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Thomas J. Schall et al. 
Application No.: 09/919,224 
Page 9 



PATENT 



REMARKS 



I. 



Status of the Claims 



Claims 1-49 are currently pending. Upon entry of this amendment, claims 21-38 



and 44-49 are elected for further prosecution. Claims 21-28, 31-36, 38 and 44-49 are amended 
without prejudice or disclaimer. These claims are not amended for reasons of patentability. 
Instead, the claims are amended to conform the claims to the elected subject matter, i.e., methods 
involving administration of rhesus CMV IL-10 instead of human CMV IL-10. Claims are also 
amended to correct typographical errors and for increased clarity and consistency in term usage. 
Also upon entry of this amendment, new claims 50-61 are introduced. 



The amended and new claims find support throughout the specification including, 



for example, at page 9, paragraph 46, and page 24, paragraph 129 to page 26, paragraph 134. 
Claims 54-55 and 60-61 are also supported at page 15, paragraph 72. 

If the Examiner believes a telephone conference would expedite 
prosecution of this application, please telephone the undersigned at 303-571-4000. 



TOWNSEND and TOWNS END and CREW LLP 

Two Embarcadero Center, 8 th Floor 

San Francisco, California 941 1 1-3834 

Tel: 303-571-4000 

Fax:415-576-0300 

SLA:bhr 

DE 7093605 v1 




Scott L. Ausenhus 
Reg. No. 42,271 



Thomas J. Schall et al. 
Application No.: 09/919,224 
Page 10 



PATENT 



VERSION WITH MARKINGS TO SHOW CHANGES MADE 

The title has been replaced as follows: 

IMMUNOLOGIC ACTIVITIES 
OF RHESUS CYTOMEGALOVIRUS ENCODED IL-10 
AND HUMAN CYTOMEGALOVIRUS ENCODED IL 10 

IN THE SPECIFICATION: 

Paragraph 48 has been amended as follows: 

As used herein, "rhesus cytomegalovirus interleukin 10" or "rhesus CMV IL-10" 
is defined as a protein which has an amino acid sequence having substantial identity to a known 
sequence of rhesus CMV IL-10 as described in Lockridge et al, Virology (2000) 268:272-280, 
which is incorporated herein by reference. For the purposes of this invention, some methods 
used use glycosylated {e.g., produced in eukaryotic cells such as yeast or CHO cells) rhesus 
CMV IL-10 and some methods used use unglycosylated {e.g., chemically synthesized or 
produced in prokaryotic cells, such as E. coli) rhesus CMV IL-10. 

Paragraph 49 has been amended as follows: 

As used herein, "human cytomegalovirus interleukin 10" or "human CMV IL-10" 
is defined as a protein which has an amino acid sequence having substantial identity to a known 
sequence of human CMV IL-10 as discussed in Kotenko et al, PNAS (2000) 97(4): 1695-1700, 
which is incorporated herein by reference. For the purposes of this invention, some methods 
used use glycosylated {e.g., produced in eukaryotic cells such as yeast or CHO cells) human 
CMV IL-10 and some methods used use unglycosylated {e.g., chemically synthesized or 
produced in prokaryotic cells such as E. coli) human CMV IL-10. 

Paragraph 67 has been amended as follows: 

Rhesus and human CMV IL-10 can be used in a number of in vitro or ex vivo 
methods. In some methods, cellular responses to these agents are analyzed to provide 



Thomas J. Schall et al. PATENT 
Application No.: 09/919,224 
Page 1 1 

information to optimize dosage regimes of these agents in vivo. In som e , methods some 
methods, rhesus and human CMV IL-10 are used as positive controls to screen other drugs for 
effects on lymphocyte proliferation. If the positive control inhibits proliferation of the 
lymphocytes, whereas a candidate drug does not in a parallel reaction, then it can be concluded 
that the test drug is ineffective. In other methods, rhesus and human CMV IL-10 are used as 
research reagents to inhibit proliferation of cells and thereby analyze underlying cellular 
processes associated with cellular physiology. In other methods, proliferating PBMCs are 
obtained from a patient with an immune disorder. The lymphocytes are treated with rhesus 
CMV IL-10 or human CMV IL-10 ex vivo and then returned to the patients. 



Paragraph 70 has been amended as follows: 

Immune disorders preventable or treatable by methods of the invention include^ 
but are not limited to A the following. 



Paragraph 82 has been amended as follows: 

Defects in the functioning of the cell-mediated immune response have been 
implicated in various c e ll m e diat e cell-mediated cytotoxicity immune diseases, such as graft 
v e rs e s host graft-versus-host disease. Cytotoxic T lymphocytes (CTLs) are generated by the 
activation of T cytotoxic (T c ) cells. CTLs have lytic capability and are critical in the recognition 
and elimination of altered self-cells (e.g., virus-infected cells and tumors). Cytotoxic T 
lymphocytes (CTLs) are generally CD8 + are therefore class I MHC restricted. Since virtually all 
nucleated mammalian cells express class I MHC molecules, CTLs can recognize and eliminate 
almost any altered mammalian cell. This ability of CTLs to recognize and eliminate almost any 
altered mammalian cell can result in cell-mediated cytotoxicity related immune diseases. 
Consequently, a decrease in cell surface expression of class I MHC molecules is expected to 
ameliorate or prevent cell-mediated cytotoxicity related diseases. Thus, decreasing cell surface 
expression of class I MHC molecules in a patient suffering from a cell-mediated cytotoxicity 
immune disease by administering an effective dosage of rhesus CMV IL-10 or human CMV IL- 
10 would be beneficial. 



Thomas J. Schall et al. 
Application No.: 09/919,224 
Page 12 



PATENT 



Paragraphs 83 and 84 have been amended as follows: 
1. Graft V e rs es Ho s t Graft-versus-Host Disease 

Graft v e rs e s - host Graft-versus-host disease (GVHD) occurs as a result of in vivo 
cell-mediated cytotoxicity. The disease develops when immunocompetent lymphocytes are 
introduced into an allogeneic recipient whose immune system is compromised. The grafted 
lymphocytes begin to attack the recipient and the recipients compromised state prevents an 
immune response against the graft. The grafted lymphocytes are carried to the spleen, where 
they begin to proliferate in response to the allogenetic MHC antigens of the recipient. This 
proliferation induces an influx of recipient cells to the spleen and results in splenomegaly. The 
intensity of GVHD can be quantitated by calculating the spleen index (SI). A spleen index of 1.3 
or greater is considered to be indicative of GVHD. Enlargement of the spleen is a result of 
proliferation of both CD4 + and CD8 4 * T-cell populations. 

Paragraph 94 has been amended as follows: 

DTH plays an important role in host defense against intracellular pathogens. A 
variety of pathogens and contact antibodies can induce a DTH response. The initial immune 
response is nonspecific and often results in significant damage to healthy tissue. Although 
healthy tissue can be damaged, the patient can successfully eliminate cells infected by 
intracellular pathogens. When this defense process is not entirely effective, the continued 
presence of the pathogen's antigens can provoke a chronic DTH reaction. The chronic DTH 
reaction is characterized by excessive numbers of macrophages and the continued release of lytic 
enzymes resulting in tissue destruction. Thus, the DTH response to an intracellular pathogen can 
cause such extensive tissue damage that the DTH response is a pathologic condition. The 
granulomatous skin lesion seen with Mycobacterium leprae and the lung cavitation seen with 
Mycobacterium tuberculosis infections are examples of such pathology resulting from a chronic 
DTH reaction. Chronic DTH responses can result in granulomatous disease. 

Paragraph 285 has been amended as follows: 



Thomas J. Schall et al. 
Application No.: 09/919,224 
Page 17 

PENDING CLAIMS 

1-20. Non-Elected. 

21 . (Once amended) A therapeutic or prophylactic method for treating an 
immune disorder, comprising: 

administering to a patient suffering from or susceptible to the immune disorder a 
pharmaceutically acceptable dose of rhesus CMV IL-10. 

22. (Once amended) The method of claim 21, wherein the rhesus CMV IL-10 
is a component of a pharmaceutical composition further comprising a pharmaceutically 
acceptable carrier, 

23. (Once amended) The method of claim 22, wherein the pharmaceutical 
composition is sterile, substantially isotonic and prepared under GMP conditions. 

24. (Once amended) The method of claim 21, wherein the immune disorder is 
selected from the group consisting of graft-versus-host disease, an autoimmune disease, an 
inflammatory response, a pathologic delayed type hypersensitivity response, endotoxin-induced 
toxic shock, granulomatis disease, psoriasis, uveitis, systemic lupus erythematous, multiple 
sclerosis and contact-dermatitis. 

25. (Once amended) The method of claim 50, further comprising monitoring 
proliferation of lymphocytes in the patient to detect a reduction in the level of lymphocyte 
proliferation responsive to the administering step. 

26. (Once amended) The method of claim 21, further comprising monitoring 
a symptom of the patient to detect amelioration of the symptom responsive to the administering 
step. 

27. (Once amended) The method of claim 21, wherein the patient is suffering 
from the disorder and the method is a therapeutic treatment method. 




PATENT 



Thomas J. Schall et al. PATENT 
Application No.: 09/919,224 
Page 18 

28. (Once amended) The method of claim 21, wherein the patient is 
susceptible to the disorder and the method is a prophylactic treatment method. 

29. The method of claim 28, wherein the patient is an organ transplant patient. 

30. The method of claim 29, wherein the organ is a kidney. 

3 1 . (Once amended) The method of claim 30, wherein IFN-a levels of the 
patient are detectably decreased responsive to the administering of rhesus CMV IL-10. 

32. (Once amended) The method of claim 21, wherein the immune disorder is 
a chronic inflammatory disease. 

33. (Once amended) The method of claim 32, wherein the chronic 
inflammatory disease is selected from the group consisting of rheumatoid arthritis, inflammatory 
bowel disease, Crohn's disease, ulcerative colitis, Graves* disease, Hashimoto's thyroiditis, 
systemic lupus erythematosus, multiple sclerosis, scleroderma, and insulin-dependent diabetes 
mellitus. 

34. (Once amended) The method of claim 21, wherein the immune disorder is 
an allergic response. 

35. (Once amended) The method of claim 34, wherein the immune disorder is 

asthma. 

36. (Once amended) The method of claim 21, wherein the patient is suffering 
from a type TH1 immune response to a transplanted graft. 

37. The method of claim 36, wherein the transplanted graft is an organ 
selected from the group consisting of cornea, lung, heart, liver, bone marrow, kidney, pancreas, 
blood, and skin. 



Thomas J. Schall et al PATENT 
Application No.: 09/919,224 
Page 19 

38. (Once amended) The method of claim 25, wherein the immune disorder is 

leukemia. 

39-43. Non-elected. 

44. (Once amended) A therapeutic or prophylactic method for treating an 
inflammatory response, comprising administering to a patient suffering from or susceptible to the 
inflammatory response a pharmaceutically acceptable dose of rhesus CMV IL-10. 

45. (Once amended) The method of claim 44, further comprising monitoring 
proliferation of leukocytes in the patient to detect a reduction in the level of leukocyte 
proliferation responsive to the administering step. 

46. (Once amended) The method of claim 44, further comprising monitoring 
a symptom of the patient to detect amelioration of the symptom responsive to the administering 
step. 

47. (Once amended) The method of claim 44, wherein the patient is suffering 
from the disorder and the method is a therapeutic method. 

48. (Once amended) The method of claim 44, wherein the inflammatory 
response is a chronic inflammatory disease. 

49. (Once amended) The method of claim 48, wherein the chronic 
inflammatory disease is selected from the group consisting of rheumatoid arthritis, Crohn's 
disease, ulcerative colitis, Graves' disease, Hashimoto's thyroiditis and insulin-dependent 
diabetes mellitus. 

50. (New) The method of claim 21, wherein the patient is a human. 



5 1 . (New) The method of claim 2 1 , wherein the pharmaceutically acceptable 
dose is administered as a single dose. 



Thomas J. Schall et al. 
Application No.: 09/919,224 
Page 20 




PATENT 



52. (New) The method of claim 21, wherein the pharmaceutically acceptable 
dose is administered as part of a multi-dose regime. 

53. (New) The method of claim 50, wherein rhesus CMV IL-10 is 
administered in an amount sufficient to inhibit proliferation of lymphocytes in the human patient. 

54. (New) The method of claim 50, wherein rhesus CMV IL-10 is 
administered in an amount sufficient to inhibit proliferation of peripheral blood mononuclear 
cells in the peripheral blood of the human patient. 

55. (New) The method of claim 50, wherein rhesus CMV IL-10 is 
administered in an amount sufficient to inhibit cytokine production in the human patient. 

56. (New) The method of claim 44, wherein the patient is susceptible to the 
inflammatory response and the method is a prophylactic treatment method. 

57. (New) The method of claim 44, wherein the patient is a human. 

58. (New) The method of claim 44, wherein the pharmaceutically acceptable 
dose is administered as a single dose. 

59. (New) The method of claim 44, wherein the pharmaceutically acceptable 
dose is administered as part of a multi-dose regime. 

60. (New) The method of claim 57, wherein rhesus CMV IL-10 is 
administered in an amount sufficient to inhibit proliferation of peripheral blood mononuclear 
cells in the peripheral blood of the human patient. 

61 . (New) The method of claim 57, wherein rhesus CMV IL-10 is 
administered in an amount sufficient to inhibit cytokine production in the human patient. 



DE 7093605 v1