinite

Court: "identifiable by reference to an x-ray powder diffraction pattern as shown in [any of] FIG[S] ... "

B. "1-[2 [ (2,4-dimethylphenylsulfanyl)-phenyl]piperazine hydro bromide salt [alpha form, beta form, gamma form]"

Plaintiffs: a crystalline form of vortioxetine hydro bromide, referred to in the patent specification as r"alpha" /"beta" / "gamma"l, that can be distinguished from other forms ...

Defendants: vortioxetine hydrobromide salt crystalline form described in the specification as the [alpha / beta / gamma] form and having all characteristics assigned to the [ alpha / beta / gamma] form in the specification

Court: vortioxetine hydrobromide salt crystalline form described in the specification as the [alpha / beta / gamma] form and being identifiable by reference to the [ alpha / beta / gamma] form in the specification

C. "mixtures thereof”

Plaintiffs: No construction necessary. Alternatively, "mixtures including vortioxetine hydrobromide salt alpha form, vortioxetine hydrobromide salt beta form, vortioxetine hydrobromide salt gamma form, vortioxetine hvdrobromide salt hemihydrate, and vortioxetine hydrobromide salt ethyl acetate solvate".

Defendants: "mixtures of only the foregoing listed forms"  

Court: "mixtures of only the foregoing listed forms"

D. "alleviates/ alleviating"

Plaintiffs: No construction necessary. Alternatively, "mitigates/ mitigating"

Defendants: Indefinite

Court: "mitigates / mitigating"

*The following defendants join in the proposed constructions of all disputed terms: Alembic, Alkem, Apicore, Apotex, Macleods, MSN, Sigmapharrn, Torrent, and Unichem.

The following two defendants join in all proposed constructions, but do not join the argument that the term "alleviates/alleviating" is indefinite: Cipla and Sandoz.

The following four defendants do not join in any of the proposed constructions: Hetero, Lupin, Prinston, and Zydus.

Cinacalcet - USA

On Jul 16, 2019, Court of appeals for the third circuit affirmed Delaware court’s decision & denied preliminary injunction sought by Amgen.

Previously, on May 02, 2019 Delaware court denied Amgen’s request for preliminary injunction as it failed to show a likelihood of success on its claim that Cipla breached the agreement by selling the product (reported here on this blog).

The second sentence of § 5.6 provide:

“[n]otwithstanding anything to the contrary in this Settlement Agreement, if any Third Party that has made an At Risk Launch of a Generic Cinacalcet Product (where such At Risk Launch is before or after an at risk launch by [Cipla]) is not found to have infringed one or more valid and enforceable claims of the [’]405 patent or has not ceased or agreed to cease selling such Generic Cinacalcet Product following an At Risk Launch, then Amgen shall not be entitled to seek or recover any relief from [Cipla] for [Cipla’s] at risk sales, offers for sale, distribution, or importation of [Cipla’s] product”.

Third circuit concluded that based on reading of the second sentence of § 5.6, Amgen was not authorized to seek relief against Cipla for its launch. The parties agree that (1) Teva, a Third Party under the Settlement Agreement, made an at risk launch of its generic cinacalcet, and (2) the district court found that Teva did not infringe the ’405 patent. Therefore, a condition in the second sentence of § 5.6 was satisfied when Cipla launched its generic cinacalcet, and thus, Amgen may not seek relief against Cipla for its at risk launch, which consequently was not prohibited by the Settlement Agreement. As a result, Amgen has not demonstrated a likelihood of success on its breach of contract claim.

Dimethyl fumarate - EPO

EPO opposition / appeal decision:

Case number	Decision date	Online available	Patentee	Opponent(s)	Patent No.	Final Decision
T 1537/16	Apr 18, 2019	Jul 15, 2019	Forward pharma	Generics [UK] Limited Biogen MA Inc. Wohldorff GmbH	EP2379063	Decision under appeal is set aside

EP2379063 B1 (Forward pharma; Exp: Jan 08, 2030):

1. A pharmaceutical formulation in the form of an erosion matrix tablet comprising:

i) 10 % to 80 % by weight of one or more fumaric acid esters selected from di- (C1 -C5 )alkylesters of fumaric acid and mono-(C1 -C5 )alkylesters of fumaric acid, or a pharmaceutically acceptable salt thereof, as an active substance;

ii) 1-50 % by weight of one or more rate-controlling agents; and an enteric coating, wherein said enteric coating is applied at a level of 1.5 - 3.5 % by weight of the core,

wherein erosion of said erosion matrix permits controlled or sustained release of said active substance.

Order of Board of Appeal:

1. The decision under appeal is set aside.

2. The case is remitted to the Opposition Division with the order to maintain the patent on the basis of the first auxiliary request, filed with letter dated 5 February 2016 and a description to be adapted.

Buprenorphine & Naloxone - USA

On Jul 12, 2019, Federal Circuit affirmed non-infringement & validity decisions of district court in Suboxone® case.  

Litigated patents in this case were U.S. Patents 8,603,514; 8,900,497; 8,017,150 and 8,475,832. Broadly these patents relate to pharmaceutical films with a uniform distribution of active ingredient with their components & process parameters.  Several generic drug companies (Dr Reddy’s Lab, Teva/Actavis, Alvogen) filed ANDAs to market generic versions of Suboxone® film prior to the expiration of the patents in suit. After trial, district court found DRL & Alvogen non-infringing & Actavis infringing. District court also upheld the validity of patents except US 8,475,832. Appeals & cross appeals filed.

Appeals involve issues of infringement and invalidity of these patents. Central issue litigated here was mainly based on “drying limitation” in the asserted claims. District court construed the claims to exclude “conventional top air drying” because specification disclaimed the conventional top drying as it produces non-uniform films. Inventors thus instead used bottom drying to dry the film so that there is uniform distribution of active ingredients. Federal Circuit affirmed the district court & held that Dr. Reddy’s & Alvogen’s manufacturing processes include conventional top drying & therefore do not infringe the asserted claims. Though some drying may happen at bottom of the film but this is very insubstantial.  Indivior argued that the specification describes other factors that affect film uniformity. But the court said that unequivocal disparagement of conventional top air drying demonstrates that other factors may not substitute for controlled drying of a wet cast film to achieve uniformity.

With respect to invalidation, Federal Circuit affirmed district court that the claims are not invalid for “indefiniteness” & are not obvious. The parties’ indefiniteness dispute focused on claim 62’s recitation of a “cast film comprising a flowable water-soluble or water swellable filmforming matrix.” Defendants argued that this limitation is indefinite because a cast film in its final dosage form is not flowable, and the claim thus required a physical impossibility. While the court agreed that the final cast film could not be flowable, it reasoned that a product claim may recite elements “in the state in which they exist during manufacture, before the final product exists.” And because the intrinsic evidence made clear that the cast film was made from a matrix that was flowable only before drying, the court concluded that the defendants failed to prove that the claims were indefinite.

With respect to obviousness, the key dispute between the parties was whether the prior art’s teachings would motivate a skilled artisan to make a uniform pharmaceutical film according to the claimed invention with a reasonable expectation of success. Federal Circuit affirmed district court& said that there was limited use of air convection dryers in the context of pharmaceutical films at the time of invention. Given the nascent status of pharmaceutical films at the time of invention and the limited knowledge of drying techniques, a person of ordinary skill would not have been motivated to combine the prior art to achieve uniformity. Secondary considerations also supported nonobviousness. The court considered evidence that obtaining pharmaceutical film content uniformity was a long-felt need yet difficult to achieve, and the court gave some credit to Inventor’s’s work related to the ’514 patent in solving that need. Federal Circuit thus agreed with Indivior & district court that claims are not invalid.

Methylene Blue - USA

IPR decision: Jul 02, 2019

AIA Review	Filing Date	Institution Date	Petitioner	US Patent	Respondent	Final Written Decision
IPR2018-00182	12/18/2017	07/05/2018	Provepharm Inc.	9,382,220	WisTa Lab. Ltd.	Claims are patentable
IPR2018-00323	12/19/2017	07/06/2018	Provepharm Inc.	9,675,621	WisTa Lab. Ltd.	Claims are patentable

US 9,382,220 (WisTa Laboratories Ltd.; Exp: 07/10/2027*TD): Non-OB

1. A diaminophenothiazinium composition comprising a diaminophenothiazinium compound of the following formula: ##STR00097## wherein: each of R.sup.1 and R.sup.9 is independently --H, C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.3NA and R.sup.3NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.7NA and R.sup.7NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality; wherein the composition is characterised by the following by weight in the composition: at least 98% of the diaminophenothiazinium compound; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

2. A diaminophenothiazinium composition comprising a diaminophenothiazinium compound of the following formula: ##STR00098## wherein the composition is characterised by the following by weight in the composition: at least 98% of the diaminophenothiazinium compound; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

US 9,675,621 (WisTa Laboratories Ltd.; Exp: 07/10/2027): Non-OB

1. A method of treatment of a tauopathy in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a high-purity diaminophenothiazinium compound of the following formula: ##STR00097## wherein: each of R.sup.1 and R.sup.9 is independently --H, C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.3NA and R.sup.3NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.7NA and R.sup.7NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality; wherein high-purity is defined by: at least 98% pure; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

13. A method of treatment of a methemoglobinemia in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a high-purity diaminophenothiazinium compound of the following formula: ##STR00099## wherein: each of R.sup.1 and R.sup.9 is independently --H, C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.3NA and R.sup.3NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; each of R.sup.7NA and R.sup.7NB is independently C.sub.1-4alkyl, C.sub.2-4alkenyl, or halogenated C.sub.1-4alkyl; and X is one or more anionic counter ions to achieve electrical neutrality; and wherein high-purity is characterized by: a purity of greater than 98%; less than 1% Azure B as impurity; less than 0.15% Azure A as impurity; less than 0.15% Azure C as impurity; and less than 0.05% Methylene Violet Bernthsen (MVB) as impurity.

CONCLUSION:

PTAB concluded that Petitioner has not shown, by a preponderance of the evidence, that the challenged claims are unpatentable.

First of all the cited prior arts disclosed “total content” of methylene blue measured as “Assay”, which includes impurity also. When someone does the titration to measure the content of drug then that method does not separately identifies pure compound & impurities. Prior arts did not disclose or suggest that more than 95% methylene blue means more than 95% “pure” methylene blue. Moreover, Petitioner has not provided any evidence to support their arguments.

Second argument with respect to reasonable expectation of success in using HPLC method to purify methylene blue was also failed. Because it was contradicted by Petitioner’s own submissions in EP & AU patent offices.  During prosecution of Petitioner’s patent application which claims less than 3% impurity in methylene blue, Petitioner said that this cannot be achieved by conventional techniques such as HPLC. These statements made in foreign patent offices undermine Petitioner’s argument here. As per “Mylan v Aurobindo” decision (Isosulphan Blue; CAFC 2017), purity claims can be given patentable weights if the route or method to obtain said pure compound is inventive.

Amphetamine mix salts (MYDAYIS) - USA

IPR decision: Jul 03, 2019

AIA Review	Filing Date	Institution Date	Petitioner	US Patent	Respondent	Final Written Decision
IPR2018-00290	12/11/2017	07/06/2018	KVK-Tech, Inc.	8,846,100	Shire, LLC	Claims are patentable
IPR2018-00293	12/11/2017	07/06/2018	KVK-Tech, Inc.	9,173,857	Shire, LLC	Claims are patentable

Note: On US’100 patent, Amerigen previously filed IPR (IPR2017-00665) on 01/13/2017 which was terminated by PTAB.

US 8,846,100 (Shire; Exp: 08/24/2029) –

1. A pharmaceutical composition comprising: (a) an immediate release bead comprising at least one amphetamine salt; (b) a first delayed release bead comprising at least one amphetamine salt; and (c) a second delayed release bead comprising at least one amphetamine salt; wherein the first delayed release bead provides pulsed release of the at least one amphetamine salt and the second delayed release bead provides sustained release of the at least one amphetamine salt; wherein the second delayed release bead comprises at least one amphetamine salt layered onto or incorporated into a core; a delayed release coating layered onto the amphetamine core; and a sustained release coating layered onto the delayed release coating, wherein the sustained release coating is pH-independent; and wherein the first delayed release bead and the second delayed release bead comprise an enteric coating.

US 9,173,857 (Shire; Exp: 05/12/2026) –

1. A method for treating attention deficit hyperactivity disorder (ADHD) which comprises: administering to a patient in need thereof, a pharmaceutical composition comprising: (a) an immediate release bead comprising at least one amphetamine salt; (b) a first delayed release bead comprising at least one amphetamine salt; and (c) a second delayed release bead comprising at least one amphetamine salt; wherein the first delayed release bead provides pulsed release of the at least one amphetamine salt and the second delayed release bead provides sustained release of the at least one amphetamine salt; wherein the second delayed release bead comprises at least one amphetamine salt layered onto or incorporated into a core; a delayed release coating layered onto the amphetamine core; and a sustained release coating layered onto the delayed release coating, wherein the sustained release coating is pH-independent; and wherein the first delayed release bead and the second delayed release bead comprise an enteric coating.

CONCLUSION:

PTAB concluded that petitioner has not shown that a skilled artisan would have been motivated to add Burnside’s Example 4 sustained release beads to Adderall XR (two-bead system) to arrive at the composition recited in claim 1 and would have had a reasonable expectation of success in doing so. Because Burnside only provides in-vitro results & lacks any in-vivo or IVIVC data, it was not predictable to add sustained release beads to Adderall XR which is two-bead system. The lack of in vivo data would have been a significant obstacle to a reasonable expectation of success given a skilled artisan would have been aware that GI barriers to drug absorption introduced variability and unpredictability. Furthermore, the record contains ample evidence that a skilled artisan would not have had a reasonable expectation of success because she would have been aware of the possibility that a patient might develop acute tolerance to amphetamine delivered in a sustained release dose, as opposed to a pulsed delivery.