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% United States Patent and Trademark Office 



UNITED STATES DEPARTMENT OF COMMERCE 
United States Patent and Trademark Office 
Address: COMMISSIONER FOR PATENTS 
P.O. Box 1450' 

Alexandria, Virginia 22313-1450 
www.uspto.goy 



APPLICATION NO. 


FILING DATE 


FIRST NAMED INVENTOR 


ATTORNEY DOCKET NO. 


CONFIRMATION NO. 


09/864,621 


05/23/2001 


H. Ralph Snodgrass 


4414720Q0110 


3487 



25226 7590 , 12/24/2003 

MORRISON & FOERSTER LLP 

755 PAGE MILL RD 

PALO ALTO, CA 94304-1018 



V- V 1 



EXAMINER 



CHEN, SHIN LIN 



ART UNIT 



PAPER NUMBER 



'.. ' 1632 
DATE MAILED: 12/24/2003 



Please find below and/or attached an Office communication concerning this application or proceeding. 



PTO-90C (Rev. 10/03) 



Office Action Summary 



Application No. 

09/864,621 



Examiner 

Shin-Lin Chen 



Applicant(s) 

SNODGRASS, H. RALPH 



Art Unit 

1632 



« The MAILING DATE of this communication appears on the cover sheet with the correspondence address 
Period for Reply 

A SHORTENED STATUTORY PERIOD FOR REPLY IS SET TO EXPIRE 3 MONTH(S) FROM 
THE MAILING DATE OF THIS COMMUNICATION. 

- Extensions of time may be available under the provisions of 37 CFR 1 .136(a). In no event, however, may a reply be timely filed 
after SIX (6) MONTHS from the mailing date of this communication. 

- If the period for reply specified above is less than thirty (30) days, a reply within the statutory minimum of thirty (30) days will be considered timely. 

- If NO period for reply is specified above, the maximum statutory period will apply and will expire SIX (6) MONTHS from the mailing date of this communication. 

- Failure to reply within the set or extended period for reply will, by statute, cause the application to become ABANDONED (35 U.S.C. § 133). 

- Any reply received by the Office later than three months after the mailing date of this communication, even if timely filed, may reduce any 
earned patent term adjustment. See 37 CFR 1.704(b). 

Status 

1 )S Responsive to communication(s) filed on 29 July 2003 . 
2a)D This action is FINAL. 2b)K This action is non-final. 

3) D Since this application is in condition for allowance except for formal matters, prosecution as to the merits is 

closed in accordance with the practice under Ex parte Quay/e, 1935 CD. 1 1 , 453 O.G. 213. 

Disposition of Claims 

4) ^ Claim(s) 1-28 is/are pending in the application. 

4a) Of the above claim(s) 12-28 is/are withdrawn from consideration. 

5) D Claim(s) is/are allowed. 

6) I3 Claim(s) 1-11 is/are rejected. 

7) D Claim(s) is/are objected to. 

8) D Claim(s) are subject to restriction and/or election requirement. 

Application Papers 

9) D The specification is objected to by the Examiner. 

10) D The drawing(s) filed on is/are: a)D accepted or b)D objected to by the Examiner. 

Applicant may not request that any objection to the drawing(s) be held in abeyance. See 37 CFR 1 .85(a). 
Replacement drawing sheet(s) including the correction is required if the drawing(s) is objected to. See 37 CFR 1.121(d). 

1 1) D The oath or declaration is objected to by the Examiner. Note the attached Office Action or form PTO-152. 
Priority under 35 U.S.C. §§119 and 120 

12) D Acknowledgment is made of a claim for foreign priority under 35 U.S.C. § 1 19(a)-(d) or (f). 

a)D All b)Q Some * c)D None of: 

1 .□ Certified copies of the priority documents have been received. 
2.D Certified copies of the priority documents have been received in Application No. 



3.Q Copies of the certified copies of the priority documents have been received in this National Stage 
application from the International Bureau (PCT Rule 17.2(a)). 
* See the attached detailed Office action for a list of the certified copies not received. 

13) ^3 Acknowledgment is made of a claim for domestic priority under 35 U.S.C. § 1 19(e) (to a provisional application) 

since a specific reference was included in the first sentence of the specification or in an Application Data Sheet. 
37 CFR 1.78. 

a) D The translation of the foreign language provisional application has been received. 

14) ^ Acknowledgment is made of a claim for domestic priority under 35 U.S.C. §§ 120 and/or 121 since a specific 

reference was included in the first sentence of the specification or in an Application Data Sheet. 37 CFR 1 .78. 

Attachment(s) 

1 ) ^ Notice of References Cited (PTO-892) 4) □ Interview Summary (PTO-41 3) Paper No(s). 



2) □ Notice of Draftsperson's Patent Drawing Review (PTO-948) 5) □ Notice of Informal Patent Application (PTO-152) 

3) ^ Information Disclosure Statement(s) (PTO-1449) Paper No(s) 3,_4 . 6) □ Other: 



U.S. Patent and Trademark Office 
PTOL-326 (Rev. 11-03) 



Office Action Summary 



Part of Paper No. 20031218 





Application/Control Number: 09/864,621 
Art Unit: 1632 



Page 2 



DETAILED ACTION 



1. Applicant's election without traverse of group I, claims 1-1 1, in Paper No, 12 is 
acknowledged. 

2. Claims 12-28 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as 
being drawn to a nonelected invention, there being no allowable generic or linking claim. 
Election was made without traverse in Paper No. 12. 

3. Applicant's preliminary amendment filed 7-31-02 has been entered. Claims 1-28 are 
pending and claims 1-11 are under consideration. Applicant also elected the following species 
for examination: (a) gene expression, (b) troglitazone and erythromycin, (c) hepatic toxins. 

It should be noted that examiner for the present application has been changed. Any 
inquiry concerning this communication or earlier communications from the examiner should be 
directed to Shin-Lin Chen. 



4. The following is a quotation of the first paragraph of 35 U.S.C. 112: 

The specification shall contain a written description of the invention, and of the manner and process of making 
and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it 
pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode 
contemplated by the inventor of carrying out his invention. 

5. Claims 1-1 1 are rejected under 35 U.S.C. 112, first paragraph, as failing to comply with 
the written description requirement. The claim(s) contains subject matter which was not 
described in the specification in such a way as to reasonably convey to one skilled in the relevant 
art that the inventor(s), at the time the application was filed, had possession of the claimed 



Claim Rejections - 35 USC § 112 



invention. 



Application/Control Number: 09/864,621 Page 3 

Art Unit: 1632 

Claims 1-11 read on a library of molecular profiles of chemical compositions having 
predetermined toxicities by contacting an isolated mammalian embryoid body with the chemical 
compositions, recording alterations in gene expression or protein expression in said mammalian 
embryoid body and compiling a library of molecular profiles for at least two chemical 
compositions. 

The chemical compositions encompass therapeutic agents, neurotoxins, renal toxins, 
hepatic toxins, toxins of hematopoietic cells, myotoxins, agents that are toxic to cells of 
reproductive organs, teratogenic agents, carcinogens, agricultural chemicals, cosmetics, and 
environmental contaminants. The specification only discloses the protein expression profiles of 
mouse embryoid body treated with troglitazone or erythromycin compared to the control having 
no treatment of troglitazone or erythromycin. The chemical compositions set forth above include 
numerous different chemical compounds having different chemical structures, physical 
properties, and biological functions. They don't have common chemical structures, chemical 
activities, and biological functions. Common structural feature of the chemical compositions 
that would have a certain effect on the gene expression or protein expression pattern in a 
mammalian embryoid body has not been disclosed in the present invention. Further, different 
embryoid bodies derived from various mammal, such as humans, mice, rats, pigs, sheep, cows, 
whales, primates, dogs etc., would differ from each other physiologically, and their response to 
same chemical composition, not to mention different chemical compositions, could vary. 
Therefore, the alterations in gene expression or protein expression in various mammalian 
embryoid bodies responding to numerous different chemical compositions would not be 
predictable at the time of the invention. One skilled in the art at the time of the invention would 



Application/Control Number: 09/864,62 1 Page 4 

Art Unit: 1632 

not be able to anticipate the gene expression or protein expression pattern in the mammalian 
embryoid body treated with various chemical compositions other than the disclosed protein 
expression pattern of mouse embryoid body treated with either troglitazone or erythromycin. 
The general knowledge and level of skill in the art do not supplement the omitted description 
because specific, not general, guidance is what is needed. 

The limited information disclosed in the present invention is not sufficient to reasonably 
convey to one skilled in the art that applicants were in possession of the claimed libraries of 
molecular profiles of numerous different chemical compositions. Thus, it is concluded that the 
written description requirement is not satisfied for the libraries of molecular profiles of numerous 
different chemical compositions as claimed. 

6. Claims 1-1 1 are rejected under 35 U.S.C. 112, first paragraph, because the specification, 
while being enabling for the library of protein expression profile of troglitazone and 
erythromycin in the mouse embryoid body, does not reasonably provide enablement for libraries 
of molecular profiles of numerous different chemical compositions in various mammalian 
embryoid bodies. The specification does not enable any person skilled in the art to which it 
pertains, or with which it is most nearly connected, to make and/or use the invention 
commensurate in scope with these claims. 

Claims 1-11 read on a library of molecular profiles of chemical compositions having 
predetermined toxicities by contacting an isolated mammalian embryoid body with the chemical 
compositions, recording alterations in gene expression or protein expression in said mammalian 
embryoid body and compiling a library of molecular profiles for at least two chemical 



Application/Control Number: 09/864,621 Page 5 

Art Unit: 1632 

compositions. Claim 2 specifies the embryoid body is of human. Claims 6 and 7 specify the 
embryoid body is of non-human mammals, such as rodents. Claims 3-5 and 8-10 specify the 
chemical compositions are therapeutic agents, neurotoxins, renal toxins, hepatic toxins, 
teratogenic agents, carcinogens, agricultural chemicals, cosmetics, environmental contaminants 
etc. 

As discussed above, the chemical compositions encompass therapeutic agents, 
neurotoxins, renal toxins, hepatic toxins, toxins of hematopoietic cells, myo toxins, agents that 
are toxic to cells of reproductive organs, teratogenic agents, carcinogens, agricultural chemicals, 
cosmetics, and environmental contaminants. The specification only discloses the protein 
expression profiles of mouse embryoid body treated with troglitazone or erythromycin compared 
to the control having no treatment of troglitazone or erythromycin. The chemical compositions 
set forth above include numerous different chemical compounds having different chemical 
structures, physical properties, and biological functions. Further, different embryoid bodies 
derived from various mammal, such as humans, mice, rats, pigs, sheep, cows, whales, primates, 
dogs etc., would differ from each other physiologically, and their response to same chemical 
composition, not to mention different chemical compositions, could vary. Therefore, the 
alterations in gene expression or protein expression in various mammalian embryoid bodies 
responding to numerous different chemical compositions would not be predictable at the time of 
the invention. One skilled in the art at the time of the invention would not be able to anticipate 
the gene expression or protein expression pattern in the mammalian embryoid body treated with 
various chemical compositions other than the disclosed protein expression pattern of mouse 
embryoid body treated with either troglitazone or erythromycin. Applicants were not in 



Application/Control Number: 09/864,621 Page 6 

Art Unit: 1632 

possession of the claimed libraries of molecular profiles of numerous different chemical 
compositions. Thus, the present invention does not enable the use of the broadly claimed 
libraries of molecular profiles of numerous different chemical compositions. 



Claim Rejections - 35 USC § 103 

7. The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all 
obviousness rejections set forth in this Office action: 

(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in 
section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are 
such that the subject matter as a whole would have been obvious at the time the invention was made to a person 
having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the 
manner in which the invention was made. 

8. Claims 1-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over Spielmann et 
al., 1997 (In Vitro Toxicology, Vol. 10, No. 1, p. 1 19-127) in view of Craig et al., 1996 
(Biomarkers, Vol. 1, No. 2, p. 123-135) and Wobus et al, 1999 (US Patent 6,007,993). 

Claims 1-11 read on a library of molecular profiles of chemical compositions having 
predetermined toxicities by contacting an isolated mammalian embryoid body with the chemical 
compositions, recording alterations in gene expression or protein expression in said mammalian 
embryoid body and compiling a library of molecular profiles for at least two chemical 
compositions. Claim 2 specifies the embryoid body is of human. Claims 6 and 7 specify the 
embryoid body is of non-human mammals, such as rodents. Claims 3-5 and 8-10 specify the 
chemical compositions are therapeutic agents, neurotoxins, renal toxins, hepatic toxins, 
teratogenic agents, carcinogens, agricultural chemicals, cosmetics, environmental contaminants 
etc. 



Application/Control Number: 09/864,62 1 Page 7 

Art Unit: 1632 

Spielmann teaches a method of using mouse embryonic stem cells in vitro for 
embryotoxicity testing comprising culturing the embryonic stem cells to a stage where the cells 
form embryoid bodies, contacting the bodies with a variety of chemical compositions, and 
determining the cytotoxicity of the chemical compositions by MTT cytotoxicity assay. 
Spielmann uses 16 test chemicals which are assigned to three classes of in vivo embryotoxicity 
and compiles libraries of the "molecular profiles" of the test chemicals and ranks the chemical 
compositions with respect to their relative toxicities (e.g. abstract, p. 120, 121, Figure 1, Table 
!)■ 

Spielmann does not teach creating the molecular profiles of gene expression or protein 
expression. 

Craig teaches using embryos of the topminnow, Fundulus heteroclitus, for reproductive 
toxicity screening by exposing the embryos to teratogenic concentrations of sodium valproate 
(VP A) or arsenic acid (arsenate) and evaluating the frequency and types of induced 
malformations. Craig correlates the teratogenic outcomes to specific alterations in the 
expression of a panel of developmentally regulated genes and the genetic expression profiles 
revealed a number of genes whose expression levels were significantly altered by exposure to the 
test compounds (e.g. abstract). Craig also teaches generating cDNA from mRNA and using P- 
labeled probes for the detection of gene expression in establishing gene expression profiles (e.g. 
p. 125, left column). 

Wobus teaches an in vitro test procedure for detecting chemically-induced 
embryotoxic/teratogenic effects based on differentiated pluripotent embryonic stem cells or 
embryonic germ cells obtained from primordial germ cells of the mouse or rat. A differentiation- 



Application/Control Number: 09/864,621 Page 8 

Art Unit: 1632 

dependent expression of tissue-specific genes of embryonic stem cell clones or embryonic germ 
cell clones is furnished in the presence of teratogenic substances. The substances act at specific 
times of the in vitro differentiation and subsequent differentiation. A chemically-induced 
activation, repression or modulation of the tissue-specific genes which influence embryonic 
development is detected (e.g. column 2, lines 53-67). The cell clones contain reporter gene 
constructs which can be specifically activated, repressed or modulated in the course of the 
differentiation by exogenic test substances, such as retinoic acid, and the differentiation- 
dependent expression during the test procedure can be carried out by embryoid body 
differentiation in different lines (e.g. column 3, lines 1-23). The reporter gene can be LacZ or 
the luciferase gene and detection can be by a simple staining reaction (e.g. column 3, lines 53- 
63). Promoters of the reporter gene constructs can be neuronal, cardiogenic, muscle and skeletal 
specific to monitor development (e.g. column 4, lines 2-14) in the presence of the exogenic test 
substance. Wobus teaches recording alterations in gene expression by monitoring protein 
expression after contacting an embryoid body with a chemical composition, and the change in 
expression is detected by a colorimetric label, e.g. X-Gal staining (e.g. column 4, 7). 

It would have been obvious for one of ordinary skill at the time of the invention to 
substitute the MTT cytotoxicity assay as taught by Spielmann with detection of gene expression 
as taught by Craig or detection of protein expression as taught by Wobus to establish molecular 
profiles of different chemical compositions by treating a mammalian embryoid body with said 
chemical compositions because both Craig and Wobus teach testing the effect of teratogenic 
agents on embryoid body by determining the resulting gene expression pattern and it was known 




Application/Control Number: 09/864,62 1 Page 9 

Art Unit: 1632 

in the art to determine the effect of a chemical compound by detecting the alteration of gene 
expression or alteration of protein expression. 

One ordinary skill in the art at the time the invention was made would have been 
motivated to do so in order to generate a gene expression profile or protein expression profile of 
a teratogenic agent by using embryos or embryoid bodies as compared to a control having no 
treatment of said teratogenic agent as taught by Craig and Wobus, respectively, or to generate a 
library of gene expression or protein expression profiles of a test composition for typing or 
ranking toxicity of said test composition by using embryos or embryoid bodies according to the 
collective teachings of Spielmann, Craig, and Wobus with reasonable expectation of success. 

9. Claims 1-11 are rejected under 35 U.S.C. 103(a) as being unpatentable over Serbedzija et 
al., 2001 (US Patent 6,299,858) in view of Spielmann et al., 1997 (In Vitro Toxicology, Vol. 10, 
No. l,p. 119-127). 

Claims 1-11 read on a library of molecular profiles of chemical compositions having 
predetermined toxicities by contacting an isolated mammalian embryoid body with the chemical 
compositions, recording alterations in gene expression or protein expression in said mammalian 
embryoid body and compiling a library of molecular profiles for at least two chemical 
compositions. Claim 2 specifies the embryoid body is of human. Claims 6 and 7 specify the 
embryoid body is of non-human mammals, such as rodents. Claims 3-5 and 8-10 specify the 
chemical compositions are therapeutic agents, neurotoxins, renal toxins, hepatic toxins, 
teratogenic agents, carcinogens, agricultural chemicals, cosmetics, environmental contaminants 
etc. 



Application/Control Number: 09/864,62 1 Page 1 0 

Art Unit: 1632 

Serbedzija teaches exposing zebrafish embryos in test compounds at different 
concentrations, such as aspirin and dexamethasone, to determine the toxic effect of those test 
compounds on zebrafish embryos (e.g. column 53, 56). A wide range of test compounds can be 
used for screening toxic activity, including chemical compounds, pharmaceuticals, therapeutics, 
environmental and agricultural agents, industrial agents, pollutants, cosmeceuticals, synthetic or 
natural compounds, drugs, organic compounds, lipids, glucocorticoids, peptides, antibiotics, 
chimeric molecules, sugars, carbohydrates etc. (e.g. column 51, lines 27-42). A response 
indicating toxic activity can be detected as a change in gene expression profile via subtractive 
library experiments using PCR-select cDNA Subtraction System. A response indicating toxic 
activity also can be detected as a change in a protein expression profile using two-dimensional 
polyacrylamide gel electrophoresis or combination of other techniques, such as in situ 
hybridization, antibody staining of specific proteins, colorimetry, fluorescence microscopy, light 
microscopy etc. (e.g. column 51, 52). Serbedzija also teaches using cDNA microarray 
technologyto profile combinations of gene expression in drug toxicity response and molecular 
activation phenomena and automation of the screening with standard instrumentation and 
computer software program to screen hundreds of chemical compounds (e.g. column 59). 

Serbedzija does not specifically teach using embryoid body for creating library of 
molecular profiles of chemical compositions. 

Spielmann teaches a method of using mouse embryonic stem cells in vitro for 
embryotoxicity testing comprising culturing the embryonic stem cells to a stage where the cells 
form embryoid bodies, contacting the bodies with a variety of chemical compositions, and 
determining the cytotoxicity of the chemical compositions by MTT cytotoxicity assay. 



Application/Control Number: 09/864,62 1 Page 1 1 

Art Unit: 1632 

Spielmann uses 16 test chemicals which are assigned to three classes of in vivo embryotoxicity 
and compiles libraries of the "molecular profiles" of the test chemicals and ranks the chemical 
compositions with respect to their relative toxicities (e.g. abstract, p. 120, 121, Figure 1, Table 
1). 

It would have been obvious for one of ordinary skill in the art at the time of the invention 
to use the embryoid body as taught by Spielmann to test the cytotoxicity of the chemical 
composition on said embryoid body by using testing methods as described in Serbedzija to 
determine the alteration of gene expression or protein expression in said embryoid body because 
both Serbedzija and Spielmann teach method of detecting the toxic effect of chemical 
compositions and it would have been obvious to one of ordinary skill to substitute embryo with 
embryoid body for the detection of toxic effect of chemical compositions. 

One having ordinary skill in the art at the time the invention was made would have been 
motivated to do so in order to screen for the chemical compositions or compounds that have 
toxic effect on embryos or embryoid body as taught by Serbedzija and Spielmann or to rank the 
toxicity of the chemical compositions as taught by Spielmann with reasonable expectation of 
success. 

It should be noted that the claims do not specify the alterations in gene expression or 
protein expression in the mammalian embryoid body, therefore, although the specification only 
enables the disclosed protein expression pattern of embryoid body treated with troglitazone or 
erythromycin, the 35 U.S.C. 103(a) rejections as set forth above are considered proper. 



Application/Control Number: 09/864,621 
Art Unit: 1632 



Page 12 



Conclusion 



No claim is allowed. 

Any inquiry concerning this communication or earlier communications from the 
examiner should be directed to Shin-Lin Chen whose telephone number is (703) 305-1678. Due 
to the move of USPTO to new site in Alexandria, Virginia, examiner's telephone number will be 
changed to (571) 272-0726 after January 12, 2004. The examiner can normally be reached on 
Monday to Friday from 9:30 am to 6 pm. 

If attempts to reach the examiner by telephone are unsuccessful, the examiner's 
supervisor, Deborah Reynolds can be reached on (703) 305-4051. The fax phone number for 
this group is (703) 872-9306. 

Any inquiry of a general nature or relating to the status of this application should be 
directed to the Group receptionist, whose telephone number is (703) 308-0196. 




Shin-Lin Chen, Ph.D.