generics ulletin nforma · 4 ftc rules impax $112mn pay-for-delay deal with endo was illegal ... 15...

12 April 2019No.394

Pharma IntelligenceInformaBulletin

Genericsg e n e r i c s . p h a r m a i n t e l l i g e n c e . i n f o r m a . c o m

REGULATION

IGBA Wants A Harmonized And Streamlined Global Framework, p. 14

BIOSIMILARS

Second-Medical-Use Patents Pose Problems For Biosimilars, p. 5

SIEGFRIED

Siegfried Keeps An Eye On Deal Targets As It Pursues Organic Growth, p. 11

UK Supreme Court Backs Actavis, Mylan And Teva On TadalafilDAVID WALLACE [email protected]

A ctavis, Mylan and Teva have suc-ceeded in convincing the UK Su-preme Court to reject an appeal

brought by Eli Lilly over the UK part of Eu-ropean dosage patent EP1,173,181 pro-tecting the originator’s Cialis (tadalafil) treatment for erectile dysfunction.

While Lilly had asserted that the es-sence of the invention was the discovery that tadalafil was effective in treating erec-tile dysfunction at a low dose with mini-mal side effects – thereby allowing it to be taken daily, rather than on demand, “thus avoiding the need to anticipate when sexual activity might occur” and providing an advantage over sildenafil, the active

ingredient in Viagra – the Supreme Court backed the finding of the Court of Appeal that claims 1, 7 and 10 of the ‘181 patent were invalid for lack of inventive step.

This was because the pre-clinical and clinical tests involved in determining the lowest effective dose of tadalafil “involved familiar and routine procedures and nor-mally progressed to the discovery”.

“The balance or symmetry in patent law and the pre-established or at least read-ily foreseeable target of the skilled team’s tests hold the key to the resolution of this dispute,” the Supreme Court explained. “In this case, the trial judge’s findings of what would have been the sequence of the

tests, which did not depend upon hind-sight, included the finding, which the evi-dence clearly justified, that the team, hav-ing found a therapeutic plateau, would be very likely to test lower doses and so come upon the dosage regime.”

The Supreme Court also found that the Court of Appeal had been “entitled to inter-fere with the trial judge’s assessment of ob-viousness and to hold that the ‘181 patent was invalid for lacking an inventive step”.

BIA WELCOMES RULINGResponding to the ruling, the UK BioIn-dustry Association (BIA) said it “welcomed the clarity provided by the decision on principles of patent law that have a wider impact on the biotech sector beyond the parties in this particular case”.

The BIA had “intervened in the case to ask that the Supreme Court not provide a decision that could have unintended adverse consequences for patents for in-ventions made during the pre-clinical or clinical trial process, which would signifi-cantly raise the hurdle for companies to attract the investment needed to identify and develop new medical innovations”.

Martin Turner, the BIA’s head of pol-icy and public affairs, welcomed the Supreme Court’s “clear statement that valuable medical discoveries made through clinical trials or other research that might be viewed as routine can be considered inventive and thus worthy of a patent”, adding that the association was “pleased that the Supreme Court has addressed the key points that we raised and provided this important clar-ity for the biotech community”.

“Notwithstanding this,” Turner con-CONTINUED ON PAGE 4

scripintelligence.com

2 | Generics Bulletin | 12 April 2019 © Informa UK Ltd 2019

I N T H I S I S S U E

from the [email protected]

As the global representative association for the off-patent industry, the International Generic and Biosimilar medicines Association (IGBA) monitors and lobbies on worldwide developments affecting generics and biosimilars companies.

This week, we bring you the first part in an exclusive three-part interview with IGBA secretary general Suzette Kox and chair Jim Keon. Alongside the first part of the interview that deals with current regulatory harmoni-zation efforts (p.14), you can find links to the second and third parts of the interview – which cover biosimilar naming and regulation, as well as the Pat-INFORMED originator database of intellectual-property information – at the Generics Bulletin website.

Meanwhile, our coverage from a recent European industry conference on legal affairs includes a look at the barriers posed to biosimilars by second-medical-use patents (p.5), as well as a review of current European pharmaceutical incentives (p.12) and a report on legislative moves in Poland to create dedicated intellectual-property courts that can resolve patent disputes more efficiently (p.13).

Also this week, we have seen a UK Supreme Court ruling that favors ge-nerics firms while also leaving the door open for originators to patent inventions made during the pre-clinical or clinical trial process, as well as addressing the weight that should be given by UK courts to parallel European litigation covering similar subject matter (see front cover).

Teva has seen mixed fortunes, with a positive EPO decision on a Euro-pean patent for its thrice-weekly Copaxone (p.8) as well as a reversal on a previously-favorable US decision on oxymorphone (p.9), while Sandoz has refiled its pegfilgrastim biosimilar in the US as part of its attempt to catch up with Mylan and Coherus that are already in the market (p.15).

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you an exclusive

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general Suzette Kox

and chair Jim Keon”

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COVER / UK Supreme Court Backs Actavis, Mylan And Teva On Tadalafil

4 FTC Rules Impax $112mn Pay-For-Delay Deal With Endo Was Illegal

5 Second-Medical-Use Patents Pose Problems For Biosimilars

7 Alvogen Settles With Celgene Over US Revlimid

8 EPO Upholds Teva’s Copaxone 40mg Dosing-Regimen Patent

9 Teva Hit By US Reverse On Oxymorphone Use Patent

11 Siegfried Keeps An Eye On Deal Targets As It Pursues Organic Growth

12 EU Incentives Review Must Restore A Sense Of Balance

13 Polish Plans For Courts Will Not Remove All Biosimilar Barriers

14 IGBA Wants A Harmonized And Streamlined Global Framework

15 Sandoz Tries Again With US Pegfilgrastim

16 Zentiva Strikes Deal To Buy UK’s Creo Pharmaceuticals As It Pursues ‘Champion’ Ambitions

18 Advanz Embarks On Strategic Plan By Buying Two Eisai Brands

19 Nucynta ER Ruling Preserves US Status Quo On Tapentadol

US House Committee Clears Bills To Prevent Pay-For-Delay Deals, Assure Generic Access To SamplesLegislation on patent settlement agreements will not be retroactive; CREATES Act amended to give brand companies affirmative defense to litigation.

https://bit.ly/2U5MXx5

EU Countries Examine Reasons Behind Wide Differences In Biosimilar UsageSpeakers from several EU countries at last week’s Medicines for Europe conference discussed the reasons behind the often wide inter-country disparities in biosimilar usage and the policies they are pursuing to try to remedy the situation.

https://bit.ly/2Vwu4Vr

Korea Overhauls Rules On Generics To Enhance Responsibility And CompetitivenessFollowing the worldwide generic valsartan quality woes, South Korea moves to improve the quality of generics and will eventually scrap joint bioequivalence tests, while implementing effective price cuts to later products to curb excessive competition and improve pharma firms’ responsibility for their drugs.

https://bit.ly/2G9OAGb

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7 4 16



I N T E L L E C T UA L P R O P E R T Y

ceded, “the application of the principles by the court in this particular case did not lead to the patent being found to be valid, so the individual facts of each case, as always, will have a significant influence on the court’s assessment.”

Meanwhile, Nicholas Jones, partner and patent attorney at European intellec-tual property law firm Withers & Rogers described the judgement as a “relief for the biopharma industry, where the pat-enting of new dosage regimes and other forms of administration for known drugs is relatively commonplace”.

The Supreme Court had decided that “while such patents may not be valid in all circumstances, there should not be a blanket rule”, Jones noted, “and a range of factors must be considered before decid-ing whether they are too obvious to meet the inventive step requirement”.

FOREIGN JUDGEMENTS ‘NOT HELPFUL’While parallel revocation proceedings on the ‘181 patent in other European juris-dictions had been cited as part of the UK litigation – particularly referring to judg-ments in the Netherlands and Germany, where national courts revoked the pat-ent on grounds of obviousness, as well as proceedings in Belgium, the Czech Republic, Denmark, Poland and Portugal – the Supreme Court said these were “not particularly helpful”.

While consistency might be “desir-able”, the Supreme Court said, “we are not bound by the judgments of other national courts and it is possible that national courts applying the same law may come to different conclusions for various reasons”.

“One can draw some support from ju-dicial decisions in other national courts which reach the same conclusion as one has come to,” the Supreme Court stated. “But it is necessary to recognize not only that the first-instance decisions in the Netherlands and Germany are the sub-ject of appeals, but also that the evidence led before different courts in parallel pro-ceedings may differ and, even when the same evidence is led, each court’s find-ings of fact based on that evidence may not be the same.”

Published online 1 April 2019

CONTINUED FROM PAGE 1 FTC Rules Impax $112mn Pay-For-Delay Deal With Endo Was IllegalPENELOPE MACRAE

T he US Federal Trade Commission has ruled Impax Laboratories entered into an illegal $112mn “pay-for-delay” settlement to block consumers’ access to a cheaper version of Endo Pharmaceuticals’ branded extended-release opioid

pain reliever Opana ER.Overturning an earlier decision, the FTC found that Amneal’s Impax received a “large

and unjustified payment” of more than $112mn for an illegal pay-for-delay or “reverse payment” agreement that included a pledge not to launch an authorized generic (AG) of extended-release opioid pain-reliever Opana ER during the 180-day exclusivity pe-riod reserved for the first-generic filer.

The Commission also concluded in its 5-0 decision on March 28 that the two com-panies agreed Endo would pay an “additional credit” to Impax if the market for Opana ER, a version of oxymorphone hydrochloride, declined before Impax’s generic product entered the market.

The Commission’s decision reversed a ruling by the agency’s chief Administrative Law Judge D. Michael Chappell last May.

The FTC’s administrative complaint filed in January 2017 alleged that, seven years earlier, Impax and Endo illegally agreed Impax would refrain from marketing its generic version of Opana ER until January 2013. In exchange, the complaint said, Endo paid Impax more than $112 million to delay release of its rival to Opana ER.

Impax can file a petition for review of the FTC decision in the US Federal Circuit Court of Appeals within 60 days.

For years, the FTC been seeking to crack down on drugmakers striking agreements that delay generic drugs from hitting the market when patents on the medicines expire. Such pay-for-delay settlements are often concluded as part of moves to resolve patent litigation and the FTC says paying rivals to keep drugs off the market violates antitrust laws and costs consumers billions of dollars annually.

DEAL BLOCKED ‘CONSUMER ACCESS’ TO CHEAPER GENERIC OF OPANA ER: FTC

The agreement between Amneal’s Impax, whose US headquarters are in Malvern, Pa., and Endo blocked “consumers access” to the cheaper Opana ER generic, used to treat pain severe enough to require around-the-clock treatment, the FTC opinion written by Commissioner Noah Philips said.

In July 2017, Endo, whose global headquarters are in Dublin, Ireland, announced it would “voluntarily withdraw” Opana ER from the market at the request of the US Food and Drug Administration which said the benefits of the opioid, first approved in 2006, “no longer outweighs the risks.” Opana ER’s sales totalled $158.9mn in 2016.

In reversing the decision by its chief administrative law judge, the Commission cited a landmark 2013 US Supreme Court ruling, FTC v. Actavis, which held eliminating risk of competition through a reverse-payment settlement constituted anticompetitive harm. The Commission found “there was ample evidence” Impax could have launched a ge-neric product before the agreed-upon date had it not entered into the reverse-payment pact with Endo.

Chappell’s 2018 decision dismissing the FTC’s antitrust complaint against Impax said evidence showed Endo gave Impax a reverse payment to abandon its patent challenge and not to launch a generic Opana ER until January 2013, which constituted “anticom-petitive harm.” But Chappell also found the “extent of any anticompetitive harm” was


H E A D L I N E N E W SI N T E L L E C T UA L P R O P E R T Y

“largely theoretical” and evidence showed earlier entry of a ge-neric version of Opana ER “was unlikely.”

FTC ORDER BARS IMPAX FROM STRIKING ANY NEW REVERSE PAYMENTS CURBING GENERIC ENTRY

The FTC’s “Final Order” bars Impax from entering into any type of reverse payment that delays or restricts generic entry, includ-ing AG commitments, but does not affect the company’s exist-ing agreements. The ruling also bars Impax from entering any accord with another oxymorphone extended-release manu-facturer that prevents or curbs competition between oxymor-phone ER products.

When the FTC filed suit against Endo and Impax in 2016, it marked the agency’s first complaint challenging an AG provision in a patent-settlement agreement. The agency settled with Endo in January 2017 and filed its administrative complaint against Impax.

In February, the FTC scored a significant win in its drive to end pay-for-delay agreements with its global settlement with Teva over accusations that deals by the world’s largest generics-maker blocked consumer access to cheaper generics. The broad settle-ment ended three reverse-payment fights with Teva and barred it from entering into what the FTC said were any such types of “perni-cious” agreements including a “no AG” commitment.


Overturning an earlier decision, the FTC found that Amneal’s Impax

received a “large and unjustified payment” of more than $112mn

for an illegal pay-for-delay or “reverse payment” agreement

H E A D L I N E N E W SB I O S I M I L A R S

Second-Medical-Use Patents Pose Problems For BiosimilarsAIDAN FRY [email protected]

T he increasing prevalence of sec-ond-medical-use patents in Eu-rope is providing major problems

for biosimilars developers, according to speakers at Medicines for Europe’s recent legal affairs conference held in Amster-dam, the Netherlands.

A roundtable on second-medical-use patents hosted during the conference by two partners at law firm Stibbe, Ignace Vernimme and Manuel Campolini, raised the issue of procurement tenders be-ing run by international non-proprietary name (INN) where certain of a drug’s indi-cations may still be under patent.

By bidding in such tenders, biosimi-lar and generics companies risked being sued for patent infringement, even if their labeling carved out the patented use. Some roundtable participants suggested a solution could be to encourage payers and authorities to run separate tenders for

each indication, although they acknowl-edged that this increased complexity.

Observing the “huge number” of pat-ent applications, many of which were divisional, that originators were filing to cover subsequent indications, one partici-pant said these were often based on “little or no data”, so it was vital to oppose such patents as soon as possible. Jurisprudence from the Court of Justice for the EU (CJEU) had provided little clarity, even after the recent Abraxane verdict, the round table participants felt. (Also see “New Formula-tions Of Old Ingredients Do Not Qualify For SPCs” - Generics Bulletin, 22 Mar, 2019.)

Another conference delegate remarked

that originators were increasingly patent-ing side-effect profiles and safety issues, aspects that were impossible to carve out from biosimilar and generic labels.

“Second-medical-use patents are a real issue,” insisted Alexander Ott, senior pat-ent attorney at Sandoz, during a plenary session on legal challenges for biosimilar developers. As biosimilars were approved through the European Medicines Agen-cy’s (EMA’s) centralized procedure, he said it was expensive to carve out patented in-dications through duplicate applications.

“If there are two or three indications, it is doable,” he suggested. But with mul-tiple indications that had different patent

“You are forced by the system at the moment to infringe the patent. That is something that we definitely have to change”



B I O S I M I L A R S

expiry dates across different countries, it was extremely challenging to manage the process with the EMA.

CANNOT CARVE OUT PENDING PATENTS IN ADVANCE

“And then,” Ott observed, “you can hear from the European Patent Office (EPO) that a patent is going to be granted. But the EMA allows you to file for a duplicate only when there is a granted patent.” Thus, he said, it was impossible to carve out a pending patent in advance. “You are forced by the system at the moment to infringe the patent. That is something that we definitely have to change.”

Kristin Cooklin, global head of patents at Zentiva, agreed that second-medical-use patents were “a big issue”, particularly in a biosimilars sphere in which huge commer-cial expectations were matched by consid-erable lack of legal certainty. “Sometimes you have 11, 12 or 13 indications in a prod-uct’s summary of product characteristics (SmPC), so even if you want a skinny label, how do you do that?” she wondered.

Divisional patents covering second-medical-use indications were a huge problem, Cooklin contended. “They often pop up close to biosimilar launch,” she said, noting that even where companies have pursued carve-out strategies, such patents create uncertainty at a time when firms are ramping up sales and marketing

as well as production spending.Recognizing that the UK courts had

tried to provide greater legal certainty around adalimumab by issuing an ‘Arrow’ declaration of invalidity against pend-ing patent applications, Cooklin felt such early nullity decisions “in some of the more respected courts” could be useful in other jurisdictions.

But even armed with a reasoned UK de-cision and the Arrow declaration, all of the biosimilar entrants with adalimumab had chosen to settle with Humira originator AbbVie – paying undisclosed patent-relat-ed royalties – so as to have certainty that they could launch from October last year.

With AbbVie having “tanked the price” by around 80% on Humira upon facing direct competition, she revealed “we are hearing from the market that some of the biosimi-lars are literally paying to sell their adalim-umab, so they are losing money”.

DRAGGED INTO US SUIT WITH ORIGINATOR

Looking at the US market, Cooklin ex-pressed incredulity that companies that had spent hundreds of millions of dollars on developing and litigating over bio-similars had been dragged into the same competition lawsuits as AbbVie.

Ott observed that the US legislative framework for biosimilars includes “pat-ent linkage that forces you into mandatory litigation” on patents, including process patents, “that originators would not use anywhere else”. The benefits foreseen in the Biologics Price Competition and Innovation Act (BPCIA) of a limited scope and time-frame in which to litigate over patents had not come through in reality, he believed.

Highlighting the difficulties of trying to knock out US patents early due to a lack of legal standing until a company had a granted biosimilar marketing authoriza-tion, Ott welcomed suggestions that the BPCIA ‘patent dance’ litigation proceed-ings should start earlier in the biosimilar development process.

Outlining the latest legal develop-

ments around biosimilars in the US, Jef-frey Francer – senior vice-president and general counsel at the Association for Ac-cessible Medicines (AAM) – said “we are only beginning to have that sort of dis-cussion” about how to deal with patent thickets more effectively.

One proposal, he said, was to accelerate the BPCIA patent dance by around a year by allowing biosimilar developers to trig-ger litigation when they held an in-depth ‘type 3’ meeting with the US Food and Drug Administration (FDA) under the bio-similar product development (BPD) path-way, rather than when they filed an abbre-viated biologic license application (aBLA).

“Others have had more drastic discus-sions about how, maybe after 12 years of market exclusivity, there has to be more government involvement in forc-ing licensure of these types of patents,” he remarked.

Pharma patent abuse was a current hot topic in Washington DC, Francer stressed, highlighting recent testimony by big phar-ma CEOs before a Senate finance commit-tee. In particular, he pointed to a vigorous cross-examination of AbbVie chief Rich-ard Gonzalez by Republican Senator John Cornyn on how he could justify 246 patent applications for Humira.

US SENATE PROBES HUMIRA PATENTS AND SETTLEMENTS

Admitting that there were 136 granted US patents protecting Humira, often covering different indications, Gonzalez claimed that “in the end, the number of patents is not something that protects a product. We don’t block any biosimilars,” he asserted, adding that patent settlements that al-lowed US biosimilar competition to Hu-mira from 2023 represented “a reasonable balance”. Cornyn suggested that the Sen-ate judiciary committee should examine such patent settlements more closely.

Welcoming former FDA commissioner Scott Gottlieb’s commitment over the past two years not just to getting bio-similars approved, but also to “calling out gaming of the system”, Francer pointed out that “Gottlieb is not the patent office or the Federal Trade Commission (FTC)”.

In particular, Francer appealed to the FTC to “take a more active role” on polic-ing the gaming of the US contracting and rebate system to manipulate formularies such that patients have to make higher co-payments for biosimilars than for the reference biologic. The AAM, he noted, had filed an amicus brief to support Pfizer’s lawsuit against Johnson & Johnson over contracting tactics around infliximab.

And while Gottlieb had been active in drawing attention to “false and misleading fearmongering” amid limited patient expe-rience with biosimilars, Francer recognised that the FDA’s remit was limited to regulat-ing labeling. “The FTC has to get involved on advertising in general where it is specifi-cally product-related,” he maintained.


“We are hearing from the market that some of the biosimilars are literally paying to sell their adalimumab, so they are losing money”



Alvogen Settles With Celgene Over US RevlimidGRACE MONTGOMERY [email protected]

A lvogen and its subsidiary Lotus Pharmaceuticals have set-tled patent litigation with Celgene concerning the origi-nator’s Revlimid (lenalidomide). This allows for generic

entry of the multiple myeloma treatment on a confidential date. “As part of the settlement, the parties will file consent judg-

ments with the US district court for the district of New Jersey that enjoin Alvogen from marketing generic lenalidomide be-fore the expiration of the patents-in-suit, except as provided for in the settlement,” the firm noted.

In settling all outstanding claims in the litigation, Celgene has agreed to provide Alvogen with a license to Celgene’s patents re-quired to manufacture and sell certain volume-limited amounts of generic lenalidomide in the US, beginning on a confidential date that is “some time after the March 2022 volume-limited li-cense date that Celgene previously provided to Natco”.

“For each consecutive 12-month period – or part thereof – following the volume-limited entry-date until 31 January 2026, the volume of generic lenalidomide sold by Alvogen cannot ex-ceed certain agreed-upon percentages,” the Icelandic company explained. “Although the agreed-upon percentages are confi-dential, they increase gradually each period to no more than a single-digit percentage in the final volume-limited period.”

Alvogen will be licensed to manufacture and sell an unlimited quantity of generic lenalidomide in the US “beginning no ear-lier than 31 January 2026”. The group said its ability to market lenalidomide in the US “will be contingent on it obtaining ap-proval of an abbreviated new drug application (ANDA)”.

GLOBAL REVLIMID SALES SET TO EXCEED US$10 BILLIONCelgene reported US Revlimid sales ahead by almost a fifth to US$6.47 billion last year. The US accounted for two-thirds of global sales of the oncology brand that surged by 18.3% to US$9.69 billion. And having held off generic competition in the US until at least 2022, the New Jersey-based company is fore-casting global Revlimid sales rising by around 12% this year to about US$10.8 billion, amounting to almost two-thirds of the group’s targeted US$17.1 billion turnover in 2019.

Bristol-Myers Squibb, which at the start of this year launched a US$74 billion takeover offer for Celgene, said the settlement with Alvogen and Lotus was “consistent with our assumptions

during due diligence and provides further clarity and security around the patent estate for Revlimid”.

FOLLOWS FAILED IPR ATTEMPT AND CEE LAUNCHESAlvogen was recently denied an attempt to challenge a US pat-ent protecting Revlimid via the inter partes review (IPR) process. It concerned US patent 7,968,569, which is set to expire on 7 Oc-tober 2023 and is one of 18 patents listed against Revlimid in the US Food and Drug Administration’s (FDA’s) Orange Book. Re-fusing Alvogen’s petition, the US Patent Trial and Appeal Board (PTAB) said there was an “evidentiary gap” in Alvogen’s argu-ments of obviousness.

The Iceland-based firm recently claimed the first European launch of a generic rival to Revlimid, rolling out the oncology drug in several central and eastern European (CEE) markets. The launches took place in “a range” of markets including Bulgaria, Croatia, Romania and the Baltic states.

Alvogen’s version – developed in-house by Lotus – is available as 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 20mg and 25mg hard capsules.

“Following the launch into CEE,” Alvogen said, “the generic and bioequivalent version of Revlimid will be launched in selected Asian countries in 2019”, having previously indicated that it was eyeing a global launch this year. The firm added that the oncology brand’s global market was currently worth around US$9.8 billion.


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EPO Upholds Teva’s Copaxone 40mg Dosing-Regimen PatentAIDAN FRY [email protected]

A three-member panel of the Eu-ropean Patent Office’s (EPO) Opposition Division has upheld

Teva’s European dosing-regimen patent protecting its Copaxone (glatiramer ac-etate) 40mg/ml formulation until 2030. “The Opposition Division will issue its written underlying rationale on the de-cision within a few months,” the Israeli company commented.

European patent EP2,949,335 was granted in 2016 as a divisional fil-ing from two other European patents, EP2,405,749 and EP2,630,962. The ‘335 patent, which Teva licenses from Yeda Research & Development, covers in claim 1 “glatiramer acetate for use in a regimen for treating a human patient suffering from a relapsing form of mul-tiple sclerosis which regimen consists of administering weekly to the human patient on only three days during each week a single subcutaneous injection of a 40mg dose of glatiramer acetate”.

Other claims describe administering the regimen described in claim 1 via medici-nal formulations delivered in a pre-filled

syringe, such that tolerability is improved.EPO records show that opponents to

the ‘335 patent – including Alvogen, GL Pharma and Sandoz’ Hexal, as well as Mylan and its partner Synthon – cited a broad array of prior art, including patent applications, a clinicaltrials.gov entry, US labeling for Rebif (interferon beta-1a) and several articles.

At a national level, European courts have taken opposing views on the validity of the ‘335 patent. Teva noted that it had “already obtained preliminary injunction orders on the basis of European patent EP2,949,335 to prevent the commercial-ization of follow-on glatiramer acetate in Belgium, Denmark and Slovakia”, while

national challenges to the patent’s validity were underway in Italy and Norway.

IRISH COURT REFUSED TO GRANT AN INJUNCTION

But Ireland’s High Court last year refused Teva’s attempt to obtain an injunction on the strength of the ‘335 patent to prevent Mylan from producing glatiramer acetate 40mg/ml at a local facility in Inverin, County Galway. High Court Judge David Barniville disagreed with Teva’s asser-tion that it would not recover adequate damages if successful at trial. “I am not persuaded that the alleged potential ir-reversible loss of market share and price reductions for Copaxone 40mg creates an impossibility of assessing damages,” he declared.

And in the UK – where Mylan and Syn-thon were early last year first-to-market with their Brabio 40mg/ml hybrid alterna-tive to Teva’s thrice-weekly formulation of Copaxone – the UK High Court had in Oc-tober 2017 found the local part of the ‘335 patent to be invalid. The court refused Te-va’s application for permission to appeal.

Despite competition to both its daily 20mg/ml and thrice-weekly 40mg/ml formulations of Copaxone from gener-ics or hybrids in both Europe and the US, Teva has retained a significant proportion of its pre-expiry sales of the multiple-sclerosis blockbuster. “We are maintaining high volume share in the US and Euro-pean markets,” chief executive officer Kåre Schultz told investors in mid-February during Teva’s fourth-quarter earnings call.

Comparing the “modest decline” in Eu-rope favourably with more challenging

REGION2018 COPAXONE SALES

(US$ MILLIONS)REPORTED

CHANGE (%)LOCAL-CURRENCY

CHANGE (%)PROPORTION OF

TOTAL (%)

North America 1,759 -44 -44 74

Europe 535 -10 -14 23

International 72 -21 -8 3

Global Copaxone 2,365 -38 N/A 100

Steady decline in Teva's Copaxone sales during 2018Sales of Teva's Copaxone (glatiramer acetate) multiple-sclerosis blockbuster declined quarter-on-quarter during 2018 as competition from generics and hybrids in the US and Europe increasingly told.

800

700

600

500

400

300

200

100

0North America Europe International Global Copaxone

476

464

463

356

153

140

124

118

16 22 14 20

645

626

601

494

Download data

Q1 2018 Q2 2018 Q3 2018 Q4 2018

Steady decline in Teva’s Copaxone sales during 2018Sales of Teva’s Copaxone (glatiramer acetate) multiple-sclerosis blockbuster declined quarter-on-quarter during 2018 as competition from generics and hybrids in the US and Europe increasingly told.



market dynamics in the US, Schultz said in Europe “we are very happy to con-clude that we still, at the end of the year, had something like a 75% volume share”. However, he acknowledged, this share “will be somewhat reduced during 2019 and again in 2020”.

The result last year was a fall of a tenth in European Copaxone sales to US$535 million, which Teva said equated to a local-currency decline of 14%, “mainly due to price reductions resulting from the entry of competing glatiramer acetate products”.

A reported 38% slide in Teva’s global Copaxone sales was due to a 44% drop in North America to US$1.76 billion. Of that figure, US$1.70 billion was achieved in the US, where a decision by the US Court of Appeals in October last year confirmed that four patents protecting Copaxone

40mg/ml were invalid as obvious.The three appeals judges also found in

favour of Mylan and Amneal in rejecting Ye-da’s appeal against final written decisions of the US Patent and Trial and Appeal Board (PTAB) finding the claims of US patents 8,232,250; 8,399,413 and 8,969,302 patents unpatentable as obvious in three inter par-tes review proceedings. Those three pat-ents, as well as the invalid 9,155,776 patent, expire in August 2030.

Faced with US competition from Mylan and Sandoz’ generics, Schultz told inves-tors that Teva had lost around a fifth of all prescriptions for glatiramer acetate 40mg, and had taken a further pricing hit of around 25%, resulting in the reported 44% North American sales slide.

“Copaxone 40mg retains 74.7% share of the US 40mg glatiramer acetate mar-

ket as of December 2018,” Teva stated. North American Copaxone sales held fairly steady throughout the first three quarters of last year, but took a sharp downturn to US$356 million in the fourth quarter as competition intensified.

North America accounted for almost three-quarters of all sales of the multiple-sclerosis brand in 2018.

Globally, Copaxone made up 13% of Teva’s total group turnover last year “and a significantly higher percentage of our profits and cash flow from operations dur-ing this period”.

For 2019, Teva is anticipating a further US$900 million decline in Copaxone sales, largely in the US, to around US$1.5 billion globally.



Teva Hit By US Reverse On Oxymorphone Use Patent AIDAN FRY [email protected]

T eva and its Actavis affiliate have seen a previous US district court victory on a method-of-use pat-

ent protecting Endo’s Opana ER (oxymor-phone) controlled-release analgesic until June 2027 overturned. “Because the dis-trict court incorrectly concluded that the claims at issue are directed to a natural law, we reverse,” a Federal Court of Ap-peals panel stated.

Endo’s US patent 8,808,737 covers a method of using oxymorphone to treat pain in patients with impaired kidney function. This is based on the discovery that there is a correlation between plasma concentra-tions of oxymorphone and the degree of a patient’s renal impairment, thus allowing for lower doses in this patient subset.

• Providing 5mg to 80 mg of oxymor-phone in a controlled-release matrix;

• “Measuring” the patient’s creatinine clearance rate; and

• Orally administering the drug with a dosage calculated in line with the patient’s creatine clearance rate

The ‘737 patent at issue on appeal claims a personalized method-of-treat-ment that has three distinct steps:

Having been sued by Endo for alleged infringement, Teva moved to dismiss the

case on the ground that the ‘737 patent’s claims were ineligible for patenting. Draw-ing on the advice of a magistrate judge, Delaware district judge Richard Andrews dismissed Endo’s complaint on the rea-soning that the claims are directed to the natural law that the bioavailability of oxymorphone is increased in people with severe renal impairment. Endo appealed.

“The asserted claims are not directed to patent-ineligible subject matter,” the Court of Appeals found. “On the contrary, the claims are directed to a patent-eligi-ble method of using oxymorphone or a pharmaceutically acceptable salt thereof to treat pain in a renally impaired patient.”

Pointing out that not only the patent’s claims, but also its title, abstract and specification identified the invention as a ‘method of treating pain’, the appeals court noted that it had last year upheld similar claims in Vanda’s dispute with Hikma’s West-Ward over treating schizo-phrenia with Fanapt (iloperidone).

Hikma is urging the US Supreme Court to force the Federal Court of Appeals to respect in full the precedent set by the Supreme Court’s Mayo vs. Prometheus finding that patents claiming methods of treatment or diagnosis must satisfy an

ordinary analysis of eligibility under Sec-tion 101 of the US Patent Act.

CLAIMS DIFFER TO SUPREME COURT’S MAYO PRECEDENT

In its oxymorphone decision, the Federal Circuit insists that “the claims here differ from those in Mayo in material respects”.

While Endo had recognized a relation-ship between oxymorphone and patients with renal impairment, it had specifically claimed “a method of treatment includ-ing specific steps to adjust or lower the oxymorphone dose for patients with renal impairment”. “The claims are thus directed to more than just reciting the natural rela-tionship,” the appeals panel concluded.

Last year, several generics developers in-cluding Teva failed to overturn on appeal a New York district court’s finding that their generics of a reformulated Opana ER in-fringed US patents 8,309,122 and 8,329,216, both of which relate to controlled-release formulations of oxymorphone and expire in February 2023. In response to US Food and Drug Administration (FDA) concerns about abuse, Endo has also withdrawn the refor-mulated version of the opioid analgesic.




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Siegfried Keeps An Eye On Deal Targets As It Pursues Organic GrowthDAVID WALLACE [email protected]

S iegfried says it will “make addition-al investments in its technological capability, optimization of business

processes and additional production ca-pacity” in order to meet the requirements necessary to achieve “critical size” in the contract development and manufactur-ing organization (CDMO) market.

At the same time, the Swiss firm is keeping a close eye on “numerous poten-tial merger & acquisition (M&A) routes” as possible options for inorganic growth.

“It is Siegfried’s target to profitably grow organically in line with the market,” the firm said, “with the ambition to outgrow it in-cluding selective and value-accretive M&A.”

Speaking as Siegfried reported 2018 sales ahead by 5.8% to CHF794 million (US$797 million) – with earnings before interest, tax, depreciation and amortization (EBITDA) that outpaced turnover growth, increasing by 14.5% to CHF127 million – chairman An-dreas Casutt and CEO Wolfgang Wienand said they planned to “stabilize [our] leading position in the current year and create the preconditions for continued growth”.

Casutt and Wienand – who took over as CEO from Rudolf Hanko at the start of this year – noted that Siegfried had in 2018 “invested in research & develop-ment and in additional production ca-pacities”, with 40 new laboratory work-places added in November 2018 to the drug-product facility in Zofingen, Swit-zerland, that Siegfried reacquired from Arena Pharma earlier in the year.

“For the current year, in order to meet the requirements of the intended growth, Siegfried is planning to make ad-ditional investments,” the pair affirmed.

NEW CEO WIENAND TOURS SIEGFRIED SITES

In the first months of 2019, new CEO Wien-and had “visited each of Siegfried’s nine sites and presented his agenda to employees and management”, the firm stated. “Wien-and will pay attention to optimizing our internal business and management pro-cesses and adjust them to demands made

by the rapid growth experienced in recent years and to the connected complexity.”

Equally important to Wienand was “the network approach”, Siegfried explained: “in other words, the growing together of all our sites which, in total, have to obtain the best and most competitive offer for our customers”.

Wienand “attaches particular value to Siegfried acting as a global team across all of its sites and continuing to

strengthen competitiveness through scientific and technological excellence and efficiency in all of [our] technical and business procedures”.

EYEING ‘TARGETED ACQUISITIONS’“Targeted acquisitions will represent an essential share of the Siegfried Group’s growth,” Siegfried commented. “In this way, the Siegfried Group can rapidly gain market share, strengthen the global network thanks to the resulting syner-gies, and further strengthen its position among the leading integrated CDMOs.”

While no transactions had been carried out in 2018, this was because none of the potential acquisitions had fulfilled Sieg-fried’s internal criteria in terms of the “as-set quality and transaction value” and the “long-term corporate value” they would bring. “In the recent past, many transac-tions were made at very high valuations,” Siegfried observed, without naming spe-cific companies.

Noting that biopharmaceuticals were

expected to become more significant for the company, Siegfried noted that it had “consistently invested in this market seg-ment for several years, for instance, in the finished dosage forms of this substance class at our site in Hameln”.

“By means of selective investments, Sieg-fried will continue to access certain ele-ments of the biologics market,” the firm said, adding: “Where the conditions are right, a corresponding acquisition is conceivable.”

Siegfried said it was also eyeing growth in finished dosage-forms, both in solid oral doses and in sterile filling of liquids. “By means of external growth, mainly in the US and Europe, Siegfried aims to obtain access to competition-related capacity and technologies to consolidate critical size in this field,” Sieg-fried outlined. And “hand in hand with this expansion, we aim to strengthen our capabilities in development”.

“Overall,” the firm summarized, “Siegfried has at its disposal numerous potential M&A routes to follow which do not mutually ex-clude each other. On the contrary, they can be implemented in line with the best of val-ue-added logics and availability of assets. This circumstance increases the likelihood for Siegfried to implement a transaction that will generate sustained value.”

Of Siegfried’s CHF794 million sales total in 2018, around three-quarters came from drug substances and intermediates, with the remainder finished products. The firm said it had “showed a slight growth in drug substances and a strong growth in sterile filing of liquids – vials, ampoules, cartridg-es and others – and solid dosage forms: tablets and capsules”.

For the first time, Siegfried’s drug sub-stances business included sales from products manufactured at its site in Nantong, China.

In 2019, Siegfried said it “expects to grow sales at least in the mid single-digit range and to continue to improve the EBITDA margin”.


“Siegfried has at its disposal numerous

potential M&A routes to follow”



R E G U L AT I O N

EU Incentives Review Must Restore A Sense Of BalanceAIDAN FRY [email protected]

A lack of checks and balances on regulatory rewards for phar-ma innovation has created an imbalanced system in need of correction through an ongoing incentives review, speak-

ers at Medicines for Europe’s Legal Affairs conference argued. The industry association expects to learn within the next month or so how the European Commission will respond to the evidence gath-ered as part of the review with which it was entrusted under the Dutch presidency of the European Council in 2016.

Addressing delegates in Amsterdam, the Netherlands, Marcel van Raaij from the Dutch ministry of health, welfare and sports said the Dutch authorities had acted on an impression that the complex incentive system’s “checks and balances were not ap-propriate”. And the initiative, he said, had found a large degree of common ground among other member states.

“Most of these regulations we are talking about now were cre-ated in the 1990s, when there was not a huge discussion around affordability and sustainability,” he observed. “The thinking then was that if we create a system that contained enough carrots, it would turn out alright. We lack sticks in the system.”

Acknowledging that it was natural for pharma originators to seek to maximize revenues by capitalizing on exclusivity periods and other incentives for innovation, van Raaij said this had cre-ated tension with publicly-funded health systems in terms of ac-cess to medicines and affordability. While originators continued to bring innovations to market, he insisted it was not clear what impact the EU having “the most generous incentive system in world” was exerting.

INTENT BEHIND SPC REGULATION WAS DIFFERENT TO OUTCOME

Reviewing research conducted within the remit of the review, he insisted it was “clear policymakers intended to do something dif-ferent with supplementary protection certificate (SPC) regulation than what has been the outcome in reality”. Van Raaij also high-lighted a lack of checks and balances on orphan designations re-warded with 10-year exclusivity, “often based purely on incidence”.

Presenting the key findings of a study conducted by Tech-nopolis for the Dutch ministry, Sven Bostyn from the University of Copenhagen observed that, by late 2017, almost 3,000 ap-plications for orphan-drug status had been received, and nearly 2,000 preliminary designations had been granted.

Noting that just 142 orphan drugs had reached the market, a “very low percentage” of the designations filed, Bostyn observed that the marketed medicines were heavily concentrated in the large, lucrative oncology sector. He acknowledged concerns over ‘indication-stacking’ strategies whereby originators subdivide pa-tient populations to secure multiple indications, each of which can qualify for 10-year orphan exclusivity, plus a potential two-year pe-diatric extension. For example, he said, Alexion’s Soliris (eculizum-ab) was benefitting from not only an exclusivity period expiring this year, but also two others running until 2023 and 2027 respectively.

Similarly, he said, originators tended to seek six-month paediat-

ric SPC extensions to their best-selling brands, rather than those that were most useful for treating conditions prevalent in children.

ORIGINATOR STRATEGIES QUESTIONABLE UNDER COMPETITION LAW

Summarizing the study’s findings, Bostyn observed that origi-nators were putting “enormous effort into combining as many exclusivities as they can in a very strategic manner”. Such strate-gies, he suggested, “might be questionable from a competition-law perspective”. He proposed that one solution could be to en-courage greater mutual understanding between the regulatory and intellectual-property systems.

Ellen ‘t Hoen, director of thinktank Medicines Law & Policy, expressed high hopes that the pharma incentives review would restore a balance between encouraging innovation and promot-ing public health.

“The current innovation system is broken,” she insisted. “It is based on the single idea that if we keep handing out exclusive rights, wonderful things will continue to happen.”

Observing that even the most affluent countries were strug-gling to fund life-saving drugs, she called on the review to pro-duce substantial legislative changes, “not just tinkering”. Her or-ganization, she added, was working on concrete proposals on how to revise EU pharma law.

The current system relied heavily on over-inflated estimates of research and development expenses, ‘t Hoen contended. “What is sufficient profit?” she questioned, calling for greater transpar-ency on R&D costs relative to drug pricing. In general, she ar-gued, incentives such as SPCs were based on assumptions that were not tested, leading to extensions being granted on mo-nopolies for billion-dollar blockbusters long after the developer had more than recouped any costs.

While the patent system had some in-built flexibilities such as compulsory licenses, ‘t Hoen noted that there were “no remedies to abuses” in the case of regulatory exclusivities. “Waivers for data exclusivity exist in other pieces of legislation,” she observed.

“The thinking then was that if we create a system that contained enough carrots, it would turn out alright. We lack sticks in the system”


R E G U L AT I O N

Discussing incentives in the context of trade agreements, ‘t Hoen bemoaned that “the Commission has a habit of shopping around internationally the kind of regulations that we struggle with here”. As part of the debate around appropriate pharma incentives, she called on the Commission’s director-general for trade to stop pushing third countries to increase levels of intel-lectual-property protection.

NEED MECHANISMS FOR CHALLENGING REGULATORY EXCLUSIVITIES

Acknowledging the importance of incentivizing originators to develop novel medicines that provided a pipeline for generics and biosimilars companies, George Moore – Mylan’s assistant general counsel for Europe, Australia and Asia – stressed “the

need for transparent mechanisms to challenge exclusivities”.The considerable amount of patent and SPC litigation in Europe

served as an important correctional mechanism, Moore contend-ed. “It is the other side of the industry stepping up to challenge and clarify the grant of patents and SPC,” he maintained.

“But when it comes to incentives on the regulatory side, we do not have a transparent system of court litigation,” Moore pointed out. Rather, he said, orphan, pediatric and similar exclusivities were based on conversations between originators and regula-tors without third-party intervention. Rules on legal standing had, he believed, made it difficult to establish a substantial body of case law on regulatory exclusivities.


B I O S I M I L A R S

Polish Plans For Courts Will Not Remove All Biosimilar BarriersAIDAN FRY [email protected]

Legislative moves in Poland to create dedicated intellectual-property (IP) courts that can resolve patent disputes more effi-ciently are to be welcomed, according to Jacek Myszko, senior

counsel at local law firm Soltysinski, Kawecki & Szlezak. But this ini-tiative will not remove all of the considerable barriers to greater bio-similar uptake in Poland, Myszko told delegates to Medicines for Eu-rope’s legal affairs conference held in Amsterdam, the Netherlands.

Participating in a session dedicated to legal issues around bio-similars, Myszko expressed optimism that dedicated IP courts would provide greater certainty around disputes over patents protecting medicines, including biological drugs. “It currently takes years to get to a first-instance decision, and even longer to get a final verdict,” he observed.

However, Myszko cautioned, creating specialist IP courts was un-likely to address other weaknesses of the Polish legal system, such as difficulties in recouping legal costs from losing parties, especially in the case of damages due following preliminary injunctions ob-tained to prevent biosimilar and generic competition. “In the event that you have a first-mover advantage,” he remarked, “it is very dif-ficult to convince courts that your anticipated profits are justified.”

Preliminary injunctions had also proved problematic in other respects, he commented, citing the example of a reimbursement listing for a generic triggering an injunction prior to launch. “De-leting the generic from the reimbursement list required a lot of time and created considerable tension,” he said.

Adverse press coverage for the industry had also resulted from an opinion delivered by Poland’s patients ombudsman that a hospital had violated patients’ rights by switching them to a bio-similar. “This decision was miscommunicated in the market,” he said, noting that this was presenting barriers to switching. A final court decision was likely to follow “in a year or two”, he added.

BIOSIMILAR REIMBURSEMENT HELD UP WITHOUT EXPLANATION

Myszko observed that reimbursement decisions on several bio-similars had been pending for some time without any clear indi-cation as to what was causing a delay. More promisingly, plans to introduce specific rules on public tenders for biosimilars had been stopped at an early stage.

“Polish competition authorities are not generally minded to look deeply into the pharmaceuticals market,” Myszko remarked. However, he predicted, this could change in the near future if the European Commission and national authorities stepped up their attention on the sector.

A survey of Polish hospital pharmacists just published in the BioDrugs journal found that biosimilars were being used in 77% of the surveyed hospitals, below the 90% figure for original biologics. But while the vast majority of hospital pharmacists questioned – 87% – appreciated the ability of biosimilar com-petition to drive down costs, a similar proportion expressed concerns that biosimilars were “not identical” to their reference brand in terms of immunogenicity or certain pharmacokinetic properties. Thus, the survey found, the hospital pharmacists did not generally feel they were able to lead biologic substitution without a physician’s permission.

“There is a need for more precise legal regulations relating to biosimilars, improved communication between physicians and pharmacists, as well as educational initiatives to improve the safe and effective usage of biosimilars,” suggested the BioDrugs paper’s authors from the Medical University of Gdansk.




R E G U L AT I O N

IGBA Wants A Harmonized And Streamlined Global FrameworkDAVID WALLACE [email protected]

A s the global industry association for generics and biosimilars com-panies, the International Generic

and Biosimilar medicines Association (IGBA) is at the center of the latest devel-opments for off-patent drugs.

Under the tenure of current chair Jim Keon – who is also president of the Cana-dian Generic Pharmaceutical Association (CGPA) – and newly-appointed secretary general Suzette Kox (Also see “Kox Named As IGBA Secretary General” - Generics Bul-letin, 21 Feb, 2019.), the IGBA has recently been grappling with issues as diverse as global regulatory harmonization plans for small-molecule generics; controversy over divergent international approaches to biosimilars, particularly on naming conventions; and a worldwide intellec-tual property (IP) database introduced by originators that threatens to undermine access to medicines by providing a tool for patent-linkage around the globe.

Speaking to Generics Bulletin in the first of three exclusive interviews with both Kox and Keon, Kox made it clear that the IGBA was pleased with the latest reflection paper on global bioequivalence standards published by the International Conference on Harmonisation of Technical Require-ments for Registration of Pharmaceuticals for Human Use (ICH). (Also see “ICH Sets Out Proposals On Harmonizing Standards For Generics” - Generics Bulletin, 7 Feb, 2019.)

“The IGBA highly welcomes the an-nouncement by the ICH on harmonizing standards for generic medicines,” Kox indi-cated. “For the first time ever, generic medi-cines will have a new focus within the ICH.”

Responding to the globally-applicable guidance – which includes establishing an informal generic drug discussion group (IGDG) to review existing ICH guidelines from a generics perspective – Kox said the IGBA perceived the move as “as a recogni-tion by the ICH assembly of the importance of generic medicines in healthcare and the value of harmonization of technical stan-dards to guarantee access to high-quality generic medicines to patients worldwide”.

ACTIVELY PARTICIPATING IN ICH“An active participation in ICH is an IGBA priority,” Kox observed. “IGBA-nominated experts will need to take a leadership role in the new IGDG,” she said, particularly when it came to scientific contributions and offering the benefits of “long-stand-ing industry experience”.

“Harmonizing standards is an essential part of an international regulatory frame-work allowing true global generic drug development,” Kox pointed out.

Having joined the ICH as an industry member of the ICH general assembly in June 2016, the IGBA was elected by the assembly to the ICH’s management com-mittee two years later. The association is represented on the committee by Nick Cappuccino and Beata Stepniewska, who also serve as the IGBA representatives to the ICH assembly.

“IGBA has been contributing to the ICH with IGBA technical experts included on certain expert working groups as an inter-ested party during the last 20 years,” Kox highlighted. And following the most recent developments, she added, “IGBA will be en-gaging even more fully in the ICH activities at the management level, along with more representation on the various expert work-ing groups through the representation of our members across the five continents.”

“We are looking forward to strongly contributing to the new IGDG,” Kox said, “as the agenda for ICH hopefully will be-

gin to address more topics relevant to the registration of generic medicines as well as new medicines.”

The IGDG discussion group within the ICH “will serve as an advisory and technical discussion resource to the ICH assembly for issues relevant to harmonization of sci-entific and technical standards for generic medicines”, Kox explained. “The IGDG will recommend areas for harmonization un-der ICH, and assess the feasibility of har-monization of various topic areas within existing regional regulatory frameworks.”

“We trust that the group will be opera-tional very soon,” she said, “as the expres-sion of interest from all ICH members and observers has been already collected and the nomination of experts is ongoing.”

It was “particularly urgent at this mo-ment”, Kox said, “because this is the time in the ICH annual cycle when new topics pro-posed for harmonization are evaluated by the ICH management committee prior to endorsement by the ICH assembly meeting, which takes place in Amsterdam in June”.

AMBITIOUS SCOPE“The IGDG gives a real opportunity to shape the international program for harmoniza-tion of standards for generic medicines,” Kox suggested. “The scope of activities for the IGDG is very ambitious, covering an identification of specifically recommended new topics for harmonization under ICH related to generic medicines, recommend-

“The IGDG gives a real opportunity to shape

the international programme for

harmonization of standards for generic

medicines”

ANALYZE

See more exclusive interviews and information related to this story here: https://bit.ly/2Vv5l3Rhttps://bit.ly/2OWlPzA


R E G U L AT I O N / B I O S I M I L A R S

ing any revisions or resequencing of work, assessing any gaps in guidance for generic medicines and suggesting priorities for fu-ture generic medicines-related harmoniza-tion work under ICH.”

Kox said the IGBA was “aware of limited capacities for the ICH to handle all requests for harmonization”. However, she said, “we believe that the momentum and global health need are there to dedicate increased resources from the drug regulatory author-ities and the other ICH industry parties to invest in appropriate standards for generic medicines, which are an essential and basic treatment for patients worldwide”.

Referring to the US Food and Drug Ad-ministration’s (FDA’s) recent proposal on harmonizing bioequivalence standards for immediate-release solid oral dosage forms (Also see “Global development path proposed to ICH by FDA” - Generics Bulletin, 26 Oct, 2018.), Kox said the IGBA “strongly endorses” these proposals within the ICH management committee.

“ICH’s mission is to achieve greater har-monization worldwide to ensure that safe, effective, and high-quality medicines are developed and registered in the most re-source-efficient manner,” Kox concluded. “Harmonized ICH technical guidelines are essential for efficient global generic medicines development, which supports equity of access to healthcare and the UN member states’ vision of Universal Health Coverage (UHC) by 2030.”

Kox has also backed recent industry calls for a global comparator product, call-ing for “strong engagement by industry at national and international level” to make the concept a reality.


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Sandoz Tries Again With US PegfilgrastimDAVID WALLACE [email protected]

Sandoz has refiled its application for biosimilar pegfilgrastim with the US Food and Drug Administration

(FDA), nearly three years after the firm was knocked back by a complete response letter (CRL) in June 2016 for its initial application.

Having originally planned to refile the application for its LA-EP2006 biosimilar version of Amgen’s Neulasta in late 2018, Sandoz in 2017 pushed back the filing to early 2019 “in order to accommodate a change in study design”.

Novartis CEO Vas Narasimhan – who was at the time global development head for the company – explained in 2017 that the firm had “resized the US study to give our-selves plenty of margin to be successful”.

The resubmission includes new data from a pivotal pharmacokinetics (PK) and pharma-codynamics (PD) study. “This was a single-dose, three-period cross-over study compar-ing Sandoz’ pegfilgrastim with US-sourced reference pegfilgrastim; Sandoz’ pegfilgras-tim with EU-sourced reference pegfilgrastim; and US with EU-sourced reference pegfil-grastim,” the Novartis subsidiary explained.

Sandoz is pursuing approval for its pegfilgrastim to decrease the incidence of infec-tion, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant in-cidence of febrile neutropenia.

FOLLOWS MYLAN AND COHERUS LAUNCHESLast year, Mylan launched the first US biosimilar pegfilgrastim with its Fulphila (peg-filgrastim-jmdb) developed with Biocon. (Also see “Biocon confirms US Neulasta rival launch” - Generics Bulletin, 3 Aug, 2018.) The product soon captured a significant market share. Coherus BioSciences followed with a launch of its Udenyca (pegfilgrastim-cbqv) biosimilar at the start of this year.

“The US market is just beginning to benefit from biosimilars, as shown by the success of our filgrastim, the first approved biosimilar in the US,” observed Mark Levick, Sandoz’ global head of development for biopharmaceuticals. “The submission of our pegfilgras-tim biosimilar application is another step for us as we continue to lead the way in creat-ing early and expanded patient access to life-changing biologics.”

In late 2018, Sandoz received a pan-European marketing authorization for its Ziex-tenzo biosimilar pegfilgrastim from the European Commission.

Sandoz has not always persisted with biosimilar applications that have been knocked back by the FDA. Last year it decided not to pursue biosimilar rituximab in the US fol-lowing a CRL from the agency asking for more information on the candidate, despite it having already been approved in the EU, Japan and Australia.


“The US market is just beginning to benefit from biosimilars, as

shown by the success of our filgrastim,

the first approved biosimilar in the US”



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Zentiva Strikes Deal To Buy UK’s Creo Pharmaceuticals As It Pursues ‘Champion’ AmbitionsPENELOPE MACRAE

C zech generics company Zentiva Group has begun bulk-ing up on acquisitions and says it is on the lookout for more opportunities as it seeks to become “the champion

of generics in Europe” under its new owner, private-equity giant Advent International.

Zentiva, which has a strong presence in Eastern Europe, partic-ularly in the Czech Republic, Slovakia and Romania, announced it is acquiring UK company Creo Pharmaceuticals from Amneal Pharmaceuticals, a New Jersey-based generics and specialty drug firm, to increase its presence in the UK.

Creo’s purchase will assist the Prague-based company to “strengthen Zentiva’s position in the UK,” Zentiva’s chief executive Nick Haggar, a pharmaceutical industry veteran who pledged to “accelerate growth” after he was named to head the company in January, said in a statement. (Also see “Industry Veteran Haggar To Lead Private Equity-Backed Zentiva From Next Month” - Generics Bulletin, 16 Jan, 2019.)

The purchase marks Zentiva’s second acquisition announce-ment since being sold for EUR1.9bn ($2.2bn) to Advent last Octo-ber by Sanofi in a deal that marked the French drug-maker’s exit from the European generics market. Sanofi spun off Zentiva as part of a slimming drive to concentrate on core operations like global medicines and emerging markets and restore profit growth.

“We have new ownership and so we’re currently looking for opportunities,” Zentiva’s head of corporate affairs Ines Windisch told Generics Bulletin on April 2. “Creo is a perfect fit for us – they have strong customer orientation and strong products,” she said.

CREO SAYS IT WILL ACHIEVE ‘FULL POTENTIAL’ UNDER ZENTIVA

Creo, founded in 2007, offer partners direct marketing access in the UK generics market. Its key focus is on supplying the wholesale, pharmacy and hospital sectors with products ranging from gener-ic medicines to commercial brands. “The combination of Creo and Zentiva will allow us to accelerate our growth and achieve our full potential,” Creo’s managing director Luke Hart said.

Zentiva, already one of Europe’s biggest generic firms operat-ing in 25 European countries and distributing over 350mn packs a year, declined to disclose financial details of the acquisition.

Just last month in its first acquisition since being carved out of Sanofi and sold as an independent company, Zentiva and Romanian pharmaceutical products manufacturer Siyiara Enter-prises signed a conditional shared-purchase agreement to ac-quire Romania-based pharmaceutical firm Solacium. Solacium, a fast-growing food supplement and OTC medicines producer, is currently part of Dr. Max Group, a leading central European pharmacy chain and is owned by Siyiara Enterprises and entre-preneur Alexandru-Tony Trascu. (Also see “Zentiva Set To Acquire Romania’s Solacium” - Generics Bulletin, 13 Mar, 2019.)

Zentiva, which sells drugs for cardiovascular, nervous system,

gastrointestinal and metabolic disorders as well as pain and anti-inflammatory medicines, is seeking to fulfil ambitions set by Advent, which knocked out competition from heavyweight buyout funds and pharmaceutical firms to acquire the Czech firm. Advent said last year it aimed to create a “new independent European generics leader” out of Zentiva which employs over 2,500 people. (Also see “Zentiva sets strategy as it starts out alone” - Generics Bulletin, 5 Oct, 2018.)

ZENTIVA IS UPGRADING PRAGUE MANUFACTURING PLANTThe purchase announcements followed Zentiva’s move in Janu-ary to invest EUR30mn to upgrade and capacity at its Prague manufacturing site which now produces up to 120mn packages a year. Zentiva said the investment was “part of a broader ambi-tion to become the champion of generics in Europe” and added it would pump a further EUR8mn into the plant later in the year. Zentiva also has a manufacturing site in Bucharest.

Amneal, which operates in North America, Asia and Europe and is one of the fastest-growing Fortune 500 companies, fo-cuses on developing, manufacturing and distributing generic, brand and biosimilar products. Creo has been running Amneal’s UK commercial operations.

Amneal’s chief executive Rob Stewart said the transaction would allow Zentiva “gain additional products and an enhanced competitive market share position.” Creo’s sale will also benefit Amneal, one of the fastest-growing Fortune 500 companies, by permitting it “to concentrate management time and resources to support our continued focus on strengthening our growing position in the US market,” he said.


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D E A L S

“We’ll focus on niche established medicines

and will seek to capitalize on our existing sales and marketing strengths in

markets such as the UK, the Nordic countries and Australia, as well

as through partners in continental Europe and

the US through partners”

Advanz Embarks On Strategic Plan By Buying Two Eisai BrandsAIDAN FRY [email protected]

Advanz Pharma has acted on its stra-tegic goal of acquiring legacy off-patent brands and specialty generics

by paying US$30 million in cash, plus around US$3.3 million for purchased inventory and related pre-payments, for international rights to Eisai’s Salagen (pilocarpine hydro-chloride) and Panretin (alitretinoin) gel.

The deal for the established medicines, which Advanz is funding through cash on hand, excludes rights in Japan to Salagen tablets, which are indicated for treating symptoms of dry mouth, both in patients with Sjogren’s Syndrome and in patients suffering from salivary gland hypofunction caused by radiotherapy for head and neck cancer. It gives Advanz full global rights to Panretin 0.1% gel that is used for topical treatment of cutaneous lesions in patients with AIDS-related Kaposi’s sarcoma (KS).

In the territories where it will hold rights, Advanz said combined Salagen and Panretin sales totalled around US$13 million in 2018.

“We believe these medicines are excel-lent strategic fits with our global com-mercial infrastructure and are well aligned with our product acquisition focus,” stated Advanz’ chief executive officer, Graeme Duncan. “In addition, the transaction demonstrates that the company has re-turned as a participant in the global merg-ers & acquisitions (M&A) marketplace, and reinforces our commitment to our new strategy, known as ‘PLAN’.”

The four elements that comprise Ad-vanz’ PLAN corporate strategy are:

Product expansionLeverage global capabilityAcquire & integrateNew start/visionAs it looks to stave off the negative ef-

fects of the increasing genericization of its existing portfolio, the company has identified two strategic guiding policies that it believes can restore the company to a growth trajectory: product expan-sion through pipeline filling, optimization, licensing and development partnerships; and acquiring and integrating assets - both

companies and products - that fit with its core product, market and commercial ca-pabilities, particularly those that enable Advanz to extend its commercial capabili-ties within western Europe.

These two guiding policies are under-pinned by two operational imperatives: leveraging the group’s global capability and commercial platform via a “lean and fully leveraged operating model”; and a new start and vision that will “re-energize the company through clarity, culture, brand and leadership”.

In an exclusive interview with Gener-ics Bulletin, Duncan said Advanz had built an extensive and experienced business-development team that was scouring the globe for attractive acquisition and part-nering opportunities in the niche estab-lished medicines sector. “We’ll focus on niche established medicines and will seek to capitalize on our existing sales and mar-keting strengths in markets such as the UK, the Nordic countries and Australia, as well as through partners in continental Europe and the US through partners,” he explained, identifying Japan as the “only significant pharmaceutical geography where we prob-ably do not have commercial capability”.

While Advanz is considering strategic op-tions, including divestment, for its US Pin-nacle Biologics business that markets the Photofrin (porfimer sodium) oncology treat-ment, Duncan recently clarified that “we are actively out in the M&A market at the mo-ment, including looking at products where the rights are global, including the US”.

FOCUSING ON COMPANY ACQUISITIONS IN WESTERN EUROPE

By contrast, he explained, Advanz’ focus on acquiring companies was centred on western Europe, where the firm was look-ing to add to its existing sales and market-ing capabilities in the UK, Ireland and the Nordic countries.

“It is a very vibrant M&A market at the mo-ment, particularly in the product area,” Dun-can observed. “We are assessing, and are through at least the first couple of stages, on

two or three different projects,” he revealed.The financial firepower to pursue trans-

actions was provided by a recapitaliza-tion process completed in September 2018 that wrote off around US$2.4 billion of debt. Shortly afterwards, the company dropped its Concordia name in favor of the new Advanz Pharma livery.

Asked about the scale of Advanz’ M&A ambitions, Duncan told Generics Bulletin: ““I am not worried about size, I am wor-ried about getting the right assets and the right level of attractiveness in those assets.”

“Looking ahead,” the Canada-domiciled company commented on announcing the deal with Eisai, “with a clear strategic focus, Advanz Pharma believes it will have addi-tional opportunities to expand its product portfolio to deliver mid-term value and long-term growth, through further acqui-sitions, pipeline expansion, optimization, and licensing and development partner-ships. The company intends to focus on niche and differentiated generics, complex specialty and value-added medicines.”




Nucynta ER Ruling Preserves US Status Quo On TapentadolAIDAN FRY [email protected]

N ew Jersey district judge Claire Cecchi was right to find that generics of Nucynta ER (tapentadol) extended-release tablets from Hikma and Teva’s Actavis did not

infringe a method-of-use pain patent running until September 2028, the US Court of Appeals for the Federal Circuit has found. But the appeals court simultaneously upheld the validity of a US polymorph patent protecting Assertio Therapeutics’ opioid anal-gesic until at least June 2025.

The appeals panel chose first to tackle Assertio and partner Grü-nenthal’s appeal against Cecchi’s finding that Hikma and Actavis did not, but Alkem did, infringe US patent 8,536,130. The ‘130 pat-ent claims a method of using tapentadol and its salts to treat poly-neuropathic pain caused by damage to multiple nerves.

“Because neither Hikma’s nor Actavis’ proposed label is indi-cated to treat polyneuropathic pain, and the case is made by Grünenthal and [Assertio predecessor] Depomed for indirect infringement depended on the proposed label indications, we agree with the trial court that Hikma and Actavis do not induce infringement of, or contributorily infringe, claims 1 and 2 of the ‘130 patent,” judge Jimmie Reyna wrote for the appeals court.

HIKMA AND ACTAVIS CARVED OUT PATENTED INDICATIONNoting that both Hikma and Actavis had made ‘Section viii’ cer-tifications to carve out Nucynta ER’s labeling for diabetic periph-eral neuropathy (DPN), a type of polyneuropathic pain, Reyna said the question of induced infringement turned on whether the generics firms’ labels encouraged infringement by carrying an indication for severe chronic pain, such as lower back pain. “Even if severe chronic pain includes polyneuropathic pain, it also includes mononeuropathic pain and nociceptive pain,” Rey-na stated in dismissing induced infringement.

On contributory infringement, the appeals court found no er-ror in Cecchi’s conclusion that the generic tapentadols would be indicated for substantial non-infringing uses.

Addressing Cecchi’s finding that US patent 7,994,364 - which is directed to a Form A polymorph of tapentadol hydrochloride, as well as a method of treating pain and/or urinary incontinence - was not invalid for obviousness, Reyna acknowledged Alkem’s argument that, in light of FDA guidance on polymorph screen-ing, Cecchi had clearly erred in finding no motivation to com-bine prior art to arrive at the claimed innovation. However, he said Alkem had failed to “prove a reasonable expectation of suc-cess” in arriving at polymorph Form A.

“Polymorphism of tapentadol hydrochloride was unknown at the time of the filing of the ‘364 patent,” he stated, noting that Form B was the only crystal structure of the drug known at the time. Dismissing as irrelevant previous rulings on amlodipine besylate, budesonide and daptomycin, Reyna clarified: “Our decision today does not rule out the possibility that polymorph patents could be found obvious.”

PATENT RUNNING TO 2025 WAS NOT OBVIOUS TO TRYAlkem’s contention that it would have been obvious to try to pro-duce Form A of tapentadol hydrochloride in light of a finite num-ber of disclosed solvents was of no avail. Cecchi had not erred, Reyna stated, in finding that the cited Byrn prior-art article “identi-fied many variables for screening” that presented a “huge number of possible choices”.

Turning to the question of the ‘364 patent’s utility, Reyna de-scribed as “without merit” Hikma’s argument that the patent’s specification gave only a vague hint that the invention might be useful. “The ‘364 patent teaches that ‘the crystalline Form A according to the invention is used for the treatment of pain or the treatment of urinary incontinence’,” he countered. It was suf-ficient for utility, he added, that a skilled person would have be-lieved at the filing date that Form A was more stable than Form B at room temperature.

Anticipating obtaining a six-month paediatric extension, As-sertio said “the ‘364 patent covers the entire Nucynta franchise until December 2025”. This includes immediate-release tablets as well as an oral solution formulation that is not currently mar-keted. Assertio early in 2018 licensed commercial rights to the Nucynta franchise to Collegium Pharmaceutical in return for a royalty on net sales that brought in US$156 million last year. Assertio anticipates Nucynta franchise royalties to be around US$120 million in 2019.


“Our decision today does not rule out the possibility that polymorph patents could be found obvious”



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