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PATENT 
Customer No. 22,852 
Attorney Docket No. 08702.0039-02000 

REMARKS 

In the specification, the paragraph beginning at page 1 , line 1 has been amended 
to correct the priority claim. 

Claims 24-26, 29, 30, 33, 35, 36, 38, 39, 41 , and 42, to the extent that they are 
drawn to polynucleotides encoding amino acids 299-396 of Figure 2, remain pending in 
the application. Claims 1-23, 27, 28, 31 , 32, 34, 37, 40, and 43-49 have been 
cancelled. Claims 24-26, 29, 30, 33, 35, 36, 41 , and 42 have been amended to more 
clearly define the claimed subject matter. Applicants reserve the right to pursue the 
subject matter of all cancelled claims in one or more divisional applications. 

OBJECTION TO PRIORITY INFORMATION 

The Examiner has requested correction of the paragraph containing continuing 
data. Applicants have amended the specification to provide the correct history of the 
application. To clarify, U.S. Serial No. 07/721 ,847 is a continuation-in-part of three 
separate applications: 07/493,272; 07/378,537; and 07/655,579. 07/655,579 is a 
divisional of 07/179,100. Applicants believe that the amended paragraph accurately 
reflects the proper continuing data. 

REJECTIONS UNDER 35 U.S.C. § 112. SECOND PARAGRAPH 

Claims 33, 36, 39, and 42 have been rejected under 35 U.S.C. § 1 12, second 
paragraph, as allegedly indefinite. The Examiner contends that the definition of 
"stringent hybridization conditions" in claim 33 is unclear and suggests that Applicants 
incorporate the actual conditions into the claim. 



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PATENT 
Customer No. 22,852 
Attorney Docket No. 08702.0039-02000 



Applicants traverse. The claim term "stringent hybridization conditions" is clearly 
defined in the specification at page 23, lines 25-27 and in the enclosed copy of Maniatis 
et al., Molecular Cloning (A Laboratory Manual) , Cold Spring Harbor Laboratory (1982). 
In addition, Applicants submit copies of U.S. Patent Nos. 6,733,965; 6,734,003; 
6,734,009; 6,734,293; 6,743,907; and 6,746,861 , all of which issued with claims reciting 
"stringent conditions" in the absence of specific conditions in the claims. Applicants 
submit that it is proper practice for the claims to refer to hybridization conditions defined 
in the specification and request that the Examiner withdraw the rejection of claim 33 and 
claims 36, 39, and 42, which depend from claim 33. 

Claim 42 has been rejected under 35 U.S.C. § 1 12, second paragraph, as 
allegedly indefinite. The Examiner indicates that "BMP-2" should be replaced with 
"bone morphogenetic protein-2," to more clearly identify the claimed subject matter. 
Applicants have made the suggested claim amendment and request that the Examiner 
withdraw this rejection. 

REJECTIONS UNDER 35 U.S.C. S 112. FIRST PARAGRAPH 

Claims 24, 35, and 38 have been rejected under 35 U.S.C. § 1 12, first 
paragraph, as allegedly lacking written support in the specification. The Examiner 
objects to the language "naturally occurring allelic variants" and contends that the 
specification does not provide any definition of the term "allele," nor does it describe 
which nucleotides may vary in these allelic variants. Applicants traverse. 



PATENT 
Customer No. 22,852 
Attorney Docket No. 08702.0039-02000 

The language "allelic variant" is clearly defined in the specification. Specifically, 

on page 7, lines 4-18, the specification describes: 

"factors into which modifications are naturally provided 
(allelic variations in the nucleotide sequence which may 
result in amino acid changes in the polypeptide) . . . These 
sequences, by virtue of sharing primary, secondary, or 
tertiary structural and conformational characteristics may 
possess bone growth factor biological properties in common. 
Thus, they may be employed as biologically active 
substitutes." 

On page 8, lines 10-16, the specification describes sequences that "differ in codon 
sequences due to degeneracies of the genetic code or allelic variations (naturally 
occurring base changes in the species' population which may or may not results in an 
amino acid change)." Applicants submit that with this definition of "allelic variant," one 
skilled in the art would readily understand how the sequence disclosed in Figure 2 is 
representative of other allelic variants. 

In addition, Applicants have provided the necessary information for one skilled in 
the art to identify and isolate nucleotides encoding BMP-2 from natural sources, which 
would provide the claimed naturally occurring allelic variants. See, e.g., Examples IV 
and V, which describe the isolation of bovine and human sequences encoding BMP-2. 
Accordingly, Applicants submit that the language "naturally occurring allelic variants" 
has written description support in the specification. 

Finally, Applicants submit that the term "allelic variant" is well understood by 
those of skill in the art. The term is commonly allowed by the U.S.P.T.O. in claims 
recited DNA or amino acid sequences. For example, Applicants direct the Examiner's 



PATENT 
Customer No. 22,852 
Attorney Docket No. 08702.0039-02000 

attention to U.S. Patent Nos. 5,846,770; 5,849,880; 5,932,216; 5,948,639; and 
5,586,388, which all claim allelic variants. U.S. Patent Nos. 5,586,388 and 5,948,639 
do not contain a definition of this term in the specification. U.S. Patent Nos. 5,846,770; 
5,849,880; and 5,932,216 (all assigned to Genetics Institute) have the same definition of 
allelic variants used in this application: sequences that "differ in codon sequences due 
to degeneracies of the genetic code or allelic variations (naturally occurring base 
changes in the species' population which may or may not results in an amino acid 
change)." Accordingly, Applicants submit that the "naturally occurring allelic variants" 
claim language is supported by the specification and allowable. Applicants request that 
this rejection of claims 33, 36, 39, and 42 be withdrawn. 

Claims 33, 36, 39, and 42 have been rejected under 35 U.S.C. § 112, first 
paragraph, as allegedly lacking enablement. The Examiner contends that sequences 
capable of hybridizing to the sense strand of the sequence of Figure 2 will not encode a 
protein with bone morphogenetic activity. Applicants have amended claim 33, which 
now recites a DNA molecule that hybridizes to a sequence complementary to the 
sequence of Figure 2. The claimed DNA molecule will contain a sequence similar to 
that of the sense strand of Figure 2 and will encode a BMP-2 protein. Applicants 
request that the Examiner withdraw this rejection of claim 33, and dependent claims 36, 
39, and 42. 



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PATENT 
Customer No. 22,852 
Attorney Docket No. 08702.0039-02000 

REJECTIONS UNDER 35 U.S.C. § 101 

Claims 24-26, 29, 30, 33, and 42 have been rejected under 35 U.S.C. § 101 as 
directed to DNA sequences, which are not patentable subject matter. As suggested by 
the Examiner, Applicants have amended these claims to recite "isolated polynucleotide" 
instead of "DNA sequence." In light of this amendment, Applicants request that the 
claim rejections under 35 U.S.C. § 101 be withdrawn. 

CONCLUSION 

In view of the foregoing amendments and remarks, Applicants respectfully 
requests reconsideration and reexamination of this application and the timely allowance 
of the pending claims. 

Please grant any extensions of time required to enter this response and charge 
any additional required fees to Deposit Account No. 06-0916. 



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PATENT 
Customer No. 22,852 
Attorney Docket No. 08702.0039-02000 



Respectfully submitted, 

FINNEGAN, HENDERSON, FARABOW, 
GARRETT & DUNNER, LLP. 



Dated: September 9. 2004 



By 




Elizabeth E. McNamee 
Reg. No. 54,696 



Attachments: 

• Maniatis et al., Molecular Cloning (A Laboratory Manual) . Cold Spring Harbor 
Laboratory (1 982), pages 387-389. 
U.S. Patent No. 6,733,965 
U.S. Patent No. 6,734,003 
U.S. Patent No. 6,734,009 
U.S. Patent No. 6,734,293 
U.S. Patent No. 6,743,907 
U.S. Patent No. 6,746,861 
U.S. Patent No. 5,846,770 
U.S. Patent No. 5,849,880 
U.S. Patent No. 5,932,216 
U.S. Patent No. 5,948,639 
U.S. Patent No. 5,586,388 



-11- 




Molecular 

Cloning 

A LABORATORY MANUAL 
SECOND EDITION 



J. Sambrook 

UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER 

E.F. Fritsch 

GENETICS INSTITUTE 

T. Maniatis 

HARVARD UNIVERSITY 



fcSH) 



Cold Spring Harbor Laboratory Press 
1989 



concentrations of protein are believed to interfere with the annealing of 
the probe to its target. This quenching bf the hybridization signal is 
particularly noticeable when oligonucleotides or probes less than 100 
nucleotides in length are used. 

7. In the presence of 10% dextran sulfate or 10% polyethylene glycol, the 
rate of hybridization is accelerated approximately tenfold (Wahl et al. 
1979; Renz and Kurz 1984; Amasino 1986) because nucleic acids are 
excluded from the volume of the solution occupied by the polymer and 
their effective concentration is therefore increased. Although dextran 
sulfate and polyethylene glycol are useful in circumstances where the 
rate of hybridization is the limiting factor in detecting rare sequences 
(e.g., northern or genomic Southern blots), they are of no benefit when 
screening bacterial colonies or bacterial plaques. In addition, they can 
sometimes lead to high backgrounds, and hybridization solutions con- 
taining them are always difficult to handle because of their viscosity. We 
therefore recommend that dextran sulfate and polyethylene glycol not be 
used unless the rate of hybridization is very slow, the filter contains very 
small amounts of DNA, or the amount of radiolabeled probe is limiting. 

8. To maximize the rate of annealing of the probe with its target, hybridiza- 
tions are usually carried out in solytions of high ionic strength (6 x SSC 
or 6 x SSPE) at a temperature that is 20-25°C below the melting 
temperature (T m ). Both solutions work equally well when hybridization 
is carried out in aqueous solvents. However, when formamide is included 
in the hybridization buffer, 6 x SSPE is preferred because of its greater 
buffering power. 

9. In general, the washing conditions should be as stringent as possible (i.e., 
a combination of temperature and salt concentration should be chosen 
that is approximately 12-20°C below the calculated T m of the hybrid 
under study). The temperature and salt conditions can often be de- 
termined empirically in preliminary experiments in which samples of 
genomic DNA immobilized on filters are hybridized to the probe of 
interest and then washed under conditions of different stringencies. 

10. To minimize background problems, it is best to hybridize for the shortest 
possible time using the minimum amount of probe. For Southern 
hybridization of mammalian genomic DNA where each lane of the gel 
contains 10 /xg of DNA, 10-20 ng/ml radiolabeled probe (sp. act. = 10 9 
cpm//xg or greater) should be used and hybridization should' be carried 
out for 12-16 hours at 68°C in aqueous solution or for 24 hours at 42°C in 
50% formamide. For Southern hybridization of fragments of cloned DNA 
where each band of the restriction digest contains 10 ng of DNA or more, 
much less probe is required. Typically, hybridization is carried out for 
6-8 hours using 1-2 ng/ml radiolabeled probe (sp. act. = 10 9 cpm//xg or 
greater). 

11. Useful facts: 

a. The T m of the hybrid formed between the probe and its target may be 
estimated from the following equation (Bolton and McCarthy 1962): 



9.50 Analysis and Cloning of Eukaryotic Genomic DNA 



T m = 81.5°C + 16.6(log 10 [Na + ]) + 0,41(fractionG + C) - 0.63(%' form- 
amide) - (600//) ' , 

where I = the length of the hybrid in base pairs. 
This equation is valid for: 

• Concentrations of Na + in the range of 0.01 m to 0.4 m. It predicts T m 
less accurately in solutions of higher [Na + ]. ' 

• DNAs whose G + C content is in the range of 30% to 75%. Note that' 
the depression of T m in solutions containing formamide is greater 
for poly(dA:dT) (0.75°C/1% formamide) and less for DNAs rich in 
poly(dG:dC) (0.50°C/1% formamide) (Casey and Davidson 1977). 

The equation applies to the "reversible" T m that is defined by optical 
measurement of hyperchromicity at OD 257 . The "irreversible" T m , 
which is more important for autoradiographic detection of DNA hy- 
brids, is usually 7-10°C higher than that predicted by the equation. 
Similar equations have been derived for: 

i. RNA probes hybridizing to immobilized RNA (Bodkin and 
Knudson 1985) • . • 

T m = 79.8°C + 18.5(log 10 [Na + ]) + 0.58(fraction G + -C) 

+ 11.8( fraction G + C) 2 - 0.35(% formamide) - (820/Z) 

ii. DNA:RNA hybrids (Casey and Davidson 1977) 

T m = 79.8°C + 18.5(log 10 [Na + ]) + 0.58(fraction G + C) 

+ 11.8( fraction G + C) 2 - 0.50(% formamide) - (820/Z) 

Comparison of these equations shows that the relative stability of 
nucleic acid hybrids decreases in the following order: RNA:RNA (most 
stable), RNA:DNA (less stable), and DNA:DNA (least stable). In 
aqueous solutions, the T m of a DNA:DNA hybrid is approximately 
10°C lower than that of the equivalent RNA:RNA hybrid. In 80% 
formamide, the T m of an RNA.DNA hybrid is approximately 10°C 
higher than that of the equivalent DNA:DNA hybrid. 

b. The T m of a double-stranded DNA decreases by 1-1. 5°C with every 1% 
decrease in homology (Bonner et al. 1973). 

The above equations apply only to hybrids greater than 100 nucleotides in length. 
The behavior of oligonucleotide probes is described in detail in Chapter 11. 

•For a general discussion of hybridization of nucleic acids bound to solid 
supports, see Meinkoth and Wahl (1984). 



Analysis and Cloning of Eukaryotic Genomic DNA 9*51