IP Library › Granted Patent US 9,605,059

Granted Patent B2

US 9,605,059 · App. 14/532,531 · Granted Mar 28, 2017

Human anti-tau antibodies

Inventors: Roger Nitsch (Zumikon, CH); Feng Chen (Zurich, CH); Jan Grimm (Duebendorf, CH); Jean-Luc Baeriswyl (Zurich, CH); Christoph Hock (Erlenbach, CH)

Assignees: Biogen International Neuroscience GmbH; University of Zürich

C07K16/18 A61K39/3955 C07K14/47 C07K14/4711 G01N33/6896 A61K2039/505 C07K2317/10 C07K2317/21 C07K2317/24 C07K2317/34 C07K2317/41 C07K2317/52 C07K2317/56 C07K2317/565 C07K2317/90 C07K2317/92 G01N2333/47 G01N2800/56

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Quick Facts

Patent No.: US 9,605,059
App. No.: 14/532,531
Granted: Mar 28, 2017
Kind: B2

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Abstract

Provided are novel human tau-specific antibodies as well as fragments, derivatives and variants thereof as well as methods related thereto. Assays, kits, and solid supports related to antibodies specific for tau are also disclosed. The antibody, immunoglobulin chain(s), as well as binding fragments, derivatives and variants thereof can be used in pharmaceutical and diagnostic compositions for tau targeted immunotherapy and diagnosis, respectively.

Claims (183)

1. A polynucleotide or polynucleotides encoding an anti-tau antibody or a tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

(a) the VH comprises a heavy chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:23, 24, and 25, respectively;

(b) the VL comprises a light chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:26, 27, and 28, respectively; and

wherein the VH does not comprise an asparagine at Kabat numbering position 30.

2. The polynucleotide or polynucleotides of claim 1 , wherein the antibody or tau-binding fragment thereof is selected from the group consisting of a single chain Fv fragment (scFv), an F(ab′) fragment, an F(ab) fragment, and an F(ab′)2 fragment.

3. The polynucleotide or polynucleotides of claim 1 , wherein the VH comprises a glutamine at Kabat numbering position 30.

4. The polynucleotide or polynucleotides of claim 1 , wherein the antibody or tau-binding fragment thereof is a human or a chimeric human-murine antibody.

5. The polynucleotide or polynucleotides of claim 1 , wherein the antibody or tau-binding fragment thereof is a human monoclonal antibody.

6. A vector or vectors comprising the polynucleotide or polynucleotides of claim 1 .

7. A host cell comprising the polynucleotide or polynucleotides of claim 1 .

8. A method for preparing an anti-tau antibody or tau-binding fragment thereof, the method comprising:

(a) culturing the host cell of claim 7 ; and

(b) isolating the anti-tau antibody or tau-binding fragment thereof from the culture.

9. A polynucleotide or polynucleotides encoding an anti-tau antibody or a tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), and wherein:

(a) the VH comprises a heavy chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:23, 24, and 25, respectively;

(b) the VL comprises a light chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:26, 27, and 28, respectively; and

10. The polynucleotide or polynucleotides of claim 9 , wherein the antibody or tau-binding fragment thereof is a human or a chimeric human-murine antibody.

11. The polynucleotide or polynucleotides of claim 9 , wherein the antibody or tau-binding fragment thereof is a human monoclonal antibody.

12. A vector comprising the polynucleotide or polynucleotides of claim 11 .

13. A host cell comprising the polynucleotide or polynucleotides of claim 11 .

14. A method for preparing an anti-tau antibody or tau-binding fragment thereof, the method comprising:

(a) culturing the host cell of claim 13 ; and

(b) isolating the anti-tau antibody or tau-binding fragment thereof from the culture.

15. A polynucleotide or polynucleotides linked to a heterologous nucleic acid, wherein the polynucleotide or polynucleotides are selected from the group consisting of:

(a) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:11 binds to tau (SEQ ID NO:6);

(b) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:26, 27, and 28, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:9 binds to tau (SEQ ID NO:6);

(c) a polynucleotide or polynucleotides encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:26, 27, and 28, respectively;

(d) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:9, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:11 binds to tau (SEQ ID NO:6);

(e) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:11, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:9 binds to tau (SEQ ID NO:6);

(f) a polynucleotide or polynucleotides encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:9 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:11;

(g) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:8;

(h) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:10;

(a′) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:29, 30, and 31, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:15 binds to tau (SEQ ID NO:6);

(b′) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:32, 33, and 34, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:13 binds to tau (SEQ ID NO:6);

(c′) a polynucleotide or polynucleotides encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:29, 30, and 31, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:32, 33, and 34, respectively;

(d′) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:13, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:15 binds to tau (SEQ ID NO:6);

(e′) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:15, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:13 binds to tau (SEQ ID NO:6);

(f′) a polynucleotide or polynucleotides encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:13 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:15;

(g′) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:12;

(h′) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:14;

(a″) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:35, 36, and 37, respectively, wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:19 binds to tau (SEQ ID NO:6);

(b″) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:38, 39, and 40, respectively, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:17 binds to tau (SEQ ID NO:6);

(c″) a polynucleotide or polynucleotides encoding (i) an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:35, 36, and 37, respectively; and (ii) an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:38, 39, and 40, respectively;

(d″) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:17, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:19 binds to tau (SEQ ID NO:6);

(e″) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:19, wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:17 binds to tau (SEQ ID NO:6);

(f″) a polynucleotide or polynucleotides encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:17 and an immunoglobulin light chain or a fragment thereof comprising a VL comprising the amino acid sequence set forth in SEQ ID NO:19;

(g″) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:16; and

(h″) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:18.

16. The polynucleotide or polynucleotides of claim 15 , wherein the heterologous nucleic acid is a regulatory element.

17. The polynucleotide or polynucleotides of claim 16 , wherein the regulatory element is a promoter, an enhancer, a ribosome binding site, or a transcription terminator.

18. The polynucleotide or polynucleotides of claim 15 , wherein the heterologous nucleic acid is a secretory signal peptide.

19. The polynucleotide or polynucleotides of claim 18 , wherein the secretory signal peptide is a mammalian signal peptide.

20. The polynucleotide or polynucleotides of claim 19 , wherein the mammalian signal peptide is from tissue plasminogen activator.

21. A vector or vectors comprising a polynucleotide or polynucleotides selected from the group consisting of:

(g) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:8;

(h) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO: 10;

(g′) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:12;

(h′) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:14;

(g″) a polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:16; and

(h″) a polynucleotide encoding an immunoglobulin light chain or a fragment thereof, comprising the nucleic acid sequence set forth in SEQ ID NO:18.

22. A host cell comprising the vector or vectors of claim 21 .

23. A polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively, wherein the VH does not comprise an asparagine at Kabat numbering position 30, and wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:11 binds to tau (SEQ ID NO:6).

24. A vector comprising the polynucleotide of claim 23 .

25. A host cell comprising the polynucleotide of claim 23 .

26. A polynucleotide encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:9, with the exception that the VH does not comprise an asparagine at Kabat numbering position 30, and wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:11 binds to tau (SEQ ID NO:6).

27. A vector comprising the polynucleotide of claim 26 .

28. A host cell comprising the polynucleotide of claim 26 .

29. A polynucleotide that encodes encoding an immunoglobulin heavy chain or a fragment thereof comprising a VH comprising the amino acid sequence set forth in SEQ ID NO:93, wherein the VH when paired with a VL comprising the amino acid sequence set forth in SEQ ID NO:11 binds to tau (SEQ ID NO:6).

30. A polynucleotide or polynucleotides encoding an anti-tau antibody or a tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein:

(a) the VH comprises a heavy chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:29, 30, and 31, respectively;

(b) the VL comprises a light chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:32, 33, and 34, respectively; and

31. A vector comprising the polynucleotide or polynucleotides of claim 30 .

32. A host cell comprising the polynucleotide or polynucleotides of claim 30 .

33. A method for preparing an anti-tau antibody or tau-binding fragment thereof, the method comprising:

(a) culturing the host cell of claim 32 ; and

(b) isolating the anti-tau antibody or tau-binding fragment thereof from the culture.

34. A polynucleotide or polynucleotides encoding an anti-tau antibody or a tau-binding fragment thereof, wherein the anti-tau antibody or tau-binding fragment comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein

(a) the VH comprises a heavy chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:35, 36, and 37, respectively;

(b) the VL comprises a light chain CDR1, CDR2, and CDR3 with the amino acid sequences set forth in SEQ ID NO:38, 39, and 40, respectively; and

35. A vector comprising the polynucleotide or polynucleotides of claim 34 .

36. A host cell comprising the polynucleotide or polynucleotides of claim 34 .

37. A method for preparing an anti-tau antibody or tau-binding fragment thereof, the method comprising:

(a) culturing the host cell of claim 36 ; and

(b) isolating the anti-tau antibody or tau-binding fragment thereof from the culture.

38. A cDNA comprising a polynucleotide encoding a polypeptide comprising:

an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively, and wherein the VH when paired with a light chain variable region (VL) comprising the amino acid sequence set forth in SEQ ID NO:11 binds to tau; or

an immunoglobulin light chain or a fragment thereof comprising a VL comprising CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:26, 27, and 28, respectively, and wherein the VL when paired with a VH comprising the amino acid sequence set forth in SEQ ID NO:9 binds to tau.

39. The cDNA of claim 38 , wherein the polypeptide comprises:

an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:9;

an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:93; or

an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:11.

40. An expression vector comprising a heterologous promoter operably linked to a polynucleotide encoding a polypeptide comprising:

41. The expression vector of claim 40 , wherein the polypeptide comprises:

an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:9;

an immunoglobulin heavy chain or fragment thereof comprising a VH with the amino acid sequence set forth in SEQ ID NO:93; or

an immunoglobulin light chain or fragment thereof comprising a VL with the amino acid sequence set forth in SEQ ID NO:11.

42. An expression vector comprising:

a first polynucleotide encoding a first polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively; and

a second polynucleotide encoding a second polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:26, 27, and 28, respectively,

wherein the immunoglobulin heavy chain or fragment thereof when paired with the immunoglobulin light chain or fragment thereof forms an anti-human tau antibody or human tau-binding fragment thereof, and

wherein the expression vector is a plasmid, phage, or virus.

43. The expression vector of claim 42 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:9; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

44. The expression vector of claim 42 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:93; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

45. A host cell comprising:

a first expression vector comprising a first heterologous promoter operably linked to a first polynucleotide encoding a first polypeptide comprising an immunoglobulin heavy chain or a fragment thereof comprising a heavy chain variable region (VH) comprising VH complementarity determining regions (CDRs) 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:23, 24, and 25, respectively; and

a second expression vector comprising a second heterologous promoter operably linked to a second polynucleotide encoding a second polypeptide comprising an immunoglobulin light chain or a fragment thereof comprising a light chain variable region (VL) comprising VL CDRs 1, 2, and 3 with the amino acid sequences set forth in SEQ ID NOs:26, 27, and 28, respectively,

wherein the immunoglobulin heavy chain or fragment thereof when paired with the immunoglobulin light chain or fragment thereof forms an anti-human tau antibody or human tau-binding fragment thereof.

46. The host cell of claim 45 , wherein the first heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter and the second heterologous promoter is a cytomegalovirus, simian virus 40, or retroviral promoter.

47. The host cell of claim 45 , wherein the first expression vector is a plasmid, phage, or virus and the second expression vector is a plasmid, phage, or virus.

48. The host cell of claim 45 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:9; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

49. The host cell of claim 45 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:93; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

50. The host cell of claim 49 , wherein the first polypeptide comprises a human IgG1 heavy chain constant region and the second polypeptide comprises a human lambda light chain constant region.

51. The host cell of claim 45 , wherein the host cell is a mammalian host cell.

52. The host cell of claim 45 , wherein the host cell is a Chinese Hamster Ovary (CHO) cell, a HEK 293 cell, or a NSO cell.

53. A host cell comprising an expression vector comprising:

wherein the expression vector is a plasmid, phage, or virus.

54. The host cell of claim 53 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:9; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

55. The host cell of claim 53 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:93; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

56. The host cell of claim 55 , wherein the first polypeptide comprises a human IgG1 heavy chain constant region and the second polypeptide comprises a human lambda light chain constant region.

57. The host cell of claim 53 , wherein the host cell is a mammalian host cell.

58. The host cell of claim 53 , wherein the host cell is a Chinese Hamster Ovary (CHO) cell, a HEK 293 cell, or a NSO cell.

59. A method for preparing an anti-human tau antibody or human tau-binding fragment thereof, the method comprising:

culturing the host cell of claim 45 in a cell culture; and

isolating the anti-human tau antibody or human tau-binding fragment thereof from the cell culture.

60. The method of claim 59 , further comprising formulating the anti-human tau antibody or human tau-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject.

61. The method of claim 60 , wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration.

62. The method of claim 59 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:9; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

63. The method of claim 59 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:93; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

64. The method of claim 63 , wherein the first polypeptide comprises a human IgG1 heavy chain constant region and the second polypeptide comprises a human lambda light chain constant region.

65. A method for preparing an anti-human tau antibody or human tau-binding fragment thereof, the method comprising:

culturing the host cell of claim 53 in a cell culture; and

isolating the anti-human tau antibody or human tau-binding fragment thereof from the cell culture.

66. The method of claim 65 , further comprising formulating the anti-human tau antibody or human tau-binding fragment thereof into a sterile pharmaceutical composition suitable for administration to a human subject.

67. The method of claim 66 , wherein the pharmaceutical composition is suitable for intravenous or subcutaneous administration.

68. The method of claim 65 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:9; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

69. The method of claim 65 , wherein:

the VH consists of the amino acid sequence set forth in SEQ ID NO:93; and

the VL consists of the amino acid sequence set forth in SEQ ID NO:11.

70. The method of claim 69 , wherein the first polypeptide comprises a human IgG1 heavy chain constant region and the second polypeptide comprises a human lambda light chain constant region.

Assignments (4)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 13, 2016

From: CHEN, FENG; GRIMM, JAN; BAERISWYL, JEAN-LUC

To: PANIMA PHARMACEUTICALS AG

Reel/Frame 038271/0112 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 13, 2016

From: NITSCH, ROGER; HOCK, CHRISTOPH

To: UNIVERSITY OF ZÜRICH

Reel/Frame 038271/0236 →

CHANGE OF NAME Recorded Apr 13, 2016

From: PANIMA PHARMACEUTICALS AG

To: BIOGEN IDEC INTERNATIONAL NEUROSCIENCE GMBH