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Appl. No. 09/919,224 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 



PATENT 



REMARKS/ARGUMENTS 

I. Status of the Claims 

Claims 1-61 are currently pending, with claims 1-20 and 39-43 withdrawn from 
consideration as directed to a non-elected invention. Upon entry of this amendment, the 
amended and canceled claims are canceled and amended without prejudice or disclaimer. 
Claims 1-20 and 39-43 are canceled solely because they are directed to non-elected subject 
matter. Applicants reserve the right to reintroduce the unamended or canceled claims in this or 
another application. Claims 21-38 and 44-61 are thus pending following entry of this 
amendment. 

II. Objections to the Specification 

The title has been amended to be more descriptive of the currently claimed 
invention as requested. 

III. Claim Rejections under 35 U.S.C. $112, Second Paragraph 

Claims 26 and 46 are said to be unclear because the specification does not define 
what symptom to monitor. In response, it is submitted that those of ordinary skill know what 
symptoms are associated with a particular immune disorder. Moreover, the specification lists 
exemplary symptoms for a number of different immune diseases. For example, the specification 
describes symptoms for the following disorders: 1) endotoxin-induced septic shock (see, e.g., 
paragraph 75); 2) endotoxin-induced toxic shock (see, e.g., paragraph 78 and 79); 3) cell- 
mediated cytotoxicity immune disorders (see, e.g., paragraph 82); 4) graft-versus host disease 
(see, e.g., paragraphs 84 and 86); 5) asthma (see, e.g., paragraph 91); 6) delayed-type 
hypersensitivity reactions (see, e.g., paragraphs 94 and 97); 7) chronic immune disorders (see, 
e.g., paragraph 99); 8) granulomatis disease (see, e.g., paragraph 102); 9) Crohn's disease (see, 
e.g., paragraph 110); 10) ulcerative colitis (see, e.g., paragraph 1 1 1), 1 1) Graved disease (see, 
e.g., paragraph 112); 12) Hashimoto's thyroiditis (see, e.g., paragraph 113); 13) systemic lupus 
erythematous (see, e.g., paragraph 114); 14) multiple sclerosis (see, e.g., paragraph 115); 15) 



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Appl. No. 09/919,224 PATENT 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 

scleroderma (see, e.g., paragraph 116); 16) diabetes (see, e.g., paragraph 117); 17) uveitis (see, 
e.g., paragraph 118); 18) hepatitis (see, e.g., paragraph 1 19); and 19) psoriasis (see, e.g., 
paragraph 120). 

These claims have also been amended to clarify that the symptom that is 
monitored is a symptom associated with the immune disorder that is being treated. This 
amendment is supported, for example, at paragraph 129. Claims 31 and 36 have been amended 
to address the antecedent basis concerns raised in the Office Action. 

These amendments simply clarify these claims and do not narrow the claims. 
Accordingly, these claims are entitled to the same scope of equivalents as the original claims. 

IV. Claim Rejections under 35 U.S.C. $112, Second Paragraph 

Claims 21-38, 44-61 are rejected under 35 U.S.C. §112, second paragraph 
because the specification is said not to enable one of ordinary skill in the art to practice the 
claimed invention without undue experimentation. The Office Action sets forth three major 
rationales to support this conclusion: 1) the specification only provides in vitro examples and 
not results from studies with animal model systems, thus the specification only enables claims to 
in vitro methods (see third paragraph on page 4 and first paragraph on page 5 of the Office 
Action); 2) the specification lacks adequate guidance on how to assess treatment efficacy (see, 
second paragraph of page 5 of the Office Action); and 3) for prophylactic treatment methods, the 
specification does not provide sufficient guidance on how to identify individuals at risk for an 
immune disorder (see, paragraph bridging pages 5 and 6 of the Office Action). Each of these 
issues will be addressed in turn. 

With respect to the first rationale, the Office appears to take the position that the 
enablement requirement with respect to the present claims cannot be satisfied unless the 
specification provides examples with animal models that are supportive of the claims. Such a 
standard, however, is inappropriate for assessing enablement of the current claims. 

The law is clear that in vivo examples are not required to enable treatment claims. 
Instead, in vitro examples are sufficient to constitute working examples, provided they 
reasonably "correlate" with the claimed method (see, e.g., MPEP 2164.02). An in vitro example 



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Appl. No. 09/919,224 PATENT 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 

"correlates" with the claimed method if one skilled in the art would accept the in vitro example 
as reasonably correlating with the disease that the treatment methods are claimed to treat (Id.). 

In evaluating whether there is a correlation, the law does NOT require a rigorous 
or an invariable exact correlation. The Federal Circuit has stated, for instance, that: 



[A] rigorous correlation is not necessary where the disclosure of 
pharmacological activity is reasonable based upon the probative 
evidence. (Cross v. Iizuka, 753 F.2d 1040, 1050, 224 USPQ 739, 
747 (Fed. Cir. 1985); see also MPEP 2164.02.) 



The Federal Circuit went on in the same case to conclude that often in vitro 
testing provides valuable predictive insight into the efficacy of in vivo results and that typically 
there is a reasonable correlation between the two, stating: 



[IJn vitro results with respect to the particular pharmacological 
activity are generally predictive of in vivo test results, i.e., there is 
a reasonable correlation therebetween. Were this not so, the 
testing procedures of the pharmaceutical industry would not be as 
they are. Iizuka has not urged, and rightly so, that there is an 
invariable exact correlation between in vitro test results and in vivo 
test results. Rather, Iizuka's position is that successful in vitro 
testing for a particular pharmacological activity establishes a 
significant probability that in vivo testing for this particular 
pharmacological activity will be successful. (Cross v. Iizuka, 753 
F.2d 1040, 224 USPQ 739 (Fed. Cir. 1985), emphasis added.) 



These statements from the Federal Circuit thus demonstrate two points: 1) that in 
vitro examples can be used as predictors of in vivo efficacy, and 2) that in vitro results need not 
establish an exact correlation between the proposed treatment and the disease being treated for 



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Appl. No. 09/919,224 PATENT 

Amdt. dated January 1 5, 2004 

Reply to Office Action of July 15, 2003 

the results to be predictive of in vivo utility. Instead, the results only need demonstrate a 
reasonable correlation. 

So the broad conclusion in the Office Action on page 4, third paragraph that 
fl [s]ince there is no animal model system in the specification to treat an immune disorder, ... it is 
unpredictable how to correlate test tube results with in vivo studies" is inconsistent with the 
foregoing statements from the Federal Circuit. As just noted, the court stated that in vitro results 
can, in fact, often be predictive of in vivo results. Moreover, although the Office Action appears 
to require an exact correlation between the claims and the experimental results, the court makes 
clear that this is not a requirement. 

In view of the foregoing statements, the enablement inquiry thus does not depend 
solely on whether the specification provides in vivo examples as the Office Action appears to 
imply. Rather the correct inquiry is whether one of ordinary skill in the art could reasonably 
consider the in vitro examples that are presented in the specification to correlate with treatment 
of an immune disorder. It is submitted that the answer to this inquiry is "yes." 

The in vitro results correlate with the claimed methods because the numerous 
examples presented in the application demonstrate that treatment of various immune cells with 
rhesus CMV IL-10 resulted in a decrease in the concentration of molecules (e.g., various 
cytokines and Class I and Class II MHC proteins) known to be causative agents of immune 
disorders and resulted in an increase in the concentration of molecules (e.g., HLA-G) known to 
protect against immune disorders. 

The following chart summarizes the results of studies conducted with rhesus 
CMV IL-10 that specifically illustrate this correlation: 



Example 


Molecule 


Correlation between Molecule and Immune Disorder 


4 


IFN-7 


Paragraphs 88, 94, 97, 99 and 104 note that IFN-Yis a causative 
factor associated with hypersensitive immune disorders, delayed type 
hypersensitivity disorders and chronic immune disorders like chronic 
inflammation. Example 4 demonstrates that treatment of human 



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Appl.No. 09/919,224 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 



PATENT 







peripheral blood mononuclear cells (PBMCs) with rhesus CMV IL- 
10 inhibited IFN-y synthesis, indicating that treatment with rhesus 
CMV IL-10 would protect against these disorders. 


6 and 8 


TNF-a 


Paragraphs 74, 88, 99 and 104 indicate that TNF-ais involved in 
endotoxin-induced septic shock, hypersensitive immune disorders, 
chronic immune disorders and inflammatory disease. Examples 6 
and 8 demonstrate that treatment of human PBMCs and monocytes 
with rhesus CMV IL-10 inhibited TNF-a synthesis, indicating that 
treatment with rhesus CMV IL-10 would protect against these 
disorders. 


10 


GM-CSF 


Paragraphs 88 and 95 describe the involvement of GM-CSF in 
hypersensitive immune disorders, and pathogen-induced delayed type 
hypersensitivity reactions. Example 10 shows that treatment of 
human monocytes with rhesus CMV IL-10 inhibited GM-CSF, 
thereby indicating that treatment with rhesus CMV IL-10 would 
protect against these disorders. 


12 


IL-la 


Paragraph 74 discusses, for instance, the association between IL-la 
and endotoxin induced septic shock. Example 12 demonstrates that 
treatment of human monocytes with rhesus CMV IL-10 inhibited IL- 
la, indicating that treatment with rhesus CMV IL-10 would protect 
against this disorder. 


14 


IL-6 


Paragraph 88 notes that IL-6 is correlated with hypersensitive 
immune disorders, for example. Example 14 shows that treatment of 
human monocytes with rhesus CMV IL-10 inhibited the synthesis of 
IL-6, indicating that treatment with rhesus CMV IL-10 would protect 
against these disorders. 


15 and 16 


Classical 
Class I and 


These molecules are involved in eliciting immune activation (see, 
e.g., paragraph 28). Examples 14 and 15 illustrate that treatment of 



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Appl.No. 09/919,224 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 



PATENT 





II MHC 
Molecules 


human monocytes with rhesus CMV IL- 10 reduces the surface 
expression of these molecules, thus indicating that such a treatment 
would protect against immune disorders. 


17 


HLA-G, a 
Nonclassical 
Class I 
MHC 
Molecule 


Increased expression of this molecule is associated with decreased 
immune activation and hence a decreased risk of immune disorders. 
Example 17 shows that HLA-G surface expression on human 
monocytes was increased upon treatment with rhesus CMV IL-10, 
indicating that such a treatment protects against immune disorders. 



It is submitted that this extensive evidence more than satisfies the requirement 
that the examples provide sufficient information such that one of ordinary skill could reasonably 
conclude that a correlation exists between the claimed methods and the study results. The 
burden is on the Office to explain why these numerous examples do not correlate with the 
current claims (see MPEP 2164.02). 

With regard to the second concern expressed in the Office Action, Applicants 
disagree with the assertion that the specification provides insufficient teaching to enable one of 
ordinary skill to determine whether a treatment has been effective. Applicants disagree because, 
to reiterate a point made above, symptoms associated with various immune diseases are known 
in the art. Furthermore, the specification provides considerable detail on specific symptoms that 
are associated with a large number of diverse immune disorders (see sections of specification 
referred to above in Section III). One of skill would know that one option for monitoring the 
effectiveness of a treatment would be to monitor whether the treatment ameliorated one or more 
of the symptoms associated with the particular disease being treated. 

With respect to the third concern, Applicants also respectfully disagree that the 
claims are not enabled because they encompass prophylactic methods. The Office Action takes 
the position that one skilled in the art would not know how to identify appropriate individuals for 
prophylactic treatment nor know how to determine if the treatment had been effective. 

In response, it is submitted that those of ordinary skill in the art could readily 
identify individuals that could benefit from prophylactic treatment for a number of different 



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Appl. No. 09/919,224 PATENT 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 

immune disorders and ascertain the efficacy of the treatment based upon general knowledge in 
the art. For example, individuals susceptible to a number of immune disorders can be identified 
based upon upcoming events in the individual's life that put them at risk (e.g., a medical 
procedure), past events that put the individual at risk (known exposure to a pathogen which can 
induce an immune disorder in an infected individual), genetic susceptibility, clinical history and 
risk factors associated with life style. Monitoring the efficacy of treatment can also be 
straightforward in a number of treatments. For instance, by monitoring various symptoms 
known to be associated with the disorder (see Section III above). 



The following list summarizes examples of approaches that can be taken with a 
variety of different diseases. This list is only exemplary; similar approaches could be taken for a 
number of other disorders. 



Disease 


Identification 


Assessment of Efficacy 


Graft-versus- 
host disease 


A person that is about to undergo, or has 
recently undergone, a grafting procedure or 
is at risk for rejection. 


Determine using standard 
medical evaluation whether 
there is rejection of the graft 


Hepatitis 


A person that has cirrhosis of the liver or 
antibody positivity for hepatitis virus 


Monitor liver enzymes, 
assessment of jaundice, 
enlarged liver, bilirubin levels 


Endotoxic 
Shock/Sepsis 


An individual that has been exposed to 
hospital pathogens or that has a disseminated 
bacterial infection 


Blood interferon gamma 
levels, fever, cardiovascular 
distress, tachypnoea 


Delayed Type 
Hypersensitivity 
Reactions 


As indicated in the specification, these 
diseases can be caused by various microbial 
infections (see, e.g., paragraphs 94 and 95). 
Detection of such infections via standard 
medical means can be used as a screening 


Reduction in rash or swelling. 



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Appl.No. 09/919,224 

Amdt. dated January 15, 2004 

Reply to Office Action of July 15, 2003 



PATENT 



method. Administration of CMV IL-10 to an 
infected person is still a prophylactic 
treatment because the onset of the disease is 
delayed. Treatment may also be indicated in 
cases of contact induced DTH eg poison 
ivy/oak, turpentine etc. 



So for all the foregoing reasons, it is submitted that the pending claims are 
enabled and that this rejection should be withdrawn. 



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



Respectfully submitted, 




L. Ausenhus 
Reg. No. 42,271 



TOWNSEND and TOWNSEND 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:tnd 

60119378 v1 



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