Gilenya仿制藥的前景及對(duì)口服MS定價(jià)和市場(chǎng)份額的影響

1、June 5, 2020 04:01 AM GMTGlobal BioPharma | North AmericaProspects for Gilenya GenericsMORGAN STANLEY & CO. LLCMatthew HarrisonEQUITY ANALYST HYPERLINK mailto:Matthew.Harrison Matthew.Harrison+1 212 761-8055and Impact to Oral MS Pricing and Market ShareMultiple sclerosis drug Gilenya is one of Novar

2、tiss leading medicines, with 2019 sales of $1.7B representing about 4% of the groups gross profit. Over 20 companies are seeking to make a generic version. Much of that revenue to Novartis could be lost shortly after the launch of a generic. Importantly, theMORGAN STANLEY & CO. INTERNATIONAL PLC+Mar

3、k D PurcellEQUITY ANALYST HYPERLINK mailto:Mark.Purcell Mark.PurcellMORGAN STANLEY & CO. LLC+44 20 7677-8557David RisingerEQUITY ANALYST HYPERLINK mailto:David.Risinger David.Risinger+1 212 761-6494Thomas F Lavery, J.D.RESEARCH ASSOCIATE HYPERLINK mailto:Thomas.Lavery Thomas.Lavery+1 +1-212-761-0325

4、 BiotechnologyNorth Americalaunch of a generic Gilenya could also impact the pricing and market share of other oral relapsing-remitting multiple sclerosis therapies, such as Biogens Tecfidera, Sanofis Aubagio, and Bristol Myers Squibbs recently approved Zeposia. We currently model the advent of a U.

5、S. Gilenya generics in January 2023 in our Novartis model.A launch of a generic Gilenya is possible this year. Gilenyas composition-of- matter patent expired in August 2019. Two follow-on patentsa dosing patent and a recently issued chicken pox patentdo not expire until 2027. But HEC Pharmaone of th

6、e few generics that have not settled with Novartisis seeking to defeat them. The following disputes on these patents will help determine when a generic Gilenya product could be launched:Dispute #1 - A Delaware district court may issue decision on the dosing patent by end of 2020; a decision invalida

7、ting the patent could trigger an at-risk launch: In a litigation that had involved over 20 generic companies, just one generic (HEC Pharma) made it to trial. The rest of the generics settled or agreed to sit on the sidelines and be bound by the district courts upcoming decision. We expect a decision

8、 by the end of 2020. After reviewing the post-trial briefs and transcripts, we think deciding who will win is a close call, with a real chance that the court could invalidate the dosing patent, as we describe in more detail below. If the court does invalidate the dosing patent, we think that HEC cou

9、ld try to launch at-risk. We examine that scenario below.IndustryViewIn-LineDispute #2 - A district court litigation on a new chicken pox patent poses a weak potential hurdle to generic launches: A separate litigation involving a new Gilenya patent began recently. Because it is likely that the court

10、 will not have a trial on this patent for another few years, to get around this patent in the near term, generic companies would have to try to launch at- risk, assuming that they can first defeat the dosing patent (see dispute above). We think that this chicken pox patent is highly susceptible to i

11、nvalidity and non-infringement defenses and will thus not pose much of a hurdle to an at-risk launch.Dispute #3 - Novartis dodged a bullet when the appeal of the IPR decisionMorgan Stanley does and seeks to do business with companies covered in Morgan Stanley Research. As a result, investors should

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13、isclosure Section, located at the end of this report.+= Analysts employed by non-U.S. affiliates are not registered with FINRA, may not be associated persons of the member and may not be subject to FINRA restrictions on communications with a subject company, public appearances and trading securities

14、 held by a research analyst account.on the dosing patent was dismissed: Several generics had sought to invalidate the dosing patent in an IPR, which is a separate proceeding than dispute #1 above. Novartis won at the PTAB. But on appeal, it appeared that the Federal Circuit could invalidate the pate

15、nt. Then, before the Federal Circuit could issue a decision on the patent, it dismissed the case because all the original IPR challengers had settled with Novartis and the only remaining generic (Argentum) had not yet filed an Abbreviated New Drug Application and thus did not have standing to contin

16、ue the appeal by itself. Although Argentum will likely ask the Federal Circuit to reconsider its decision, we expect that the Federal Circuit will not likely do so.We describe in more detail below how these three disputes could shape when generics may launch in the U.S. We believe that the district

17、court case involving the dosing patent, which will likely issue a trial decision this year, is a close call. If the dosing patent is found invalid or not infringed by HEC, we expect that HEC Pharma could seek to launch at-risk. The chicken pox patent, we think, will not ultimately prevent that launc

18、h. If HEC launches in the near term after a district court decision finding the dosing patent valid, it appears that itthe only challenger that both currently has final FDA approval and is still litigating could be in the market with the only generic Gilenya product initially. We will continue to ke

19、ep track of these disputes and their implications to Gilenya, the oral relapsing-remitting multiple sclerosis (RRMS) space, and beyond. Finally, we note that we are also tracking the generic challenges to Biogens Tecfidera patents (see our recent deep dive here), and note that a generic Tecfidera la

20、unch could also potentially have a broad impact on the RRMS space.The authors of this material are not acting in the capacity of attorneys, nor do they hold themselves out as such. This material is not intended as either a legal opinion or legal advice. The information provided herein does not provi

21、de all possible outcomes or the probabilities of any outcomes. The result of any legal dispute or controversy is dependent on a variety of factors, including but not limited to, the parties historical relationship, laws pertaining to the case, relative litigation and IP prosecution talent, trial or

22、proceeding location, jury composition, and judge or examiner composition. Investors should contact their legal advisor about any issue of law relating to the subject matter of this material.Status of Gilenya Patent DisputesThe composition-of-matter patent protecting Gilenya expired in August 2019. N

23、ovartis has two other patents that do not expire until 2027. Because these are not composition- of-matter patents, they are generally considered weaker patents. Our analysis confirms that these patents are vulnerable to invalidity and non-infringement defenses. Generics are challenging the these pat

24、ents in three disputes.Dispute #1 - Dosing Patent LitigationDosing patent: This patent claims methods for treating relapsing-remitting multiple sclerosis (RRMS), by orally administering fingolimod,“at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.” The key part of th

25、e claims is the absent an immediately preceding loading dose regimen, which we will discuss more below. This patent expires in 2027.We think that the dosing patent is susceptible to invalidity challenges: When obtaining this patent, Novartis added the claim limitation absent an immediately preceding

26、 loading dose regimen to get around prior art that the patent examiner said rendered Novartiss claims unpatentable. This amendment caused a problem: Novartiss patent says nothing about administering fingolimod absent a loading dose. Nor does it expressly say why a loading dose should be avoided. Gen

27、erics have sought to take advantage of this silence in their district court arguments by arguing, for example, that the patent lacks written description support. Written description is a statutory requirement that a patent provide a description of the invention. Here, the generics argue, there is no

28、 description of orally administering fingolimod, at a daily dosage of 0.5 mg, absent an immediately preceding loading dose regimen.” We thus think that this patent is highly susceptible to a written description challenge.Only one remaining active litigant: Novartis had sued 24 defendant groups but a

29、lmost all defendants have either (1) settled or (2) agreed to sit out this litigation and be bound by whatever the outcome of the case is. Only one defendant remains for trial in March: HEC Pharma. We note that HEC (along with Biocon, Hetero, and Sun) have final FDA approval for a generic Gilenya pr

30、oduct but is currently enjoined from launching due to an earlier preliminary injunction.Although an earlier preliminary injunction proceeding went in Novartiss favor, we think that has little read-through to the courts trial decision: In the summer of 2019, when the Gilenya composition-of-matter pat

31、ent was about to expire, Novartis asked the court to preliminarily enjoin defendants from launching at-risk until a full trial could be held on the dosing patent. The defendants, in response, raised several arguments as to why the dosing patent is invalid. The district court decided in Novartiss fav

32、or, preliminary enjoining all defendants until a trial can be held. Yet we think that the decision has little read-through to the district courts trial decision. First, a different judge will issue the trial decision: whereas Judge Stark issued the preliminary injunction decision, he transferred the

33、 case to Judge Jordan. Second, the preliminary injunction decision was, of course, on a preliminary record,without the benefit of a full trial.HEC Pharma raised four defenses at trial: HEC Pharma raised four defenses at trialthree invalidity defenses and one non-infringement defenses. We order these

34、 defenses from strongest to weakest. First, the claims lack written description support because the patent does not describe in words or the concept of “an immediately preceding loading dose. Second, the patent fails to provide adequate written description support for the 0.5 mg daily dose required

35、by the claims. Third, the claims are anticipated by a prior art abstract referred to as Kappos 2006. Fourth, HEC does not induce infringement because its generic product label does not expressly state that a preceding loading dose must be absent.We think that HECs primary written description argumen

36、t is the most serious challenge to the patent: HECs primary written description argument is that the patent does not describe in words or the concept of “an immediately preceding loading dose. We think that this argument is the most serious challenge for three reasons. First, the claim limitation th

37、at HEC contends has no written description support“an immediately preceding loading doseis whats called a negative limitation. When a negative claim limitation is at issue, the specification must “describe a reason to exclude the relevant limitation.” Inphi Corp. v. Netlist, Inc., 805 F.3d 1350, 135

38、5 (Fed. Cir. 2015). We do not think that Novartis has pointed to text in the patent specification that plausibly describes why an immediate load dose should not precede the 0.5 mg dose of drug product. Second, during oral arguments of a separate proceeding, the Federal Circuit expressed skepticism t

39、hat this negative claim limitation had written description support. Although that case was dismissed for reasons not related to the strength of this written description argument, we think that the Federal Circuits comments show that our viewpoint may be adopted by other judges. We note that other pu

40、blications agree with us that the Federal Circuit appeared skeptical of Novartiss arguments. See, e.g., Law360, Fed. Circ. Casts Doubt On Novartis MS Drug PTAB Win, (Jan. 9 2020).That said, we acknowledge that mere comments during an oral hearing have no read-through to the district court decision.

41、Third, HEC has raised additional defenses that has forced Novartis to take positions that although are not inconsistent, they are close to being inconsistent and highlight that Novartis has little room to maneuver in defending its patent from HECs multi-prong challenge.Although HEC has presented a s

42、erious challenge, we believe some points favor Novartis: First, the PTAB consideredand rejectedthis very written description argument in an IPR proceeding under a lower burden of proof. Second, in this district court litigation, a different judge (Judge Stark) also consideredand rejectedthis written

43、 description in a preliminary injunction hearing. We note, though, that beyond a different judge making that ruling, the evidence in that hearing was much less than what Judge Jordan heard at trial. Third, HEC bears the heavy burden of showing invalidity under the clear-and-convincing-evidence stand

44、ard.Overall, the case remains a close call: Factoring all these considerations, we think that the case is a close call, with HEC having a real chance to invalidate the patent.We expect a trial decision in 2H2020: The trial happened in March and post-trial briefs concluded on May 8. We thus expect th

45、e decision to likely be issued in the second half of the year.Dispute #2 - Chicken Pox Patent LitigationThis new litigation is separate from the dosing patent litigation and just recently begun.Chicken pox patent: Novartiss patent claims the following methodfor patients with RRMS who will be adminis

46、tered fingolimod, determining whether they have had the chicken pox, and if they havent, vaccinating them before treatment. The patent expires in 2027.Highly susceptible to invalidity challenges: This patent almost did not issue from the patent office because the primary examiner found two on-point

47、prior art references and vigorously asserted that the solution to the problem of limiting the risk of infection caused by varicella zoster virus which includes chicken pox by vaccinating the said patient against varicella zoster virus . . . is basic common sense. . . . After a series of rejections b

48、y the primary examiner, the supervisory examiner spoke with Novartis, at which point the application was finally allowed. In allowing the patent, the supervisory examiner explained that although the prior art teachesto use a daily dose of 0.5 mg fingolimod and (2) infections such as chickenpox in pa

49、tients receiving fingolimod can be very dangerous, and even deadly, and should be avoided, neither prior art reference expressly discloses verbatim that vaccinating a patient determined to be at risk of contracting infection caused by varicella zoster virus thus limits the risk of infection caused b

50、y varicella zoster virus. We think that the supervisory examiners explanation for why these claims are allowable makes little sense. After all, it would be common sense to vaccinate against varicella zoster virus before starting fingolimod treatment if such infections in patients receiving fingolimo

51、d can be very dangerous and even deadly. Moreover, the standard for obviousness does not require prior art to expressly disclose or verbatim disclose the pertinent information. We thus think that these patent claims are highly vulnerable to invalidity challenges.Susceptible to non-infringement defen

52、ses: As an initial matter, we note that this patent arguably covers the Gilenya label because the label instructs physicians to “test patients for antibodies to varicella zoster virus (VZV) before initiating GILENYA,” and that “VZV vaccination of antibody-negative patients is recommended prior to co

53、mmencing treatment with GILENYA.” Yet this patent covers just a small percentage of Gilenya patents. During prosecution of this patent, Novartis admitted that the percentage of RRMS patients who are antibody negative represents just 5% of total RRMS patient population. What does this mean? It means

54、that generic products would have substantial non-infringing usesmany uses (95%) of their product would not infringe this patent. This is a significant consideration for whether a generics label could be liable under a theory of infringement called contributory infringement. Although a generics label

55、 may still be liable under another theory of infringement called induced infringement, that a label has substantial non-infringing uses can be important for defeating a motion for a preliminary injunction, which we discuss in the section below about potential at-risk launch scenarios.No trial date s

56、cheduled yet: We note that this case is still at an early stage and no trial date has been scheduled yet.Dispute #3 - Appeal of IPR of Dosing PatentApotex, Argentum, Teva, and Sun filed IPR petitions, asking the PTAB to find the claims of the dosing patent unpatentable for anticipation and obviousne

57、ss.Although the PTAB instituted review, it ultimately found that the challengers failed to show, by a preponderance of the evidence, that the claims are unpatentable.The challengers appealed to the Federal Circuit. The Federal Circuit heard oral arguments on 1/9/2020. During those oral arguments, th

58、e three-judge panel asked questions that highly suggested that they may reverse the PTAB decision and find the claims of the dosing patent unpatentable.Yet before the Federal Circuit could issue a decision, Novartis settled with Apotex, leaving Argentum as the remaining defendant.Because Argentum ha

59、d not yet filed its ANDA, the Federal Circuit found that Argentum lacked standing to continue the appeal. Thus, the Federal Circuit dismissed the appeal, leaving the dosing patent untouched. Novartis dodged a bullet.We expect Argentum to ask the Federal Circuit to reconsider its decision en banc. Th

60、e Federal Circuit rarely grants such petitions and will thus likely reject any petition filed by Argentum.We summarize these three disputes in the following table:DisputePatentStatusDispute #1: District court case of9,187,405HEC is the only remaining active litigant. A trial happened in March 2020 a