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ECLI:DK:OLR:2023:BS0000006319 Landsretten har afsagt kendelse i tre sambehandlede kæremål om midlertidige forbud og påbud til henholdsvis Sandoz A/S o

ØSTRE LANDSRET KENDELSE afsagt den 15. december 2023 Sag BS-5667/2023-OLR (10. afdeling) Biogen International GmbH og Biogen (Denmark) A/S (advokat Jeppe Brinck-Jensen for begge) mod Viatris ApS (advokat Jakob Krag Nielsen og advokat Maria Pilh Arendsdorf Bengtsen) og Sag BS-7310/2023-OLR (10. afdeling) Sandoz A/S (advokat Anders Valentin og advokat Patris Hajrizaj) mod Biogen International GmbH og Biogen (Denmark) A/S (advokat Jeppe Brinck-Jensen for begge) og Sag BS-27713/2023-OLR (10. afdeling) Sandoz A/S 2 (advokat Anders Valentin og advokat Patris Hajrizaj) mod Biogen International GmbH og Biogen (Denmark) A/S (advokat Jeppe Brinck-Jensen for begge) Sø- og Handelsretten har ved kendelse af 20. januar 2023 (sag BS-28336/2022SHR) vedrørende Biogen International GmbH og Biogen (Denmark) A/S’ anmodning om midlertidigt forbud over for Viatris ApS bestemt: ”Biogen International GmbH og Biogen (Denmark) A/S’ anmodning om midlertidigt forbud nægtes fremme. Biogen International GmbH og Biogen (Denmark) A/S skal inden 14 dage betale 2.459.057,39 kr. i sagsomkostninger til Viatris ApS. Sagsomkostningerne bliver forrentet efter rentelovens § 8 a.” Kendelsen (i det følgende ”Viatris-kendelsen”) er kæret af Biogen International GmbH og Biogen (Denmark) A/S. Sø- og Handelsretten har endvidere ved kendelse af 31. januar 2023 (BS31825/2022-SHR) vedrørende Biogen International GmbH og Biogen (Denmark) A/S’ anmodning om midlertidigt forbud og påbud over for Sandoz A/S be-stemt: ”Hvis Biogen International GmbH og Biogen (Denmark) A/S senest den 10. februar 2023 stiller sikkerhed på 100.000.000 kr., vil retten meddele følgende forbud og påbud: Sandoz A/S forbydes at fremstille, udbyde, bringe i omsætning eller anvende lægemidlet Dimethyl fumarat "Sandoz" til behandling af mul-tipel sklerose, hvor dosen af dimethylfumarat, der skal administreres, er 480 mg pr. dag, eller importere eller besidde det med et sådant for-mål, så længe DK/EP 2 653 873 er i kraft. Sandoz A/S skal tilbagekalde allerede skete leverancer af lægemidlet Dimethyl fumarat "Sandoz" fra alle erhvervsmæssige kunder, herunder koncernforbundne selskaber og apoteker, hvortil levering er foretaget. Kopi af tilbagekaldelserne skal sendes til Biogens advokater. Sandoz A/S skal afregistrere sin pris for lægemidlet Dimethyl fumarat "Sandoz" i det danske prisregister, www.medicinpriser.dk.” 3 Efter modtagelse af sikkerhed er forbud og påbud meddelt ved Sø- og Handelsrettens kendelse af 3. februar 2023. Kendelsen (i det følgende ”Sandoz-kendelsen”) er kæret af Sandoz A/S. I sag BS-31825/2022-SHR om ophævelse af de ved kendelsen af 3. februar 2023 meddelte forbud og påbud har Sø- og Handelsretten ved kendelse af 26. maj 2023 bestemt: ”Biogen International GmbH og Biogen (Denmark) A/S frifindes. Inden 14 dage skal Sandoz A/S betale 100.000 kr. i sagsomkostninger til Biogen International GmbH og 100.000 kr. i sagsomkostninger til Bio-gen (Denmark) A/S. Sagsomkostningerne forrentes efter rentelovens § 8 a.” Kendelsen (i det følgende ”ophævelseskendelsen”) er kæret af Sandoz A/S. Landsdommerne Katja Høegh, Susanne Lehrer og Johann Herzog samt det sagkyndige medlem Jesper Levin Aamand har deltaget i kæresagernes afgørel-se. Kæremålene, der er blevet sambehandlet, har været behandlet mundtligt. Påstande Biogen International GmbH og Biogen (Denmark) A/S (”Biogen”) har i sag BS7310/2023-OLR (om forbud) og sag BS-27713/2023-OLR (om ophævelse af forbud) over for Sandoz A/S nedlagt påstand om stadfæstelse. I sag BS-5667/2023-OLR har Biogen over for Viatris ApS nedlagt påstand om, at Viatris ApS forbydes at fremstille, udbyde, bringe i omsætning eller anvende lægemidlet Dimethyl fumarate Mylan i Danmark, jf. markedsføringstilladelsesnumre EU/1/22/1634/001, EU/1/22/1634/002, EU/1/22/1634/003, EU/1/22/1634/004, EU/1/22/1634/005, EU/1/22/1634/006, EU/1/22/1634/007, EU/1/22/1634/008, EU/1/22/1634/009 og EU/1/22/1634/010, til behandling af multipel sklerose, hvor dosen af dimethylfumarat, der skal administreres, er 480 mg pr. dag, eller importere eller besidde det med et sådant formål, så længe DK/EP 2 653 873 er i kraft, subsidiært at Viatris ApS forbydes at fremstille, udbyde, bringe i omsætning eller anvende lægemidlet Dimethyl fumarate Mylan i Dan-mark, jf. markedsføringstilladelsesnumre EU/1/22/1634/001, EU/1/22/1634/002, EU/1/22/1634/003, EU/1/22/1634/004, EU/1/22/1634/005, EU/1/22/1634/006, EU/1/22/1634/007, EU/1/22/1634/008, EU/1/22/1634/ 009 og EU/1/22/1634/010, til behandling af recidiverende remitterende multipel sklerose, hvor dosen dimet- 4 hylfumarat, der skal administreres, er 480 mg pr. dag, eller importere eller be-sidde den til et sådant formål, så længe DK/EP 2 653 873 er i kraft. Sandoz A/S (”Sandoz”) har i sag BS-27713/2023-OLR (om ophævelse af forbud) nedlagt påstand om, at Sø- og Handelsrettens kendelse af 31. januar 2023 op-hæves, og har i sag BS-7310/2023-OLR (om forbud) nedlagt påstand om, at Bio-gen International GmbH og Biogen (Denmark) A/S’ anmodning om midlerti-digt forbud nægtes fremme. Viatris ApS (”Viatris”) har i sag BS-5667/2023-OLR nedlagt påstand om stadfæstelse, subsidiært at anmodningerne om midlertidige forbud og påbud fremmes mod tilvejebringelse af en af Østre Landsret fastsat sikkerhed. Om sikkerhedens størrelse har Viatris anført, at den bør fastsættes til 1 mio. kr. For landsretten har både Sandoz og Viatris gjort anbringender gældende om manglende basis, manglende nyhed, manglende opfindelseshøjde og utilstræk-kelig beskrivelse. Sandoz har − for så vidt som indsigelserne mod gyldigheden af stridspatentet ikke tages til følge − ikke bestridt, at betingelserne i retsplejelovens § 413 og § 414 for meddelelse af forbud og påbud mod en sikkerhedsstillelse som fastsat af Sø- og Handelsretten er opfyldt. Viatris har, jf. nærmere nedenfor om parternes anbringender, gjort gældende, at uanset om indsigelserne mod gyldigheden af stridspatentet ikke tages til følge, skal bredere samfundsmæssige interesser i at undgå opretholdelse af ubegrundede monopoler og heraf følgende højere medicinpriser føre til, at Biogen må henvises til at håndhæve sin ret ved lovens almindelige regler om straf og erstatning, jf. retsplejelovens § 414, stk. 1. Viatris har ikke i øvrigt bestridt, at betingelserne i retsplejelovens § 413 og § 414 for meddelelse af forbud mod en sikkerhedsstillelse som påstået af Viatris vil være opfyldt, hvis stridspatentet ikke anses for ugyldigt. Supplerende sagsfremstilling Stamansøgningen Den internationale stamansøgning WO 2008/097596 indeholder følgende patentkrav: ”1. A method of evaluating neuroprotective properties of at least one test compound, the method comprising:

  1. a)contacting a cell with the at least one test compound, 5
  2. b)determining whether the Nrf2 pathway is upregulated in the cell,
  3. c)determining whether the at least one test compound slows or prevents at least one of demyelination, axonal loss, and neu-ronal death, and
  4. d)selecting the test compound as a candidate for treating neurodegeneration in a neurological disease if 1) the Nrf2 pathway is upregulated and, optionally,
  5. e)further determining whether at least one of demyelination, ax-onal loss, and neuronal death are prevented or slowed by the compound. … 8. The method of item 1, further comprising comparing the level of Nrf2 pathway upregulation by the at least one test compound with the level of Nrf2 pathway upregulation by at least one comparator compound. 9. The method of item 8, wherein the at least one comparator com-pound is selected from dimethyl fumarate and monomethyl fumarate. … 13. A method of treating a mammal having a neurological disease, comprising:
  6. a)selecting a test compound according to the method of any one of claims 1-10, and
  7. b)administering the selected test compound a mammal in need thereof, thereby treating neurodegeneration in the mammal. 14. A method of treating a mammal having a neurological disease by combination therapy, the method comprising:
  8. a)administering to the mammal a therapeutically effective amount of at least one first compound that upregulates the Nrf2 pathway, and
  9. b)administering a therapeutically effective amount of at least one second compound that does not upregulate the Nrf2 pathway. …” Af beskrivelsen i stamansøgningen fremgår følgende: ” Nrf2 SCREENING ASSAYS AND RELATED METHODS AND COMPOSITIONS 6 [0001] Provided are certain compounds for treating neurological diseases, including demyelinating neurological diseases, such as, e.g., multiple sclerosis. [0002] Multiple sclerosis (MS) is an autoimmune disease with the autoimmune activity directed against central nervous system (CNS) antigens. The disease is characterized by inflammation in parts of the CNS, leading to the loss of the myelin sheathing around neuronal axons (demyelination), loss of axons, and the eventual death of neurons, oligodenrocytes and glial cells. [0003] An estimated 2,500,000 people in the world suffer from MS. It is one of the most common diseases of the CNS in young adults. MS is a chronic, progressing, disabling disease, which generally strikes its victims some time after adolescence, with diagnosis generally made be-tween 20 and 40 years of age, although onset may occur earlier. The disease is not directly hereditary, although genetic susceptibility plays a part in its development. Relapsing-remitting MS presents in the form of recurrent attacks of focal or multifocal neurologic dysfunction. Attacks may occur, remit, and recur, seemingly randomly over many years. Remission is often incomplete and as one attack follows another, a stepwise downward progression ensues with increasing permanent neurological deficit. [0004] Although various immunotherapeutic drugs can provide relief in patients with MS, none is capable of reversing disease progres-sion, and some can cause serious adverse effects. Most current therapies for MS are aimed at the reduction of inflammation and suppression or modulation of the immune system. As of 2006, the available treatments for MS reduce inflammation and the number of new episodes but not all have an effect on disease progression. A number of clinical trials have shown that the suppression of inflammation in chronic MS rarely significantly limits the accumulation of disability through sustained disease progression, suggesting that neuronal damage and inflamma-tion are independent pathologies. Promoting CNS remyelination as a repair mechanism and otherwise preventing axonal loss and neuronal death are some of the important goals for the treatment of MS. For a comprehensive review of MS and its current therapies, see, e.g., McAlpine’s Multiple Sclerosis, by Alastair Compston et al., 4th edition, Churchill Livingstone Elsevier, 2006. [0005] “Phase 2 enzymes" serve as a protection mechanism in mammalian cells against oxygen/nitrogen species (ROS/RNS), electrophiles and xenobiotics. These enzymes are not normally expressed at their maximal levels and, their expression can be induced by a variety of natural and synthetic agents. Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor responsible for the induction of a variety of im-portant antioxidant and detoxification enzymes that coordinate a pro-tective cellular response to metabolic and toxic stress. [0006] ROS/RNS are most damaging in the brain and neuronal tissue, where they attack post-mitotic (i.e., non-dividing) cells such as glial cells, oligodendocytes, and neurons, which are particularly sensitive to free radicals. This process leads to neuronal damage. Oxidative stress has been implicated in the pathogenesis of a variety of neurodegenera-tive diseases, including ALS, Alzheimer’s disease (AD), and Parkinson’s disease (PD). For review, see, e.g., van Muiswinkel et al., Curr. Drug Targets CNS-Neurol. Disord., 2005, 4:267-281. An anti-oxidative en- 7 zyme under control of Nrf2, NQ01 (NAD(P)H dehydrogenase, quinone

(1), was recently reported to be substantially upregulated in the brain tissues of AD and PD subjects (Muiswinkel et al., Neurobiol. Aging, 2004, 25:1253). Similarly, increased expression of NQ01 was reported in the ALS subjects’ spinal cord (Muiswinkel et al., Curr. Drug Targets--CNS. Neurol. Disord., 2005, 4:267-281) and in active and chronic lesions in the brains of patients suffering from MS (van Horssen et al., Free Radical Biol. & Med., 2006, 41 311-311). These observations indicate that the Nrf2 pathway may be activated in neurodegenerative and neuroin-flammatory diseases as an endogenous protective mechanism, indeed, most recently, it has been reported that induced activation of Nrf2-dependent genes by certain cyclopenanone-based compounds (NEPP) counters the toxic effects of metabolic inhibition and ROS/RNS produc-tion in the brain and protects neurons from death in vitro and in vivo (see Satoh et al., PNAS, 2006, 103
(3):768-773). [0007] Additionally, many publications have reported neuroprotective effects of compounds in natural plant-derived compounds (“phytochemicals”), including a-tocopherol (vitamin E), lycopene (tomatoes), resveratrol (red grapes), sulforaphane (broccoli), EGCG (green tea), etc. For review, see Mattson and Cheng, Trends in Neurosci., 2006, 29
(11):632-639. Originally, the action of these compounds was attrib-uted to their anti-oxidant properties. However, while most anti-oxidants are effective only at high concentrations, at least some of these compounds appear to exert neuroprotective effects at much lower dos-es. Emerging evidence suggests that these compounds may exert their neuroprotective effects by activating cellular stress-response pathways, including the Nrf2 pathway, resulting in the upregulation of neuropro-tective genes. However, the exact mechanism of action of these com-pounds remains poorly understood. … [0009] Provided are methods that comprise at least one of the following methods: 1) methods of screening for at least one new candidate compound for treating a neurological disease; 2) methods of evaluating neuroprotective properties of at least one drug candidate for treating a neurological disease; 3) methods of comparing (e.g., for bioequivalence) at least two pharmaceutical compositions which comprise fumaric acid derivatives; 4) methods of treating a neurological disease by administering to the subject in need thereof at least one compound that is partially struc-turally similar to DMF or MMF; and 5) methods of treating a neurological disease by a combination therapy that comprises administration of at least one first compound that up-regulates the Nrf2 pathway and at least one second compound that does not upregulate the Nrf2 pathway. [0010] In some embodiments, the neurological disease is a neurodegenerative disease such as, for example, ALS, Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. In some embodiments the neurological disease is MS or another demyelinating neurological disease. … 8 [0019] In some embodiments method 4 comprises administering to the mammal a therapeutically effective amount of at least one neuroprotective compound having Formula I, II, III, or IV, e.g., a fumaric acid derivative (e.g., DMF or MMF). … BRIEF DESCRIPTION OF THE FIGURES [0026] Figure 1 demonstrates that DMF and MMF are activators of Nrf2 at concentrations within clinical exposure range (cells in culture). [0027] Figure 2 shows results of RNAi experiments. [0028] Figure 3 shows evidence of Nrf2 activation by DMF and MMF In vivo. [0029] Figure 4 shows evidence of Nrf2 activation by DMF and MMF In vivo. [0030] Fumaric acid esters, such as DMF, have been proposed for treatment of MS (see, e.g., Schimrigk et al., Eur. J. Neurol., 2006, 13
(6):604-10; Drugs R&D, 2005, 6
(4):229-30). [0031] Provided are, among other things, means for identifying compounds with a new therapeutic modality useful in at least one of multiple neurological indications and, optionally, complementary to other drugs for the treatment of a neurological disease, including a number of currently used immunomodulators. [0032] DMF is a member of a large group of anti-oxidant molecules known for their cytoprotective and anti-inflammatory properties. These molecules also share the property of the Nrf2 pathway activation. Thus, the finding that DMF activates the Nrf2 pathway in conjunction with the neuroprotective effects of DMF further offers a rationale for identifi-cation of structurally and/or mechanistically related molecules that would be expected to be therapeutically effective for the treatment of neurological disorders, such as, e.g., MS. … [0039] The terms “therapeutically effective dose” and “therapeutically effective amount” refer to that amount of a compound which re-sults in at least one of prevention or delay of onset or amelioration of symptoms of a neurological disorder in a subject or an attainment of a desired biological outcome, such as reduced neurodegeneration (e.g., demyelination, axonal loss, and neuronal death) or reduced inflamma-tion of the cells of the CNS. … Method 2 … [0050] In other embodiments, particularly those in which the neurological disease is multiple sclerosis or another demyelinating disease, the evaluated at least one drug or drug candidate for a neurological disease is chosen from the following: … [0104] A neurological disease in methods 1-5 above can be a neurodegenerative disease such as, for example, ALS, Parkinson’s disease, 9 Alzheimer’s disease, and Huntington’s disease. The neurological dis-ease can also be multiple sclerosis (MS), or other demyelinating dis-eases of the central or peripheral nervous system. In some embodiments the form of MS in methods 1-5 is selected from: relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and malignant MS (Marburg Variant). … [0106] Neurodegenerative diseases are described in, for example, Neurodegenerative Diseases: Neurobiology, Pathogenesis and Therapeutics, M. Flint Beal, Anthony E. Lang, Albert C. Ludolph, Cambridge University Press (July 11,2005). Examples of neurological diseases suitable for the methods described herein include neurodegenerative dis-eases such as amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, and Huntington’s disease. Other examples include demyelinating neurological disease including, in addition to MS, the following diseases: acute haemorrhagic leucoencephalomyelitis, Hurst’s disease, acute disseminated encephalomyelitis, optic neuritis, Devic’s disease, spinal cord lesions, acute necrotizing myelitis, transverse myelitis, chronic progressive myelopathy, progressive multifocal leukoencephalopathy (PML), radiation myelopathy, HTLV-1 associated myelopathy, monophasic isolated demyelination, central pontine myelinolysis, and leucodystrophy (e.g., adrenoleucodystrophy, metachromatic leucodystrophy, Krabbe’s disease, Canavan’s disease, Alexander’s disease, Pelizaeus-Merbacher disease, vanishing white matter disease, oculodentodigital syndrome, Zellweger’s syndrome), chronic inflammatory demyelinating polyneuropathy (CIDP), acute in-flammatory demyelinating polyneuropathy (AIDP), Leber’s optic atro-phy, and Charcot-Marie-Tooth disease. [0107] Additional examples of diseases suitable for the methods described herein include polyneuritis and mitochondrial disorders with demyelination. These disorders may be co-presented with, and possibly aggravated by diabetes, e.g., insulin-dependent diabetes mellitus (ID-DM; type I diabetes), or other diseases. [0108] A test compound may be further assayed in an animal model of MS, known as Experimental Autoimmune Encephalomyelitis (EAE) (Tuohy et al., J. Immunol., 1988, 141:1126-1130, Sobel et al. J. Immunol., 1984, 132:2393-2401, and Traugott, Cell Immunol., 1989 119:114-129). Chronic relapsing EAE provides a well established experimental model for testing agents that would be useful for the treatment of MS. The mouse EAE is an induced autoimmune demyelinating disease with any similarities to human MS in its clinical manifestations. In both EAE and MS, clinical disease is associated with blood-brain barrier (BBB) dys-function, infiltration of central nervous system by mononuclear cells (mainly macrophages and T lymphocytes, and serum products), and demyelination (Baker et al. J. Neuroimmunol., 1990, 28:261; Butter et al., J. Neurol. Sci., 1991, 104:9; Harris et al., Ann. Neurol., 1991,29:548; Ker-monde et al., Brain, 1990, 113:1477). [0109] Clinical signs of MS and demyelinating pathology in EAE result from immunization with CNS myelin proteins or peptides (e.g., MBP, PLP, and MOG) under Th1 conditions (direct immunization model), or by adoptive transfer of CNS antigen-specific Th1 cells (adop-tive transfer model) … EAE has been used to evaluate new therapeutic 10 approaches to T-cell-mediated autoimmune disease because of the clin-ical and histopathological similarities to the human demyelinating MS. … [0111] A compound may be optionally tested in at least one additional animal model (see, generally, Immunologic Defects in Laboratory Animals, eds. Gershwin et al., Plenum Press, 1981), for example, such as the following: the SWR X NZB (SNF1) mouse model (Uner et al., J. Autoimmune Disease, 1998, 11
(3):233-240), the KRN transgenic mouse (K/BxN) model (Ji et al., Immunol. Rev., 1999, 69:139); NZB X NZW (B/W) mice, a model for SLE (Riemekasten et al., Arthritis Rheum., 2001, 44
(10):2435-2445); the NOD mouse model of diabetes (Baxter et al., Autoimmunity, 1991, 9
(1):61-67), etc.); or mouse models of multiple sclerosis (see, e.g., Linker et al., Eur. J. Immunol., 2002, 8
(6):620-624, and Eugster et al., Nat. Med., 1999, 29:626-632; and Gold et al., Brain, 2006, 129:1953-1971). [0112] Preliminary doses, for example, as determined in animal tests, and the scaling of dosages for human administration is performed according to art-accepted practices. Toxicity and therapeutic efficacy can be determined by standard pharmaceutical procedures in cell cul-tures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the 50 ratio LD /ED 50 . In some embodiments compositions that exhibit large therapeutic indices are used. [0113] The therapeutically effective dose can be estimated initially from cell culture assays. A dose may be formulated in animal models to achieve a circulating plasma concentration range that includes the IC 50 (i.e., the concentration of the therapeutic compound which achieves a halfmaximal inhibition of symptoms) as determined in cell culture as-says or animal models. Levels in plasma may be measured, for exam-ple, by ELISA or HPLC. The effects of any particular dosage can be monitored by 50 a suitable bioassay. Examples of dosages are: about 0.1 x IC , about 0.5 x IC 50 , about 1 x IC 50 , about 5 x IC50 , 10 x IC 50 , about 50 x IC50, and about 100 x IC 50 . [0114] The data obtained from the in vitro assays or animal studies can be used in formulating a range of dosages for use in humans. Therapeutically effective dosages achieved in one animal model can be converted for use in another animal, including humans, using conversion factors known in the art (see, e.g., Freireich et al., Cancer Chemother. Reports, 1966, 50
(4):219-244 and Table 2 for Equivalent Surface Area Dosage Factors). Table 2 11 [0115] In some embodiments the dosage of such compounds lies within a range of circulating concentrations that include the ED 50 with little or no toxicity. In some embodiments the dosage varies within this range depending upon the dosage form employed and the route of administration utilized. Generally, a therapeutically effective amount may vary with the subject's age, condition, and sex, as well as the severity of the medical condition in the subject. Examples of pharmaceutically ac-ceptable dosages for compounds described herein are from 1 µg/kg to 25 mg/kg, depending on the compounds, severity of the symptoms and the progression of the disease. The appropriate therapeutically effective doses can be selected by a treating clinician and in some embodiments range approximately from 1 µg/kg to 20 mg/kg, from 1 µg/kg to 10 mg/kg, from 1 µg/kg to 1 mg/kg, from 10 µg/kg to 1 mg/kg, from 10 µg/kg to 100 µg/kg, from 100 µg to 1 mg/kg. Additionally, certain spe-cific dosages are indicated in the Examples. [0116] For DMF or MMF, an effective amount can range from 1 mg/kg to 50 mg/kg (e.g., from 2.5 mg/kg to 20 mg/kg or from 2.5 mg/kg to 15 mg/kg). Effective doses will also vary, as recognized by those skilled in the art, dependent on route of administration, excipient us-age, and the possibility of co-usage with other therapeutic treatments including use of other therapeutic agents. For example, an effective dose of DMF or MMR to be administered to a subject orally can be from about 0.1 g to 1 g per pay, 200 mg to about 800 mg per day (e.g., from about 240 mg to about 720 mg per day; or from about 480 mg to about 720 mg per day; or about 720 mg per day). For example, the 720 mg per day may be administered in separate administrations of 2, 3, 4, or 6 equal doses. [0117] The dosage may be determined by a physician and adjusted, as necessary, to suit observed effects of the treatment. The compositions may be given as a bolus dose, to maximize the circulating levels for the greatest length of time after the dose. Continuous infusion may also be used after the bolus dose. … 12 [0119] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Methods to accomplish the administration are known in the art. "Administration" is not limited to any particular delivery system and may include, without limitation, parenteral (including subcutaneous, intravenous, intramedullary, in-traarticular, intramuscular, or intraperitoneal injection), rectal, topical, transdermal, or oral (for example, in capsules (e.g., as, poweder, gran-ules, microtablet, micropellets, etc.), suspensions, or tablets). Examples of some of formulations containing DMF and/or MMF are given in, e.g., US Patents Nos. 6,509,376, and 6,436,992. … Example 1 EXAMPLES [0122] Human colon carcinoma DLD1 cells were treated with DMF or MMF at indicated concentrations (5,15, or 50 µM) for 16 hours, rinsed with PBS, and harvested into reducing SDS sample buffer. The lysates were subjected to SDS PAGE and the separated proteins were electrophoretically transferred onto nitrocellulose membranes for Western blot analysis. To detect Nrf2 and NQO1, the membranes were incubat-ed with the respective primary antibodies overnight at 4°C, washed, and incubated with peroxidase-conjugated secondary antibodies fol-lowed by the chemiluminescent peroxidase substrate. Detection of the target protein band luminescence and image acquisition were done us-ing CCD-equipped imaging station Kodak2000R. The results shown in Figure 1, demonstrate that DMF and MMF are potent activators of Nrf2 at concentrations within clinical exposure range. Example 2 [0123] DLD1 cells were grown in MEM supplemented with 10% fetal bovine serum. The cells were transfected with the indicated siRNA's using the Lipofectamine reagent (Invitrogen) according to the manufacturer's instructions and 30 hrs later stimulated with 30 µM DMF for 40 hours. The cells were harvested and processed for Western blotting analysis of Nrf2 and NQO1 levels as described in Example 1. Sources and the identity of reagents used in Examples 1 and 2 are specified Ta-ble 3 below: 13 [0124] The results are shown in Figure 2 (for ease of representation, the image of the Western blot is turned upside down). The results demonstrate that DMF-induced upregulation of NQO1 requires Nrf2 and can be mimicked by activation of Nrf2 through repression of Keap1. Therefore, DMF acts as an Nrf2 agonist causing cellular accumu-lation of Nrf2 and Nrf2 target gene expression. Example 3 [0125] For induction of EAE, mice received s.c. injections in the flanks and tail base of 50 µg MOG 35-55 peptide in PBS emulsified in an equal volume of complete Freund’s adjuvant (CFA) containing Mycobacterium tuberculosis H37RA (Difco, Detroit MI, USA) at a final concentration of 0.5 mg/ml. Two injections of pertussis toxin (List Biological Laboratories Inc., California, USA; 200 ng per mouse i.
  1. p)were given on days 0 and 2. [0126] DMF and MMF was diluted in 200 µl 0.08% Methocel/H 2 0 as vehicle and administered by oral gavage starting from day 3 post immunization (p.
  2. i)until termination. Each treatment group consisted of 8 animals: vehicle alone as a negative control, 5 mg/kg body weight DMF twice a day, 15 mg/kg body weight DMF twice a day, 15 mg/kg body weight MMF twice a day. The compounds were obtained via Fumapharm AG. Oral gavage was used to ensure exact dosing and to avoid compound degradation. 14 [0127] Spinal cord tissues were fixed in 4% paraformaldehyde and embedded in paraffin. Slides were deparaffinized and rehydrated in graded alcohol solutions. Antigen retreival was performed by immers-ing the slides in 10 mM Citrate, pH 6.0 for 20 minutes in a pressure cooker at 120 C (Pascal, Dako Cytomation). [0128] Immunohistochemistry was performed using the Dako autostainer as follows. Endogenous peroxidase was quenched by a 10 minute 2 incubation in 3% H O 2 / Methanol. The rabbit anti Nrf2 antibody C-20 (sc-722, Santa Cruz Biotechnology) was added at a 1:250 dilution in Dako Diluent with Background Reducing Components (Dako # S3022) C20 antibody was detected using the Envision anti rabbit la-beled polymerHRP (Dako #K4003) and DAB (Vector Labs #SK-4100) was used as the chromogenic substrate. Morphometric analysis of Nrf2 immunostaining was performed using Imaged software from NIH (http://rsb.info.ih.qov/ii/). [0129] The resuluts, shown in Figures 3 and 4, demonstrate MMF and DMF activation of Nrf2 in vivo. [0130] All publications and patent documents cited herein are incorporated by reference in their entirety. To the extent the material incorporated by reference contradicts or is inconsistent with the present specification, the present specification will supersede any such materi-al.” Kendt teknik Parterne er enige om, at nærmeste kendte teknik udgøres af præsentationen af L. Kappos m.fl., ”Efficacy of novel oral single-agent Fumarate, BG00012, in pa-tients with relapsing-remitting multiple sclerosis: results of a phase II study” , (”Kappos D11-A3”), idet Viatris har gjort gældende, at den opdaterede udgave af præsentationen, som blev præsenteret på ECTRIMS-konferencen i 2006 (her-efter ”ECTRIMS-præsentationen”), tillige er en del af nærmeste kendte teknik. ECTRIMS-præsentationen indeholder følgende 23 slides: 15 ” Slide 1 Slide 2 16 Slide 3 Slide 4 17 Slide 5 Slide 6 18 Slide 7 Slide 8 19 Slide 9 Slide 10 20 Slide 11 Slide 12 21 Slide 13 Slide 14 22 Slide 15 Slide 16 23 Slide 17 Slide 18 24 Slide 19 Slide 20 25 Slide 21 Slide 22 26 Slide 23” Almindelig fagmandsviden på prioritetsdagen Parterne er enige om, at fagmanden er et team bestående af en klinisk farmako-log og en specialist i multipel sklerose. Viatris har yderligere henvist til det an-førte i dr. Christian Wolfs erklæring af 21. september 2022, og Sandoz har tillige gjort gældende, at fagmanden vil konsultere en statistiker. Parterne er endvidere enige om, at det på prioritetsdagen var almindelig fagmandsviden, at der generelt er udfordringer med patienternes efterlevelse (compliance) af lægens anvisninger med hensyn til indtag af lægemidlet, når patienterne skal indtage lægemidlet tre gange dagligt, og at patienternes efterlevelse i væsentlig grad forbedres, når dosisfrekvensen nedsættes fra tre til to gange dagligt. Der er også enighed om, at det med hensyn til begrebet ”statistisk signifikans” forholder sig som anført i artiklen af DG Altman m.fl., ”Absence of evidence is not evidence of absence” , Aust Vet J Vol. 74, No. 4, oktober 1994, side 311, hvorefter: ”[b]y convention a P value greater than 5% (P > 0.05) is called ”not significant” .” 27 Oplysninger efter prioritetsdagen En artikel af L. Kappos m.fl., ”Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study” , offentliggjort i Lancet
(2008)372, dvs. efter prioritetsdagen, indeholder følgende tabel 3 om det af Kappos gen-nemførte fase IIforsøg med BG00012 (DMF): “ “ Sagsbehandlingen ved Den Europæiske Patentmyndighed (EPO) i forbindelse med ud-stedelse af stridspatentet EPO’s Examining Division meddelte den
  1. juni 2022 at have til hensigt at ud-stede stridspatentet. Som svar på indsigelser af
  2. maj og
  3. juni 2022 anførte Examining Division i en meddelelse af
  4. juni 2022: “Relevance of third-party observation dated 27.05.2022 and 08.06.2022 The decision T1773/16 concerning the parent file relates to a different set of claims, more particularly they differ in that they are limited by the expression "consisting of". 28 The present set of claims is drafted with the term comprising and therefore, not limited to one sole active ingredient discussed by T1773/16 as orig-inating a selection. Therefore, the conclusions reached by the respective BoA do not apply to the present case. The examining division considers that claim 1 is not the result of a selection from two lists and complies with the require-ments of Art. 123
(2)ERG. The arguments provided in the TIPAs in relation to Art. 56 EPC relate to the parent application. The present divisional application is a new application, independent from the parent. The arguments provided by the OD in relation to the parent have been considered and found that are not applicable to the present divisional.” Complaints Management ved EPO besvarede den
  1. juni 2022 en tredjemandsklage af
  2. juni 2022 som følger: “… You refer to the pending case G2/21 and think that in view of the min-utes for the EP13156663.0, the examining division was not able to cor-rectly base its decision without having the G2/21 decision at hand. You indicate that in the parent case (EP2137537/ EP08725256.5), the opposi-tion division revoked the patent based on lack of inventive step, which was later confirmed by an appeal board. Finally, you consider that sev-eral thirdparty observations were not taken into account and believe that the application should be rejected in view of T 1773/
  3. You request therefore that the position taken by the examining division be reconsidered and that the proceedings be stayed or reopened and that these applications should be refused. We thank you for your message and have investigated the matter with the support of the relevant director and manager. For the EP13156663.0, summons dated 15.06.2022 have been sent and make also reference to T1773/
  4. We trust it therefore that the third-party observations have been duly considered and taken into account, even if maybe not according to your wishes. Please take note that it does not per se indicate a likely outcome of the Oral Proceedings. When a decision is taken for this application, and depending on its tenor, you can consider e.g., appealing against it. For the EP13169139.6, a communication under Rule 71
(3)was sent on the 02.06.
  1. Observations by third parties were filed on the 08.06.2022 and have been also duly considered by the examining divi-sion. Also in that case, when the decision is made, you can consider lodging an appeal if you find it appropriate. We can thus confirm that we did not detect any procedural flaws in the treatment of these two applications, and that the examining divisions do not seem to consider at that stage to reopen the procedure for the 29 EP13169139.
  2. About the more general question of stay of proceedings, a stay of the proceedings is a preliminary procedural measure sui generis which is justified as a preventive measure to preserve the third party's possible rights to the patent in dispute and which takes immediate effect (J 28/94, J 15/06). In particular, the stay of the grant proceedings is ordered by a communication of the EPO without having heard the applicant. However, the applicant may, in view of the said communication, re-quest the issuance of an appealable decision. …” Endvidere besvarede Complaints Management den
  3. juli 2022 en yderligere tredjemandsklage af
  4. juli 2022 som følger: “… You essentially complain about the Examining Division announcing on 12.05.2022 (minutes of Oral proceedings) its intention to grant the abovementioned divisional application (see also R 71
(3)communication dated 03.06.2022). You consider that the Examining Division should have waited for the Board's decision T 1773/16 (issued on 03.06.2022) concerning the parent application EP08725256.5 since the claims of the divisional and parent application are "similar". You mention also that the parent application was revoked for lack of inventive step, and that Third-party observa-tions mentioned that the divisional application's examination should have been suspended in view of G2/21. Finally, you submit that examination of the divisional should be re-opened and the application refused. We thank you for your message. We may not comment on the sub-stance of the case which is of the sole competence of the Examining Di-vision (or possibly at a later stage of an Opposition Division or Board of Appeal) but have investigated the matter with the support of the re-sponsible Director, Manager and Examiners. In this application, the claims are based on the text of the parent application as originally filed. It is therefore possible that their subject-matter and that of the parent application have some similarities. It does not mean however that they are identical, and you do not seem yourself to consider that it is the case. It is therefore entirely possible that claims of the divisional application are allowable while the parent application procedure was concluded by a revocation. In any case, claims of a divi-sional application must be examined on their merit and independently of the claims of the parent application (except for the provisions related to double patenting). We can also confirm that all Third-party observations were duly considered by the Examining Division, which also considered that a deci-sion on inventive step could be taken for the divisional application independently of the outcome of G2/21. 30 We therefore respectfully disagree with your statements that the divi-sional application should not have been granted in view of the revoca-tion of the parent patent, or with your opinion that the proceedings should have been suspended. From a procedural point of view, the decision to grant was announced. A possibility to reopen the examination of the application and/or to refuse it is now linked to possible outcomes of opposition and possibly appeals procedures. …” EP 819 Biogen indleverede den 19. juli 2022 patentansøgning EP 4 137 819 A1 (”EP 819”), der er afdelt af stridspatentet, hvori krav 1 lyder: “A pharmaceutical composition for use in treating multiple sclerosis, the composition comprising: (
  1. a)dimethyl fumarate or monomethyl fumarate as the sole active agent, and (
  2. b)a pharmaceutically acceptable excipient wherein the composition is to be administered orally to a subject in need of treatment for multiple sclerosis, and wherein the dose of dimethyl fumarate or monomethyl fumarate to be administered is 480 mg per day; and wherein the pharmaceutically acceptable excipient can be solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and adsorption delaying agents that are compatible with pharmaceutical administra-tion.” Examining Division har i en udvidet søgerapport af 23. januar 2023 vedrørende EP 819-ansøgningen anført blandt andet: “3 Inventive step (Art. 56 EPC) 3.1 D4 is considered as the closest prior art document. This document discloses BG00012, a dimethylfumarate preparation for oral administration to patients with relapsing-remitting multiple sclerosis (RRMS). BG00012 capsules were administered during a 24week period to four groups of patients. The different groups received 120mg once daily, 120mg three times daily with a final dosage of 360mg/day, three times daily 240mg with a final dosage of 720mg/day, or a placebo (see abstract). Compared with the placebo the group receiving 720mg/ day showed a 69% reduction of the Gd+ lesions seen in the different scans. 3.2 Technical effect and problem to be solved The presently claimed subject-matter differs from D4 on the dosage of MMF or DMF selected to treat MS, in particular the claims con-cern a dosage of 480mg/ day. 31 The two lines of argumentation can be used for defining the prob-lem to be solved: 1) the present application represents an non-obvious alternative and no need is to be made from the post-published data and 2) the present application is based on the post-published observa-tion that the selected dosage regime of 480mg/day is similarly efficacious to the much higher dose of 720mg/day disclosed in D4, and which provides for a surprising effect. 3.3 The application as originally filed, in particular [0116] indicates the effective dosages of DMF/MMF to be used. All dosages are presented as effective. The examples provided in the application show that DMF or MMF is effective in activation of the Nrf2 pathway in vivo and in vitro. The particular dosage of 480mg/day is not tested but data from the applicant available to the skilled person before the priority date shows that 120mg/day, 360mg/day and 720mg/day are effective dosages (D4), and well tolerated and safe (D3). The term effective used used in paragraph 116 is considered to concern clini-cal effectiveness this paragraph relates to therapeutic treatment and administration (page 30 lines 1-2 and 6). Therefore, based on the teaching of [0116] the skilled reader could assume that several dosages of DMF or MMF are therapeutically effective, even in absence of experimental data. Nonetheless, for the parent case the applicant provided the missing experimental data. The post-published data provide 1) proof for effectiveness of the 480mg/day dose and 2) demonstrate that 480mg/day could work better in terms of effectiveness than any of the lower concentrations like 360mg/day and that this dose is as equally effective as the upper range concentration, 720mg/day. When considering this data the ED is of the opinion that part 1) relates to an effect that was disclosed at the date of filling, i.e., that 480mg/day is effective in treatment. According to G2/21 referral the proceedings are to be stayed only if their outcome is fully depen-dent on the answers provided by the EBoA. Contrarily at least part 1) of the data submitted by the applicant concern an effect present in the application at the date of filling and therefore, independent from the answers provided by the EBoA. The OD in the parent case disregarded the post-published data as it relates to a technical effect not announced in the originally filed application and this data was considered as the first disclosure going beyond speculation. In this regard the ED considers that the case law evolved since the decision on the parent was taken by the OD and therefore, considers that the application as filed makes it plau-sible that the dosage of 480mg/day is effective in the treatment of MS. 32 Having in regard the discussion above the objective technical problem to be solved in view of D4 is formulated as the provision of an alternative effective dosage of DMF or MMF for treating MS. 3.4 Solution The applicant solves the problem by providing a dosage regime of 480mg/day. 3.5 Why the solution is not obvious The application as filed relates to compounds for the treatment of neurological diseases, such as MS (see [001]). Such compounds, like MMF or DMF are shown to activate Nrf2 in vivo (figures 3 and 4). Activation of the Nrf2 pathway was know to function as an endogenous protective mechanism in neurodegenerative and neuroinflammatory diseases ([006] last sentence). The passages on the application concerning dosages start at [0112] referring to the determination of preliminary dosages in animal tests and scaling for human administration. Paragraph [0113] refer to the initial estima-tion of therapeutically effective doses and [0114] describes how to translate in vitro results into formulation of dosages to be used in humans. Finally [0116] describes what could be considered as effec tive doses of DMF or MMF for administration. On page 30 it is reported the broader range of 200mg to 800mg a day followed by the range of about 480mg to 720mg a day. D3 and D4 try several of the dosages within the range of 120 to 720 mg/day described in the application. D3 concludes that any of the dosages of 120mg/ day, 360mg/day or 720mg/day was well tolerat-ed. A skilled person faced with these results could only assume that 480mg/day, a dosage between 360mg/day and 720mg/day would be equally well tolerated and safe. In D4 it is concluded that the 720mg/day offers a 69% reduction of Gd+ lesions but no information is given about the other concentrations. TP01, the press release related to D4, states that the results of 120mg/day and 360mg/day are not statistically significant but 720mg/day gives a clear improvement. Looking at TP02, which is the presentation for the abstract D4, it is seen that the dosages of 120mg/day, 60mg/day (on page 6 second slide) are effective in Gd+ lesions reduction for weeks 12 to 24 but provide for different results in relation to T1 and T2 lesions (pages 7 and 8). Apart from the dosages described none of these documents discloses implicitly or explicitly another dosage as possibly effective. Therefore, a skilled person would not be prompted to merely try another dosage among all possible concentrations available, in particular because the prior art does not offer any incentive to do so. It is considered that selecting 480mg/day would involve more than standard routine experimentation, it would require the skilled per-son to know that 480mg/day is effective, and this information was only given at the date of filling on paragraph 116. In addition it is 33 considered that even if the skilled person would have a general knowledge about how to do dosage optimization, it would not al-low a skilled person to identify the particularly selected dose of 480mg/day. For the reasons discussed it is considered that the skilled person would not be able to merely select the particular dose of 480mg/day from D4 alone or in combination with the mentioned documents and expect it to be capable of treating MS, in absence of an indica-tion from the prior art to do so, and in particular when this effec-tiveness is dependent from clinical outcomes.” EPO’s Oppositions Divisions foreløbige vurdering af 6. november 2023 af stridspaten-tet En række tredjeparter har efter udstedelsen af stridspatentet rejst indsigelser mod gyldigheden af patentet ved Opposition Division med henvisning til manglende basis, manglende nyhed, manglende opfindelseshøjde og utilstræk-kelig beskrivelse. Ved meddelelse af 6. november 2023 har Opposition Division indkaldt til mundtlig høring den 21. maj 2024 og er samtidig fremkommet med en foreløbig vurdering af de rejste indsigelser. Af den foreløbige vurdering fremgår: “… 1. Main request (patent as granted) Article 100(
  3. c)EPC (Art.123
(2)and 76
(1)EPC) Preliminary remark The CP is based on European patent application 13169139.6 (published as EP 2 653 873, the "application") which is a divisional application of the European patent application 08725256.5 (parent application), pub-lished as WO 2008/097596. Since the description of the application as filed correspond to the description of the parent application as filed, with the subject-matter of the original claims of the parent application being added thereto (see [0127], pages 16 to 17 of the application as filed), the application as filed contains the complete disclosure of the parent application as filed. Therefore, if the provisions of Article 123
(2)EPC are met, then the provisions of Article 76
(1)EPC will likewise be satisfied. It follows that for the assessment of the requirements of Articles 123
(2)and 76
(1)EPC, reference will be made to the parent application WO 2008/097596 only. 1.1 The OD does not see any ambiguity concerning the meaning of MMF or DMF in the context of fumaric acid derivatives. The terms "dimethylfumarate" and "monomethyl fumarate"are explicitly disclosed in claim 9 of the application as filed. This is consistent with the abbreviation used in the rest of the application, i.a. in paragraph [0053], 34 [0062], [0063]. In any case, the OD considers that questioning the meaning of terms in the CP is a clarity objection which is not a ground of opposition. 1.2 All opponents raised added subject-matter objections relating to the claims as granted. All argued that the claimed subject-matter arises from multiple selections from several lists from the original application. 1.2.1 The OD is of the preliminary opinion that the subject-matter of granted claims 1 and 5 does not introduce new technical information and is clearly and unambiguously derivable from the content of the ap-plication as filed. More particularly, the OD does not see any selection in defining the use of MMF/DMF for the treatment of multiple sclerosis (MS) in the independent claims 1 and
  1. Preference for the treatment of MS is indicated in [0001] of the application as originally filed. The application as a whole is directed to the treatment of MS as specific preferred embodiment by derivatives activating the Nrf2 pathway. This is reflected by [0001] and [0032]. This is further supported by the disclosures of example 3 together with [0108][0109]. Following this, the OD cannot agree that it is necessary to make a selection from the therapies disclosed as "method 4" out of the five methods identified in the application as filed. The OD considers that there is no ambiguity about the intention of the original application, which is the treatment of multiple sclerosis. This purpose is explicit from the first paragraph to the most advanced example, from [0001] and example 3 (read with the explanation of [108]-[109]). Therefore there is no selection of MS from the list of possible therapies. Many compounds are able to activate the Nrf2 pathway for instance the fumaric acid derivatives of formulae I-IV, DMF and MMF. It was ar-gued that DMF and MMF were not individualized as preferred active agents since they were only presented as "examples" using the term "e.g." or used in some cases as comparators, inter alia in in vitro assays, as basis for the development of further active analogues. It is not con-tested that the explicit term "preferred" in connection with DMF and MMF is missing. However, the OD notes that many compounds are presented in the originally filed application as theoretical Nrf2 activa-tors, whereas only DMF and MMF are reported in the application as compounds with a proven activity as Nrf2 activators. This is supported by the teachings of all the examples, which show the activity of these two specific agents as Nrf2 activators in vitro (in the assays of examples 1 -2) and in vivo (in the MS model of example 3, see also [108]-[109]). For this reason, the OD considers that MMF and DMF are the two preferred Nrf2 activators exemplified in the whole applica-tion. Therefore the feature "DMF/MMF" is not seen as being selected from a list. Hence, there is no selection required in order to define MMF or DMF as preferred Nrf2 activators for treating MS. 35 Furthermore, example 3 demonstrates MMF and DMF activation of Nrf2 in vivo in an animal model of MS (EAE). Paragraph [0108] clearly states that EAE provides a well established experimental model for test-ing agent that would be useful for the treatment of MS. It follows that the OD’s preliminary view is that MS is the main focus as the disease to be treated and it is clearly linked to DMF and MMF based on the explanations and experimental findings provided in the applica-tion that DMF and MMF activate Nrf2 which in turn increases neuro-protection and is therefore beneficial in the treatment of MS. Although several statements (for instance [0024] or [0081]) explicitly exclude the use of MMF and DMF, the OD considers that these statement cannot alter the teaching of the application which is linked to Nrf2 activation as a new mechanism of action. In that context, MMF and DMF are the only proven compounds with this activity disclosed in the ap-plication as filed. The dose of 480 mg per day is disclosed in paragraph (01 1 6) of the application as filed in a sentence relating to oral dosages for DMF and MMF. Note that paragraph [0116] mentions only oral administration in connection with DMF or MMF and the effective daily dosage (thus, oral therapy is individualized in that paragraph). Several ranges are listed, from the broadest range of 0.1 g to 1 g per day, to two more restricted ranges, to a range of 480 mg to 720 mg per day, followed by a dose of 720 mg per day and a sentence describing how the dose of 720 mg could be administered in sub-doses for separate administration over the day. None of the ranges or values is qualified as being preferable over any of the others (see T1 773/1 6 point 4.2). The OD considers that only one preferred oral daily dose, namely 720 mg/day, can be derived from this passage. This feature is individual-ized twice on lines 5-6 and highlighted by being repeated tour times. By contrast, the 480 mg/day is mentioned only once. This is a value select-ed from eight alternatives taken from four possible ranges of effective doses "0.1 g to 1 g", "200 mg to 800 mg", "240 mg to 720 mg", "480 mg to 720 mg". The fact that it is the "lowest value of the narrowest range" is not a sufficient indicator that the specific dose of 480 mg/day is a pre-ferred oral effective dose to be administered for the treatment of MS. However, this is the only feature which needs to be selected from a list to arrive at the claimed subject-matter. Further, the OD preliminary view is that paragraph [0118] provides sufficient basis for the definition of "one or more excipients" in claim
  2. More particularly, the second sentence of paragraph [0118] provides a definition of "pharmaceutically acceptable excipient" that makes it clear that not only a "single" pharmaceutically acceptable excipient would be intended. The OD also considers that in the context of pharmaceutical compositions (see also [0119]), the term "comprising" used in that pas-sage does not limit the disclosure to "compositions with a single excipi-ent" but encompasses "compositions with at least one excipient". Due to the term "comprising" in paragraph [0118], there is no difference be- 36 tween the term "a" and "one or more"; the term "a" would be read as "at least'' and not "a single". Furthermore, the skilled person, in view of his/her common general knowledge of pharmaceutical compositions and specifically in view of para. [0119] readily understands that it is common practice to use either one pharmaceutically acceptable excipient or more than one pharmaceutically acceptable excipient, as needed, in order to accomplish the intended administration: Conclusively, there is also direct and unambiguous disclosure with re-spect to a pharmaceutical composition comprising, in addition to DMF or MMF, one or more pharmaceutically acceptably excipients. Therefore in its preliminary view, the OD considers that the subject-matter claimed does not involve any selection in the definition of MMF or DMF as active agent for use in the treatment of MS. These features reflect the preferred aspects of the application which can be derived from both the description and the examples. The only feature which was selected is one specific oral daily dose from among eight possible alternatives in the only paragraph of the application related to oral dai-ly dases of MMF or DMF. For this reason, the OD is satisfied that the application is not taken as a "reservoir" (case law book, 10th ed. 2022, 1.6.1), but that the subjectmatter of granted claims 1 and 5 reflect the preferred aspect of the application combined with one selection for the specific oral daily dose of active agent. As a consequence, granted claims 1 and 5 meet the requirements of Art. 123
(2)/76
(1)EPC. 1.2.2 A similar basis as for claims 1 and 5 is found in the application as filed for the subject-matter of claims 2 and 3. Granted claims 2 and 3 meet the requirements of Art. 123
(2)/76
(1)EPC. 1.2.3 With regard to the additional claim 4, sufficient basis can be found in [011 9] where its penultimate sentence recites the features of the claims, namely "capsules, suspensions or tablets" as oral formulation. No further selection is made by inserting this feature which just speci-fies the nature of the oral formulation. Granted claim 4 meets the re-quirements of Art. 123
(2)/76
(1)EPC. 1.2.4 As for granted claims 6-9, the application as filed describes five methods (paragraph [0009]). Two of these methods are methods of treating a neurological disease. While method 4 describes that "at least one compound" is administered, method 5 relates to the administration of at least two active agents. Method 4 is further discussed in para-graphs [0019] and [0063]. Here, the administration of "a therapeutically effective amount of at least one neuroprotective compound" is dis-closed, followed by the possibility that this compound or these com-pounds is/include dimethyl fumarate or monomethyl fumarate ("(e.g., DMF or MMF)"). There is no doubt that the term "at least one neuropro- 37 tective compound" includes, but is not limited to, the possibility that precisely one such compound is administered. Therefore, to arrive at the subject-matter of only one neuroprotective compound a selection from the list of a least one neuroprotective compound is necessary. As mentioned in point 1.2.1 above, the oral dose of 480 mg is not disclosed as being the preferred dose; rather, it is merely, like the mononeuroprotective treatment, the result of a selection. Consequently and in line with T1773/16, the OD preliminary view is that, neither the use of dimethyl fumarate (or monomethyl fumarate) as the only neuroprotective compound nor a method of treatment admin-istering orally 480 mg per day of dimethyl fumarate (or monomethyl fumarate) is clearly preferred in the application as filed. The combina-tion of these two features is thus not the combination of two preferred embodiments. Moreover, these two features are not explicitly disclosed in combination in the application as filed. Consequently, the combina-tion of these two features constitutes a double selection of features and is therefore not directly and unambiguously derivable for the person skilled in the art from the application as filed. As a consequence, the OD's preliminary view is that the subject-matter of granted claims 6-9 does not meet the requirements of Art.123
(2)/76
(1)EPC. 1.3 Auxiliary Requests 1,3,4,5,8,10,11,13,14,15,18 do not satisfy the requirements of Art.123
(2)and 76
(1)EPC for the same reasons.
  1. Auxiliary request 2 (AR2) AR2 differs from the main request in that granted claims 6-8 have been deleted and in that the new claim 6 refers back to claim
  2. These amendments are occasioned by a ground of opposition under Ar-ticle 100(c) EPC and therefore comply with Rule 80 EPC. 2.1 Articles 123
(2)/76
(1)EPC The OD's preliminary view is that the subject-matter of claims 1 -6 of AR2 meets the requirements of Art.123
(2)/76
(1)EPC for the reasons mentioned in point 1.2.1 to 1.2.3 above with respect to the patent as granted. 2.2 Article 83 EPC The opponents question sufficiency of disclosure of the CP. According to the Opponents, the CP does not contain any evidence that the dosage of 480mg/day is suitable for the intended therapeutic use. Furthermore, O14 argued that the claims are not sufficiently disclosed for all sub-forms of MS, e.g., PPMS. O14 argued that in D127 480 mg/day DMF did not treat PPMS. 38 2.2.1 Article 83 EPC requires that an European patent application shall disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art. In relation to claims to a second medical use, this means that for acknowledging that the requirements of Article 83 EPC are fulfilled, it is not only necessary that the skilled person is enabled to make and obtain the composition to be used on the basis of the disclosure in the application and/or his common general knowledge, but also, that there is, e.g. evidence in the application that the therapeutic effect is achieved or can be plausibly achieved. Post-published evidence may be taken into account, but only to back-up the findings in the application in relation to the use of the compound. 2.2.2 The OD notes that the examples provided in the application as filed do not relate to the treatment of multiple sclerosis as such or to formulations that are to be orally administered in such a treatment. Examples 1 and 2 are carried out using cell cultures and report on the finding that DMF and MMF are Nrf2 agonists. Example 3, in an animal model of multiple sclerosis, administers DMF or MMF by oral gavage and determines Nfr2 activation. The examples merely show a proof of concept relating to the background discussed in paragraphs [0002] to [0008] of the application as filed (see point 4.1.2 of T1773/16). Furthermore, the application as originally filed explicitly defines that the term "multiple sclerosis" covers distinct forms of MS including re-lapsing remitting MS (RRMS), secondary progressive MS (SPMS), pri-mary progressive MS (PPMS), and malignant MS (paragraph [0104]). This understanding of the term "multiple sclerosis" is also in line with the knowledge of a person skilled in the art at the priority date of the CP, e.g. D115 which explains that the term "multiple sclerosis" (MS) covers several distinct forms such as RRMS, SPMS and PPMS which have a particular incidence. While patients suffering from RRMS are approximately 80 to 85% of all MS patients, PPMS is present in approx-imately 15% of the MS patients. It follows that the term "multiple sclerosis" claimed in claim 1 of the CP, in view of the definition in paragraph [0104] of the application as filed and the common general knowledge, covers all the distinct forms of MS, including the sub-form PPMS. The document D127 describes the results of an investigation on a treatment efficacy of 480 mg/day DMF in PPMS and concludes that DMF treatment showed no effects on either clinical or MRI outcomes or changes in serum concentration of neurofilament light chain (NFL). The teaching of D127 casts thus serious doubt about the therapeutic efficacy of DMF on PPMS when used in an amount of 480 mg per day. 2.2.3 P argued that D127 has many !imitations and cannot serve as proof that 480 mg/ day DMF is incapable of treating PPMS (small patient population, no placebo-controlled group, too short period of time to discern any effect on the progression of PPMS). According to P, in view 39 of its mechanism of action described in the examples of the application as filed, i.e. neuroprotection mediated by the Nrf2 pathway, it is reasonable to assume that DMF (and MMF) may well provide treatment benefit in patients with PPMS. P further argued that DMF has been used in Europe for treating PPMS patients and referred to D135. 2.2.4 The OD, in its preliminary view cannot concur with these arguments. In particular, the OD fails to see how a clinical trial performed on human patients with an amount of 480 mg/day would be less rele-vant than in vitro data or an animal model which does even not use the claimed dose. D127 clearly and unambiguously describes the lack of ef-ficacy of DMF in the treatment of PPMS in the population tested. In this respect, P did not provide any evidence that could render plausible that DMF or MMF may have any therapeutic effect in treating PPMS at the claimed dosage. D135 merely mentions that a few PPMS patients have been treated or are being treated with DMF in a Swedish study. How-ever D135 does not provide any information regarding the efficacy of DMF in PPMS nor the dose which was used. P also argued that according to established case law, sufficiency of disclosure does not require a 100% therapeutic success rate. Sufficiency of disclosure is met if a relevant proportion of patients benefits from the treatment and that non-responders are acceptable. However in the present case, PPMS is a specific subtype of MS which can be differentiated from other individual forms of MS (D126). In line with T317/20 the failure of treating an entire patient subgroup, albeit small, which is distinguished from the patient group as a whole by its pathological status, is not equivalent to an occasional failure. According to established case law, the disclosure of a patent must allow an inven-tion to be performed in the whole range claimed. A second medical use claim does not comply with the requirements of Art.83 EPC if the ther-apeutic effect is not achievable for all patients defined as the target population. The OD's preliminary view is therefore that claim 1 of AR2 of the CP does not comply with the requirements of Art. 83 EPC. 2.2.5 Auxiliary requests AR6, AR7 and AR9 do not meet the require-ments of Article 83 EPC for the same reasons. 3. Auxiliary request 12 (AR12) AR12 differs from the patent as granted in that claims 1 and 5 have been limited to the treatment of relapsing remitting multiple sclerosis (RRMS), in that granted claims 6-8 have been deleted and in that the new claim 6 refers back to claim 5. These amendments are occasioned by a ground of opposition under Ar-ticle 100(b) EPC and therefore comply with Rule 80 EPC. 40 3.1 Article 123
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(1)EPC 3.1.1 The OD is of the preliminary opinion that the subject-matter of claims 1 and 5 of AR12 is not clearly and unambiguously derivable from the content of the application as filed and contravenes therefore the requirements of Art.123
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(1)EPC. Paragraph [0104] states that the neurological diseases in methods 1-5 can be MS and that the form of MS is selected from relapsing remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS), and malignant MS. The application as filed discloses thus the possibility to use DMF or MMF in the treatment of RRMS. Howev-er, even if RRMS is the main form of MS as stated by P, RRMS is not defined as being the preferred form to be treated. Therefore, to arrive at the subject matter of claim 1 of AR12 a selection from the list of the dif-ferent forms of MS is necessary. As mentioned in point 1.2.1 above, the oral dose of 480 mg is not disclosed as being the preferred dose; rather, it is merely, like the RRMS treatment, the result of a selection. Consequently, the OD's preliminary view is that, neither the treatment of RRMS nor the oral dosage of 480 mg per day of DMF/MMF is clearly preferred in the application as filed. The combination of these two fea-tures is thus not the combination of two preferred embodiments. More-over, these two features are not explicitly disclosed in combination in the application as filed. Consequently, the combination of these two fea-tures constitutes a double selection of features and is therefore not di-rectly and unambiguously derivable for the person skilled in the art from the application as filed. 3.1.2 AR13-19 which all relate to the treatment RRMS do not satisfy the requirements of Art.123
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(1)EPC for the same reasons. 3.1.3 Note that the subject-matter of AR12 would meet the requirements of Article 83 EPC. Examples 1 and 2 of the CP (present already at the priority date) provide credible evidence for using DMF or MMF in up-regulating Nrf2 expression, thereby improving neuroprotection, which underlies the treatment of MS. It was already known that an oral dose of 720 mg/day was effective in the treatment of RRMS based on Phase 2b clinical studies (D6b). The opponents even argued that a certain efficacy was also observed with a dose of 360 mg/kg. There is thus no rea-son to doubt that DMF or MMF would have a certain level of efficacy in the treatment of RRMS when used at a dose of 480 mg per day. In other words, there are no reasons apparent to the OD as to why a skilled per-son would a priori regard the efficacy of 480 mg/day as not credible or implausible based on the experimental data provided by the CP and the prior art D6b. The preliminary opinion of the OD is that none of the requests on file meets the requirements of the EPC 41 However, the OD wants to make the following preliminary comments on the other grounds of opposition. Priority The OD sees no difference between the application as originally filed and US888921 P in term of technical content. These two documents are not strictly identical. The changes are the following: [0001] of the priori-ty application discloses the provision of a method for the treatment of e.g. MS and other aspects linked to the development of further thera-peutic compounds and biological assays; [0062] was modified when fil-ing the international application and example 3 was added. However the modifications do not change the technical content of these two documents which relate to the same invention. The passages relat-ing to the mode of action of MMF/DMF as Nrf2 activators, namely ex-amples 1-2, are unchanged. Although it was modified, [0001] of both documents explicitly covers the same purpose, the treatment of MS as the preferred disease. This intention is also derivable from [0009], [0104], [0108]-[0110] of the priority document. In both documents, the teaching of [0116] relating to the dose of MMF/DMF is strictly identical. The fact that example 3 was not present in the priority document does not alter the technical teaching of the invention especially in view of [0029] and [0108] of the priority document. These passages provide the same general information as example 3 of the patent since it states that the invention is based on the findings that DMF/MMF are potent activa-tors of the Nrf2 pathway and that this teaching was assessed in a mouse model of autoimmune degenerative disease (EAE). As a consequence, there is no difference in terms of technical content between the priority document and the application as filed. It follows that if the provisions of Articles 123
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(1)EPC are met, the validity of the priority will be acknowledged for the same reason. Novelty The Opponents cite several documents under novelty (D5, D42-D44, D46 and D49). D5 (WO2006/037342) D5 relates to controlled release pharmaceutical compositions compris-ing a fumaric acid ester such as DMF as an active substance. However, a treatment of MS with 480 mg/ day DMF or MMF is not directly and unambiguously derivable from this disclosure. A first selection involv-ing the choice of MS from a list of more than 20 diseases is required with no preference for MS. There is no indication in the description for MS as the preferred disease, either in the claims 44-45 or in the list of diseases cited from page 37, line 17 to page
  1. It should be noted that the context of D5 does not point specifically to the treatment of MS but 42 aims to achieve a reduction of the gastrointestinal-related side-effects, inter alia in the context of the treatment of psoriasis (page 1 , lines 4-10). The second selection involves the choice of the specific dose of 480 mg/day from the list of seven daily doses of equal weight disclosed on page 36, lines 16 to
  2. The OD does not contest that the scale up dosage of pages 35-36 dis-closes the administration of an oral composition of DMF at a daily dose of 480 mg at week seven. However this is a transient dose among 9 dif-ferent upscaling daily dosage schedules. In any case, there is no clear and unambiguous disclosure that the skilled reader would specifically carry out the scale up dosage up to the week seven to reach a daily dose of 480 mg in the specific treatment of MS. Therefore, a selection in at least two lists is required from the passages mentioned above. This multiple selection involves the choice of MS from among the diseases listed and that of "480 mg/day" from the list of seven dose ranges of equal weight. Therefore the passages mentioned above do not anticipate a treatment of MS with 480 mg/day DMF or MMF. The same applies to the document D5a which is a family member of D
  3. O1 referred to claim 1 of D5a (EP2792 349). However a selection from at least two lists is required which involves the choice of MS among the autoimmune diseases listed in claim 1 and that of 480 mg/day from the dose range of 480 to 720 mg. D42/D112 (W02007/042034) D42 is similar to D5 and relates also to controlled release pharmaceuti-cal compositions comprising a fumaric acid ester such as DMF as an ac-tive substance. As with D5, a treatment of MS with 480 mg/day DMF or MMF is not directly and unambiguously derivable from D
  4. Multiple selections are required. MS must be selected from lang lists of possible diseases from e.g., the list on pages 25-26 (the same list as in D5). If any disease is highlighted in D42, it is psoriasis (as in D5). Thus, MS repre-sents a first selection. Furthermore, there is no disclosure linking DMF or MMF in particular to the specific treatment of multiple sclerosis. There is additionally no preference whatsoever for a dose of 480 mg/day in
  5. It is disclosed as an endpoint within a list of daily dose ranges on page 24, lines 28-36 of D
  6. This means that the dose of 480 mg/day is a further selection. D43 (W02007/006307) This document discloses amino salts of DMF or MMF and their use for treating i.a. multiple sclerosis (claim 15). The salt can be used in combination with di(C 1-5)alkylester of fumaric acid or a mono(C1-5 )alkylester of fumaric acid (claims 8-9). A treatment of MS with 480 mg/day DMF or MMF is however not directly and unambiguously derivable from 43 D
  7. Multiple selections are required. This multiple selection involves the choice of the combination for use in the treatment of MS; the choice of 1-5 DMF or MMF from among the di(C )alkylester or mono(C15 )alkylester of fumaric acid listed on page 13, line 27 to page 14, line 4 and that of "480 mg/day" from the list of seven dose ranges of equal weight on page 15, lines 23-
  8. D44 (WO 2006/050730) This document discloses strontium salts of DMF or MMF and their use for treating i.a. multiple sclerosis (claim 10). The active principle is dif-ferent: in the CP, the active agent is DMF or MMF whereas in D44, the active agent is a strontium salt thereof. In any case, a treatment of MS with 480 mg/day DMF or MMF is not directly and unambiguously derivable from D
  9. MS must be selected from the list of diseases in claims 2 and 10 of D
  10. Regarding the dose, 480 mg/day is only one possible dose out of a list of possibilities on page 19, lines 11 -15 of D44 which range from 1080 mg in the first paragraph of page 19 down to 240 mg in the penultimate paragraph of page
  11. D46 (WO 2007/006308) D46 discloses glucopyranose or glucofuranose esters of alkylfumarates and their use for treating i.a. multiple sclerosis (claim 26). The esters can be used in combination with di(C 1-5)alkylester of fumaric acid or a mono(C 1-5 )alkylester of fumaric acid (claims 19-20). A treatment of MS with 480 mg/day DMF or MMF is however not directly and unambiguously derivable from D
  12. Similar to D43, multiple selections are required. This multiple selection involves the choice of the combination for use in the treatment of MS; the choice of DMF or MMF from among the 1-5 di(C )alkylester or mono(C 1-5 )alkylester of fumaric acid listed on page 19, lines 10-1 5 and that of "480 mg/day" from the list of seven dose ranges of equal weight on page 21, lines 21-31 . D49 D49 relates to composition for oral administration comprising a fumaric acid ester and a substance that reduces or eliminates flushing. Although DMF and MMF are options for the first component (see pages 16-17 and claims 8 and 9), a treatment of MS with 480 mg/day DMF or MMF is however not directly and unambiguously derivable from D
  13. There is no pointer to DMF or MMF as being preferred. Furthermore, as with D5, the dose and disease must be selected from two separate lists of alternatives. MS is found within a long list of diseases on pages 31-32 of D
  14. No connection is made with MS in the entire document and, like D5, psoriasis is more in focus (see e.g., pages 1-2 and 6). The list of daily doses on page 28, lines 20-30 is even larger than in D
  15. D49 does not highlight a dosage of 480 mg/ day or use this dose in any preferred narrow range meaning a further selection is required. 44 The preliminary opinion of the OD is therefore that none of the docu-ments D5, D42-D44, D46 and D49 directly and unambiguously discloses the treatment of MS with an oral dose of 480 mg/day DMF or MMF. Note also that the specific treatment of RRMS is not mentioned in any of these documents. The intermediate documents D53a, D54, D55a, D56a, D57, D63, D64 and D65 will not be considered as prior art if the priority is valid. Inventive step Inventive step will be discussed by applying the problem-and-solution approach (see Guidelines G-Vll,5), which requires to select a closest pri-or art, define the technical difference and its resulting technical effect. Based thereon, an objective technical problem can be formulated. Then it must be assessed whether the technical solution offered in the claim for said objective technical problem is obvious or not from the prior art. The opponents have mentioned a number of documents as closest prior art for the assessment of inventive step, namely D6a, D6b, D7, D9, D128, D5, D43, D44, and D
  16. The closest prior art should generally be the document which corre-sponds to a similar use and requires the minimum of modifications to arrive at the claimed invention (G-VII, 5.1). The CP concerns DMF or MMF for use in the treatment of MS, wherein DMF or MMF is to be orally administered at a dose of 480 mg per day. The closest prior art should therefore also be a document that is con-cerned with the problem of treating a MS with a DMF or MMF. It is stressed that applying the problem-solution approach from differ-ent starting points, e.g. from different prior-art documents, is only re-quired if it has been convincingly shown that these documents are equally valid springboards. In particular in opposition proceedings the structure of the problem-solution approach is not that of a forum where opponents can develop as many inventive step attacks as wished in the hope that one of said attacks has the chance of succeeding (T 320/15, Reasons 1.1.2). Documents D6a, D6b or D7 disclose the results of a successfully completed multicenter double-blind, placebo controlled dose finding study (clinical phase 2 study), a study which had the purpose of finding the optimal effective dose of DMF for treating RRMS. The study demonstrated that oral treatment with 720mg/day DMF led to a statistically significant reduction in the total number of gadolinium enhancing brain lesions with six months of treatment versus placebo. The other doses (120 mg/day and 360mg/day) did not show statistically significant effi-cacy. 45 D6a is an abstract referring to the phase 2 study. D7 is a press release al-so referring to the phase 2 study. Since D6b contains more information about the results of the clinical phase 2 study than D6a/D7, it seems to be a better starting point for the assessment of inventive step. D128 is an updated version of the presentation D6b (its public availabil-ity has still to be discussed). D128 differs from D6b in that it includes the results of the second phase (24-week blinded safety extension phase). Its general technical teaching is similar to D6b and therefore could also be considered as a valid starting point if published before the effective date. It has to be noted that the OD considers that D128 adds nothing over D6b and that the conclusions reached in view of D6b as the closest prior art would apply in the case D128 is taken as the closest prior art. D9 reports the results of an exploratory and open-label study with 10 MS patients treated with Fumaderm. Fumaderm is a drug used for pso-riasis treatment which contains other fumaric esters in addition to DMF (D72: paragraph 23; D129: paragraphs 54-56)). It is thus not clear to which extent each of the individual fumaric esters in the Fumaderm tablets contributed to the results. None of D5, D43, D44, and D46 qualifies as the closest prior art because these documents are not focused on treating MS. These documents are focused on the treatment of psoriasis. They contain no data with respect to the treatment of any diseases, let alone MS. MS is only mentioned in a list of number of different disorders and if any of the diseases could be selected, it would only be psoriasis. Furthermore, these documents disclose lists of alternative doses and daily dases which include 480 mg/day. There is no suggestion of 480 mg/day as an effective dose for treating MS. It appears therefore that the documents D9, D5, D43, D44, and D46 are less suitable starting points. For the sake of completeness, O11 referred to a range of other docu-ments as potential closest prior art (including D7, D19, D112, D11 6, D1 18, D119), some of which are filed after the priority date (D116, D119, D120). However, O11 did not present any valid inventive step attacks (in the framework of the problem-solution approach or substantiated arguments) starting from these documents. D6b differs from the subject-matter of the CP in that D6b do not dis-close that DMF (or MMF) is administered at a dose of 480 mg per day. As already mentioned, examples 1 and 2 of the CP provide credible evidence for using DMF or MMF in upregulating Nrf2 expression, thereby improving neuroprotection, which underlies the treatment of MS. Example 3 of the patent further confirms this in an in vivo model. There-fore, Examples 1 and 2 of the patent demonstrate the effectiveness of DMF and MMF in upregulating Nrf2 expression, and thereby upregu-lating the neuroprotective gene, NQO
  17. These effects show a clear rela-tionship between DMF/ MMF and neuroprotection, a key mechanism to the medical use of DMF and MMF in treating MS. Additionally, in this 46 context, paragraph [0116] of the application as filed discloses an effec-tive oral dose of 480 mg/day to 720 mg/day, and it was already known that an oral dose of 720 mg/day was effective based on Phase 2b clinical studies. There is no reason to doubt the technical teaching in paragraph [0116] of the application as filed that DMF or MMF at 480 mg to 720 mg per day would be an effective dose for treating MS, in particular RRMS (see also point 3.1.3 above). The post-published documents D20 and D25 further demonstrate that the lower dose of 480 mg/day DMF is similarly efficacious to 720 mg/day in treating RRMS. The EBoA in G2/21 decided that post-published data could not be dismissed solely because it was post-published (G2/21, Order, point 1). Thus the post-published data in the present case may be considered. Thus at the forthcoming oral proceedings it will be discussed whether the "skilled person, having the common general knowledge in mind, and based on the application as originally filed, would derive said ef-fect as being encompassed by the technical teaching and embodied by the same originally disclosed invention" (G2/21, Order, point 2). The preliminary opinion of the OD is that in the present case the postpublished evidence D20 and D25 can be relied upon for determining the technical effect under inventive step. Paragraph [0116] of the application as filed discloses that 480 mg/day is an effective dose of DMF or MMF. This disclosure is to be read in conjunction with the overall teaching provided in [0001], [0026], [0028], [0029], and by the teachings of all the examples (see point 1.2.1 above). The 480 mg/day dose was thus clearly marked out as an intended effec-tive dose for treating MS. D20 and D25 confirm the efficacy of the dose described in the original application and only provide the magnitude of the effect obtained by said dose. The technical effect substantiated in D20 and D25 was thus derivable from the original application. Therefore, the OD considers that the technical effect relied upon by P for the dose 480 mg/day was encompassed by the technical teaching of the original application regarding the therapeutic effect of DMF or MMF and was embodied by the same originally disclosed invention since DMF and MMF are clearly the two preferred Nrf2 activators exemplified in the whole application (see T0873/21 ). In line with G2/21, the technical effect demonstrated by the post-published evidence provided in D20 and D25, namely the Phase 3 DE-FINE and CONFIRM is thus to be taken into account when assessing the inventiveness of the CP. As mentioned above, D20 and D25 show that 480 mg/day is similarly efficacious to 720 mg/day. One of advantage is clearly that 480 mg daily 47 can be expected to be more beneficial in the long term compared to 720 mg daily, because the patients can take substantially less drug without any loss in efficacy (D25: page 9, paragraphs 10 and 11). Consequently, the objective technical problem can be seen as the provision of an improved oral treatment of RRMS. The solution to the problem is to use DMF (or MMF) at a dose of 480 mg/day. This problem is solved, as evidenced by the Phase 3 clinical trial studies (see D20 and D25) which clearly show that 480 mg/day is efficacious and moreover, that the substantially lower dose of 480 mg/day DMF is similarly efficacious to 720 mg/day in treating patients with RRMS. It will have to be discussed during the oral proceedings whether the claimed dosage is obvious in view of D6b alone or in combination with the remaining prior art. The preliminary opinion of the OD is that the dosage regime of 480mg per day is not obvious. There is no indication in the prior art that would have suggested to the skilled person that a dose of 480 mg/day of DMF would have similar efficacy to the 720 mg/day dose of DMF for the treatment of MS, in particular RRMS. The skilled person had no incentive to choose a dose lower than 720 mg/day, let alone with any expectation to provide an improved oral treatment of MS with a dose as low as 480 mg/day (i.e., 33% lower) which is as effective as the dose of 720 mg/day. Since a loss in efficacy would have been undesirable, the advantages of a lower dose of 480 mg/day while retaining similar efficacy to the 720 mg/day were not foreseeable at the priority date. Note that the only documents disclosing an effective dose of 480 mg/day of DMF are D16, D5, D43, D44, and D112 (D42). However, DMF is used for treating psoriasis in D
  18. The OD considers that a skilled person starting from the teaching of D6b and faced with the problem of finding an improved treatment of MS, would have had no reason to consult results related to psoriasis, i.e., an entirely different disease. In this regard, it should be noted that the skilled person who treats MS is usually a neurologist and the skilled person who treats pso-riasis is usually a dermatologist. The skilled neurologist would have been aware that considerations relating to the treatments for MS and skin conditions, like psoriasis, are significantly different - psoriasis be-ing a skin disease and MS a life-threatening neurological condition. In any case, even by taking the position that a skilled person could have expected the 480 mg/day to be effective in the treatment of MS, the fact that 480 mg/day of DMF is as efficacious as 720 mg/day is surprising and unexpected. 48 O5 and O6 argued that a dose of 480 mg/day was suggested by D5, D43, D44, and D112 (D42). However, these documents are more focused on the treatment of psoriasis. They discloses lists of alternative doses and daily doses which include 480 mg/day. There is no suggestion of 480 mg/day as an effective dose for treating MS. Note that D112 (D42) is Art. 54
(3)EPC prior art, and hence cannot be used for inventive step if the priority is valid. Certain opponents argued that the skilled person would have looked to optimise the dose by routine experimentation. The skilled person would have had a reasonable expectation of finding the optimum dose when carrying out a dose-optimising study. According to the oppo-nents, it is not surprising that there are two or more dases having the same efficacy. DMF fits the standard dose-response profile of increasing efficacy with dose up to a dose plateau where increasing the dose does not lead to greater efficacy. Building a dose-response curve and select-ing the optimum value is routine work (reference was made to D8). The OD cannot concur with this argument. The OD share P's view that the existence of an activity plateau at 720 mg/day based on the Phase 2b results (D6b) is pure speculation. There was only one effective dose in the Phase 2b study, so that there is no basis for concluding that an activ-ity plateau exists based on this one data point showing efficacy. All the other arguments put forward by the opponents are based on a problem which has been defined as the provision of an alternative daily dose of DMF for the effective oral treatment of MS. However, the preliminary opinion of the OD is that he objective technical problem can be seen as the provision of an improved oral treatment of RRMS. There is no indications in the prior art that would have led the skilled person to select the specific dose of 480 mg/day in order to solve the problem posed. As already mentioned, the fact that 480 mg/day of DMF is as ef-ficacious as 720 mg/day is surprising and unexpected.…” I Opposition Divisions foreløbige vurdering er den første Kappos præsentation, Kappos D11-A3, betegnet dokument D6b, og den efterfølgende ECTRIMSpræsentation er betegnet dokument D128. Dokumentet, som i Opposition Divisions foreløbige vurdering af 6. november 2023 betegnes D127, er en artikel af Helene Højsgaard Chow m.fl., ”Dimethyl fumarate treatment of primary progressive multiple sclerosis: results of an open-label extension study” , offentliggjort den 9. december 2022 i tidsskriftet Multiple Sclerosis and Related Disorders 70
(2023)(herefter ”Chow m.fl.”). Af artiklen fremgår: “ABSTRACT Introduction: Dimethyl fumarate treatment is approved in Europe for patients with relapsing-remitting multiple sclerosis (MS) and in the US 49 for relapsing forms of MS. We recently published the results of the first randomized placebo-controlled trial of 48 weeks of treatment with dimethyl fumarate or placebo in primary progressive MS (PPMS) (clinicaltrial.gov NCT02959658). The placebo-controlled phase of the trial did not meet its primary endpoint (reduction in cerebrospinal fluid concentrations of neurofilament light chain [NFL]). Aim: To investigate the effects of dimethyl fumarate treatment in the openlabel extension phase of the trial (week 48-96), where all patients were treated with DMF. Methods: Reported data are from screening, week 48, and week 96 visits. Patients were clinically evaluated with Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, and Brief Visuospatial Memory-Revised. Serum NFL concentrations were measured by single-molecule array analysis. MRI was performed on a 3 tesla MRI scanner and included: new /enlarging lesions, volume of lesions, cortical grey matter, putamen, thalamus, and normal-appearing white matter, and additional diffusion tensor imaging and magnetization transfer ratio measures. Results: Forty-two patients entered the open-label treatment phase, and 33 patients (61 %) had complete data sets at week
  1. The remaining 39% did not complete the trial and were not evaluated at week
  2. We found no evidence of differences in clinical and MRI measures between patients initially treated with dimethyl fumarate and patients initially treated with placebo from baseline to week 48 and from week 48-96, where all patients were treated with dimethyl fumarate. Serum NFL concentrations remained stable in both groups over 96 weeks. Assessed with either EDSS, T25FW, or 9HPT at week 96, progression was ob-served for 14 patients (45%). Interestingly, another 15 patients (46%) had improvement in one or more of these domains. Applying a cut-off of 8 points, 2 (6%) patients worsened on SDMT, 25 (78%) did not change, and 5 (16%) improved. Conclusions: Dimethyl fumarate treatment showed no effects on neither clinical nor MRI outcomes or changes in serum concentrations of NFL. An expected number of patients showed evidence of progression on standard clinical scales; however, this was matched by an equal number of patients improving. The reasons for the physical improvement in an unexpectedly high proportion of patients must be addressed in future studies.
  3. Introduction Patients with primary progressive multiple sclerosis (PPMS) comprise approximately 10–15% of the multiple sclerosis (MS) population. The pathogenesis of PPMS remains incompletely understood, but it is thought that adaptive and innate immune cells, as well as degenerative processes, including processes initiated by compromised energy metabolism due to mitochondrial injury, contribute. (Hemmer et al., 2015) Treatment options for PPMS are limited, and only B cell-depleting treatment with ocrelizumab is currently approved for PPMS treatment in Europe and has shown a significant delay in the risk of disability progression. (Montalban et al., 2017, Gajofatto et al, Wolinsky et al., 2020) 50 Dimethyl fumarate is a disease-modifying therapy with combined immunomodulatory and neuroprotective effects. (Diaz et al) Dimethyl fumarate is approved by the Food and Drug Administration as a treat-ment for relapsing forms of MS and by the European Medicines Agency for patients with relapsing-remitting MS. (Fox et al., 2012, Gold et al., 2012) Dimethyl fumarate and other fumaric acid esters have been inves-tigated in progressive MS patients. One study showed no disease pro-gression in 75% of the treated patients and that fumaric acid esters were well tolerated. (Strassburger Krogias et al., 2014) Another study showed a trend towards improvement in ambulation, compared with patients treated with glatiramer acetate. (Moreira Ferreira et al., 2021) We recent-ly completed the first randomized placebo-controlled trial investigating dimethyl fumarate treatment in patients with PPMS. (Højsgaard Chow et al., 2021) The trial did not meet its primary endpoint of reducing the cerebrospinal fluid (CSF) concentrations of neurofilament light chain (NFL), a marker of neuroaxonal injury. Neither did we find effects on other biomarkers of tissue injury or inflammation in CSF after treatment with dimethyl fumarate, except for a decrease in the number of CD4+ T cells and a corresponding increase in concentrations of the CD4+ T cell growth factor interleukin-7 in CSF. (Talbot et al., 2021) In MS, increased NFL levels in the CSF have been shown to be associated with the amount of focal inflammation, but NFL levels may al-so be associated with more diffuse pathology. (Kuhle et al., 2019, Saraste et al., 2021, Kapoor et al., 2020) NFL can be measured in serum, which provides a fast and readily accessible way of assessing neuroax-onal damage. (Kuhle et al., 2016) The serum concentration of NFL has been proposed as a treatment-responsive biomarker in MS, and treat-ment with dimethyl fumarate has been shown to reduce the concentra-tions of NFL in serum and CSF. (Sejbaek et al., 2019, Delcoigne et al., 2020) Here, we report the results from the open-label extension phase of the placebocontrolled treatment trial of dimethyl fumarate treatment in PPMS, including data on serum NFL, using a novel method for correct-ing the effect of age.
  4. Methods 2.1 Study design and patients The study was a single-center study conducted at the Danish Multiple Sclerosis Center, Copenhagen University Hospital - Rigshospitalet. Inclusion criteria for the study were in brief: age 18–65 years, Expanded Disability Status Scale (EDSS) score 0–6.5, PPMS diagnosis, and NFL concentration above 380 ng/L in CSF. Key exclusion criteria were: immunomodulatory treatment within 6 months or treatment with corticosteroids within 3 months prior to enrollment. All in- and exclusion criteria are specified elsewhere. (Højsgaard Chow et al., 2021) The openlabel extension phase with twice-daily oral dimethyl fumarate 240 mg (Biogen, Cambridge, MA, USA) followed the 48 weeks randomized, double-blind, placebo-controlled phase and lasted 48 weeks. All participants followed a titration schedule as follows: From day one to 21, dimethyl fumarate was titrated from 120 mg to 480 mg daily as maintenance dose. Sixty patients were screened to randomize 54 in the treat-ment trial. All 6 screen failures were invited for reassessment at week 51 48 to establish eligibility for the open-label phase. Eligibility was based on: 1 point increase in EDSS score if screening EDSS < 6; 0.5 point in-crease in EDSS score from screening to week 48 if screening EDSS > 5.5; 2 point increase in a physical functional system or; worsening in SDMT, 9HPT or T25FW > 20% from screening to week
  5. Only 1 out of 4 re-assessed patients were eligible for re-entry to the trial. …
  6. Statistics The group was dichotomized based on treatment allocation in the randomized placebo-controlled phase. Inter-group comparisons were made using paired t-tests. Group 1 received placebo in the randomized phase and switched to active treatment in the open-label phase, and group 2 received active treatment at both study intervals. As the study was descriptive and exploratory, endpoints were tested at a nominal significance level of 5% without adjustment for multiple testing. SPSS v25 was applied for all statistical analyses.
  7. Results Fifty-four patients were randomized in the placebo-controlled phase of the study. Four patients (7%) dropped out in this phase. Fifty (93%) patients were eligible for entry into the open-label phase. However, 5 (10%) patients did not continue in the open-label phase, and 4 (8%) were excluded due to prolonged lymphopenia. The 5 patients who did not enter the open-label phase were discounted for the following rea-sons: side effects of the treatment; difficulty with transport to the clinic; worry that the treatment worsened the MS symptoms; switching to ocrelizumab treatment; unreachable by the trial staff. Four out of 6 non-randomized patients were re-assessed at week 48, and 1 was eligible for entry into the open-label phase based on worsening in EDSS of more than 1 point. Thus, a total of 42 patients (78%) entered the open-label phase. Nine patients (21%) dropped out during the open-label phase. Thirty-three (79%) had complete data sets at week
  8. A detailed report of the trial profile can be seen in Fig. 1, and the demographics of the participants are shown in Table
  9. Additional demographics and patient characteristics can be seen in the appendix (Table A1). 52 Fig. 1 Trial profile. Overview of participant inclusion and drop out in the open-label phase week 48–
  10. Table 1 Baseline characteristics at week
  11. Characteristic Placebo (n = 22) Dimethyl fumarate (n = 20) Age (years) Female, n (%) EDSS, median [IQR] Disease duration (years) Gd-enhancing lesions 2; n (%) 1; n (%) 0; n (%) NA; n (%) Serum NFL (ng/l), median [IQR] Serum NFL-ratio, median [IQR] 56.2 (5.6) 9 (41%) 4.0 [3.5–5.6] 13.3 (8.2) 55.7 (5.6) 7 (35%) 4.5 [4.0–6.0] 13.9 (8.6) 1 (4.5%) 0 1 (4.5%) 0 20 (91.0%) 20 (100%) 1 (4.5%) 0 13.4 [11.0–16.2] 0.61 [0.53–0.82] 12.8 [8.5–16.6] 0.61 [0.47–0.72] Values are gives as mean with standard deviation (SD) unless otherwise specified. One patient was eligible for re-entry to the trial at the open-label phase after reassessment at week
  12. Data for this patient is included in the placebo column. EDSS = expanded disability status scale; Gd = Gadolinium; IQR = inter-quartile range; NFL = neurofilament light chain. There was no significant change in disability at a group level upon treatment with dimethyl fumarate from week 48-96, except for a worsening in non-dominant 9HPT in the original placebo group (p = 0.024) (Table 2). 53 Seven (12%) out of 60 screened patients had a serum NFL ratio above 1.0, indicating elevated levels for their age (range: 1.05–1.91), and 4 (10%) of the 42 patients entering the open-label phase had an in-creased NFL ratio (range: 1.20–2.49). There was no difference in serum NFL concentrations between the patients treated with dimethyl fu-marate and placebo from baseline to week 48 (Table 2), and concentra-tions remained stable over time (Fig. 2). Fig. 2 Scatterplots of serum NFL values. NFL values plotted for each period in the trial. X- and Y-axis are log-transformed. NFL = neurofilament light chain. 54 Fourteen patients (42%) had physical disease progression assessed with either EDSS, T25FW, or 9HPT at week
  13. However, another 15 patients (46%) had improved in one or more of the physical domains at week
  14. A total overview of worsening and improvement f on EDSS, T25FW, 9HPT, and SDMT can be seen in Table
  15. Six (18%) of the 7 patients with EDSS worsening was confirmed from week 72 to 96, and 5 (15%) of the 6 with EDSS improvements was confirmed from week 72 to
  16. Applying a cut-off of 8 points on the SDMT, 2 (6%) patients worsened, 25 (78%) did not change, and 5 (16%) improved. Table 3 Number of patients showing clinically relevant changes from screening to week 96 in selected clinical measures. Worsened Unchanged Improved EDSS, no. 7 (21%) 20 (61%)6 (18%) T25FW, no. 7 (22%)19 (59%)6 (19%) 9HPT dominant, no. 325 (9%) (76%) 5 (15%) 9HPT non-dominant, no. 3 (10%) 23 (77%)4 (13%) SDMT, no. 2 (6%)25 (78%) 5 (16%) Definitions of clinical change: EDSS increase or decrease of at least 1.0 point (from EDSS 2.0–5.0) or 0.5 points (from EDSS above 5.5). T25FW and 9HPT increase or de-crease of at least 20%. SDMT increase or decrease of at least 12 points. T25FW: missing data n = 1 9HPT non-dominant: data missing n = 3 SDMT: data missing n = 1 EDSS = expanded disability status scale; SDMT = Symbol Digit Modalities Test; T25FW = timed 25-foot walk; 9HPT = 9-hole peg test. …
  17. Discussion We found no obvious effects of treatment with dimethyl fumarate in the open-label, extended phase of the randomized, controlled trial, where patients were offered open-label treatment with dimethyl fu-marate for 48 weeks after the initial 48 weeks of treatment with either dimethyl fumarate or placebo. There was a significant worsening in dexterity (assessed with 9HPT) from week 48 to week 96 in the group initially treated with placebo. However, this worsening was not sup-ported by a similar deterioration from screening to week 48 in the pa-tients initially treated with dimethyl fumarate, and the finding is likely coincidental. Previously, a study reported no disease progression in 75% of progressive MS patients treated with fumaric acid esters (Strass-burger Krogias et al., 2014). This seemingly indicates a potential effect of dimethyl fumarate in progressive MS; however, there was no control group, and the follow-up time was highly variable. Our results show that PPMS patients, on average, are clinically and MRI stable over 2 years, with or without dimethyl fumarate treatment. Overall, we show comparable progression rates for this cohort of patients with PPMS compared to previous results. (Cadavid et al., 2017, Kapoor et al., 2018). 55 However, we cannot comment on confirmed worsening on T25FW and 9HPT individually, as these were not tested at week
  18. Overall, the patients were relatively stable (i.e., no signs of disease activity) during the entire trial period, as assessed with MRI. However, T2 lesion volume increased, and MD in NAWM and putamen increased over the 96 weeks of the study. We have previously demonstrated that this cohort has comparable levels of many biomarkers of inflammation in CSF with that of relapsing-remitting MS patients and significantly elevated levels compared with healthy controls. We found no effect on these factors by dimethyl fumarate treatment. (Højgaard Chow et al., 2021, Talbot et al., 2021, Talbot et al., 2022) Somewhat surprisingly, we found that several PPMS patients improved on physical measures during the 2-years of follow-up. The physical improvements seen in collectively 46% of the patients are like-ly explained by optimization of supportive measures by the trial per-sonnel, e.g., referral for physical therapy and perhaps some degree of learning effects. … Although our cohort is very small, compared with the cohort in the ASCEND study, we show an even higher degree of improvement in EDSS, T25FW, and collectively improvement of 46%. Because we have been unable to show any treatment effects of dimethyl fumarate in our cohort through several investigative measures, the cohort can be viewed as nontreated. (Højsgaard Chow et al., 2021, Talbot et al., 2021, Talbot et al., 2022) Therefore, our finding of a substantial degree of im-provement is very interesting in itself. … This study carries limitations, especially in sample size. Only 33 patients had complete datasets at week 96, meaning that 39% did not finish the study. Participants who dropped out or were excluded were not evaluated at week
  19. This loss to follow-up is a clear limitation since this may entail enrichment for responders and thereby skewing our results for improved versus worsened participants, especially since 5 were lost to follow-up for reasons such as difficulty with transport to the clinic or worries that the treatment worsened the MS symptoms. Therefore, the study may have lost patients due to a self-perceived ad-verse benefit-risk balance. However, the data set is highly uniform, hav-ing been collected by only two neurologists, two study nurses, and 1 neuropsychologist and additionally monitored by an independent GCP unit. The MRI protocol was validated, and all patients were scanned on the same 3 Tesla MRI scanner. Although progression rates were compa-rable to previous reports in progressive MS, several patients improved. Unfortunately, the follow-up period of 2 years is too short of establish-ing any conclusive results on this phenomenon. In conclusion, we show no evidence of an effect of dimethyl fumarate treatment in this PPMS cohort, despite previous findings of a high level of intrathecal inflammation. (Højsgaard Chow et al., 2021, Talbot et al., 2022) Serum NFL concentrations remained stable over 96 56 weeks, irrespective of dimethyl fumarate treatment. There was an expected degree of progression accompanied by a certain degree of MRI dynamic. Yet, many patients improved to an extent even beyond that found in the ASCEND treatment arm. This finding is very interesting and warrants further investigation. …” Dokumentet, som i Opposition Divisions foreløbige vurdering af
  20. november 2023 betegnes D135, er en erklæring af
  21. maj 2023 afgivet af dr. Wanda CastroBorrero, Global Medical Head MS, Biogen, til brug for EPO’s behandling af stridspatentet. Af erklæringen fremgår: ”…
  22. To my knowledge, PPMS patients have been or are currently being treated with Tecfidera in Europe, despite the fact that PPMS is not the clinically approved indication. As evidence of such past or cur-rent treatment, I would like to refer to data available at Biogen from MS patient registries.
  23. Biogen supports MS patient registries and has accept to data regarding patients taking Tecfidera. The following data is taken from the latest report of the Swedish registry from May 2022 (the IMSE 5 study). The study covers 2558 patients and data was collected from March 25, 2014 to April 30, 2022).
  24. As may be taken from the, PPMS patients are typically a small percentage of MS patients (1 % of the patients in the Swedish study. Moreover, the 29 PPMS patients in this study have been or are be-ing treated with DMF (Tecfidera).” 57 I en erklæring af
  25. maj 2023 afgivet af dr. Martin Duddy til brug for indsigelsessagen ved Opposition Division er anført: ”…
(7)HØJSGAARD CHOW ET AL, 2023 (D127) - TREATMENT OF PPMS 97. I have been asked whether I consider D127 to conclusively show that 480 mg/day DMF does not treat primary progressive MS (PPMS). 98. D127 presents the results of an open-label extension study (weeks 48-96) of a trial of treatment with DMF or placebo in PPMS pa-tients. Reported data are from screening, week 48, and week 96 vis-its. Patients were clinically evaluated, serum NFL concentrations were measured, and MRI was performed. The results of D127 are that no evidence of differences in clinical and MRI measures were found between patients initially treated with DMF and patients ini-tially treated with placebo from baseline to week 48 and from week 48-96, where all patients were treated with DMF (Abstract Results). Serum NFL concentrations remained stable in both groups over 96 weeks. The Abstract, Conclusions further states that an expected number of patients showed evidence of progression on standard clinical scales; however, this was matched by an equal number of patients improving. 99. The study of D127 suffers from a number of limitations, which the authors acknowledge in the paper, and which have to be kept in mind when assessing the relevance of D127. 100. First, D127 is a study limited to a small patient population at the Danish Multiple Sclerosis Center, Copenhagen University Hospital - Rigshospitalet. Only 33 patients completed treatment, as shown by Figure 1 of D127 and commented on page 6, paragraph bridging the columns. In my opinion, the small total size gives the study lim-ited power to confidently exclude differences (especially if the ef-fect size is small). In this context, the authors of D127 state on page 6, right column, first paragraph that the study may have lost pa-tients due to a self-perceived adverse benefit-risk balance. Such an imbalance is termed an "attrition bias" and it can influence (
  1. i)the statistical power of the study and (
  2. ii)the balance of confounders (variables that the trial failed to control or eliminate) between the groups. This loss of patients in my opinion further diminishes the study's ability to meaningfully and robustly compare patient groups. Indeed, D127 is a single study which has not been replicat-ed. 101. Second, D127 is limited by being an extension study in which all patients were treated with DMF. As there is no longer a placebocontrolled group, the study cannot conclusively show that 480 58 mg/day DMF is not capable of treating PPMS. I note in the Abstract Introduction of D127 that the placebo-controlled phase of the trial did not meet its primary endpoint: reduction in cerebrospinal fluid concentrations of neurofilament light chain (NFL). It is not yet established that failure to alter NFL levels over this time period would exclude a clinical effect on PPMS. 102. Already for these reasons, the skilled person would not read much into D127's conclusion. 103. Third, D127 is limited by being an open-label study, hence the patients and investigators knew that DMF was being administered. Such an open-label study does not exclude that drug-independent aspects have an impact on the study outcome and its analysis. 104. Fourth, the period of time that the PPMS patients were assessed was in total 96 weeks, during only 48 weeks of which the groups received different treatments, and this may be too short to be able to discern a treatment effect on the progression of PPMS. The au-thors of D127 seem convinced the period was too short. They write on page 6, right column, first paragraph of D127 that although pro-gression rates were comparable to previous reports in progressive MS, several patients improved, but they say that unfortunately, the follow-up period of 2 years is too short to establish any conclusive results on this phenomenon. I would agree. 105. I also note that D127 reports unusual and unexplained phenomena in their results, which I would take as an addition warning that the results of D127 have to be viewed skeptically. D127 reports that an expected number of patients showed evidence of progression on standard clinical scales, but this was matched by physical improvement in an unexpectedly high proportion of patients - see the Abstract, Conclusions. The authors suggest on page 4, right col-umn, second paragraph that the physical improvements could be explained by optimization of supportive measures by the trial per-sonnel, e.g., referral for physical therapy and perhaps some degree of learning effects, but this is not demonstrated. Reports of physical improvements in longitudinal studies in progressive MS are sparse, as D127 notes. D127 proposes that this unexpected improvement must be addressed in future studies. 106. The fact that there was a physical improvement in an unexpectedly high proportion of patients (all of whom ended up on DMF) is perhaps another indication that at the very least a treatment effect of 480 mg/day DMF on PPMS patients cannot be excluded. 107. Overall, my opinion after reviewing D127 is that it does not conclusively show that 480 mg/day DMF does not treat PPMS. 108. I still consider that in view of its mechanism of action, i.e., neuroprotection mediated by the Nrf2 pathway, it is reasonable to as-sume that DMF (and MMF) may well provide treatment benefit in 59 patients with PPMS, and indeed some previous results referenced in D127 were supportive of this assumption.” I Opposition Divisions foreløbige vurdering af 6. november 2023 henvises endvidere til “Guideline on clinical investigation of medicinal product for the treatment of Multiple Sclerosis” af 16. november 2006 fra Det Europæiske Lægemiddelagentur EMEA (i dag EMA), Committee for Medicinal Products for Human Use, CPMP/EWP/561/98, Rev. 1. Af dokumentet, som i Opposition Divisions foreløbige vurdering betegnes D115, fremgår: “… 1. INTRODUCTION (background) Multiple Sclerosis (MS) is a common neurological disease affecting more than 1 million people worldwide. Its prevalence rate varies be-tween races and geographical latitude, ranging from more than 100 per 100,000 in Northern and Central Europe to 50 per 100,000 in Southern Europe. MS is an inflammatory condition that damages the myelin of the Cen-tral Nervous System and causes neurologic impairment and, frequently, severe disability. It is the commonest cause of neurological disability in young and middle-aged adults and has a major physical, psychological, social and financial impact on patients and their families, friends and bodies responsible for health care. The aetiology of MS remains unknown. It is generally assumed that MS is mediated by some kind of autoimmune process possibly triggered by infection and superimposed upon a genetic predisposition. As many as 80 to 85 % of all patients present with a form of disease known as re-lapsingremitting MS (RRMS), which is characterised by unpredictable acute episodes of neurological dysfunction named clinical attacks or re-lapses, followed by variable recovery and periods of clinical stability. Within ten years more than 50% of patients who presented with a RR form eventually develop sustained deterioration with or without re-lapses superimposed; this form is called the secondary progressive va-riety of MS (SPMS). The term relapsing MS (RMS) applies to those pa-tients either with a RRMS form or a SPMS form that are suffering re-lapses. Patients with RMS, in spite of suffering from different MS forms, constitute a common target for current treatments. Around 15% of pa-tients develop a sustained deterioration of their neurological function from the beginning; this form is called primary progressive MS (PPMS). Some patients who begin with a progressive deterioration may experi-ence relapses with time and this form is called progressive relapsing MS (PRMS). Besides these main types of disease, the benign variety of MS refers to a RRMS form with few relapses and no significant disability af-ter several years of evolution. Conversely, the term malignant MS ap-plies to a very aggressive variety leading to severe disability or death in a few years after the onset of the disease. 60 Finally, the term clinically isolated syndrome (CIS) applies to those patients who have suffered a single clinical event but do not comply with the diagnostic criteria for definite MS. It is unclear whether the different courses of MS described are due to the same or to distinct pathophysiologic processes. Relapses are consid-ered the clinical expression of acute inflammatory focal lesions whereas progression is considered to reflect the occurrence of demyelination, axonal loss and gliosis. Relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis are probably different stages of the same disease while primary progressive multiple sclerosis may im-ply different processes. In general, current therapeutic approaches include: … 2. SPECIFIC CONSIDERATIONS WHEN DEVELOPING PRODUCTS FOR THE TREATMENT OF MULTIPLE SCLEROSIS … 2.3 Treatments intended to modify the natural course of the disease … 2.3.3 Primary progressive multiple sclerosis (PPMS) So far, clinical trials have not shown efficacy in this type of patients. Randomised, double-blind placebo-controlled clinical trials are neces-sary in order to assess the efficacy of any new treatment in PPMS. … 6. STRATEGY AND DESIGN OF CLINICAL TRIALS … 6.4 Exploratory trials Characteristics of patients to be included may vary according to the proposed mechanism of action and goal of the treatment. However, to maximise possible treatment contrast, it seems reasonable to choose patients with predictors of high clinical activity and with only mild/moderate disability. In exploratory trials in RMS, the use of MRI derived parameters, as the main endpoint, is acceptable (see 4.3). Usually, studies will have a par- 61 allel double blind design and duration of 6 month may be adequate. Relapses and other clinically meaningful outcomes should also be evalu-ated. In SPMS or PPMS, disability should be assessed in addition to support-ive MRI and longer duration of the trial will be needed. … 6.5 Confirmatory trials The annual relapse rate in RRMS is usually low and, in general, progression of disability takes years. Consequently, confirmatory studies with products intended to modify the course of the disease should be large scale and long enough to have a substantial proportion of pa-tients suffering relapses or showing progression of disability. Two years is considered the minimum duration to demonstrate efficacy. … As several subjective decisions and assessments will have to be performed, with a considerable risk of bias, all possible efforts should be done to keep the design double blind. In cases where double blind is not possible (some active comparator trials, some easily unblinded treatments,...) a blind observer design with a blinded examining physi-cian different than the treating physician may be used. All measures to ensure reliable single blind evaluation should be guaranteed (i.e. patch-es that cover injection sites to hide reddening or swellings, education of examining physicians,...). Criteria to refer the patient to evaluation of a relapse should be established a priori in the protocol to avoid selective referral. The use of two or more different dosage regimens is advisable if no conclusive results have been obtained from previous studies. …” Om behandling af forskellige typer af multipel sklerose med DMF/MMF er endvidere anført følgende i d

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