Ex Parte Peck et al

Board of Patent Appeals and Interferences

Jan 27, 2009

10394928 (B.P.A.I. Jan. 27, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte BILL J. PECK, ERIC M. LEPROUST,
and MICHAEL P. CAREN
__________

Appeal 2008-17211
Application 10/394,928
Technology Center 1600
__________

Decided: January 27, 2009
__________

Before TONI R. SCHEINER, DONALD E. ADAMS, and LORA M. GREEN,
Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1-19 and 32-34. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

1 The real party in interest is Agilent Technologies, Inc.
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BACKGROUND
“The present invention relates to [in situ synthesis of] arrays,
particularly biopolymeric arrays such as DNA arrays” (Spec. ¶ 1). The
Specification teaches that in situ synthesis methods involve
iterating the sequence of depositing droplets of: (a) protected
monomer onto predetermined locations on a substrate to link
with either a suitably activated substrate surface (or with
previously deposited deprotected monomer); (b) deprotecting
the deposited monomer so that it can react with a subsequently
deposited protected monomer; and (c) depositing another
protected monomer for linking. Different monomers may be
deposited at different regions on the substrate during any one
cycle so that the different regions of the completed array will
carry the different biopolymer sequences as desired in the
completed array.

(Spec. ¶ 6.)
The Specification further teaches that phosphoramidite nucleoside
monomers are typically used to make polynucleotide arrays by the
conventional in situ method. “In order for the phosphoramidite group to link
to a hydroxyl of a previously deposited polynucleotide monomer, it must
first be activated usually by using a weak acid such as tetrazole” (Spec. ¶ 7).
However, misplacement or misalignment of the activator and/or the
nucleoside monomers can lead to crescent-like features, and/or failure to
activate the phosphoramidite groups on the monomers completely (id. at ¶¶
8, 9). It is important that the features on the array are properly formed (i.e.,
uniformly circular) because “[m]alformed features . . . may result in a failed
analysis and raise suspicion about . . . the overall quality of the array” (id. at
¶ 8).
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The present Specification discloses an in situ method of making a
polymer array in which a first volume of fluid activator is deposited onto a
substrate, a second, smaller volume of fluid monomer is deposited onto the
fluid activator, and “mixing action is generated by the impact of the droplet
containing the monomer with the large[r] volume sessile drop containing the
activator” (Spec. ¶ 50). According to the Specification, “providing a larger
volume of fluid activator on the substrate” (Spec. ¶ 53), “lessen[s] the
placement accuracy required of the [smaller volume] monomer droplet”
(id.), virtually eliminating “misalignment problems, e.g., crescent formation
of incomplete polymers” (id.), and “allowing production speed to be
increased” (id.).
STATEMENT OF THE CASE
Claims 1-19 and 32-34 are pending and on appeal.2 Claims 1, 10 and
15 are representative of the subject matter on appeal:
1. A method of covalently bonding a monomer to a substrate surface,
said method comprising:

(a) producing a first volume of a fluid activator on said substrate
surface, wherein said substrate surface comprises a functional
moiety; and
(b) depositing a second volume of said monomer onto said first
volume on said surface so that said monomer is activated and
reacts with said functional moiety to covalently bond to said
substrate surface;
wherein said second volume is smaller than said first volume.

2 Claims 20, 23, 24, and 26-31 are also pending, but have been withdrawn
from consideration. Claims 21, 22, and 25 have been canceled.

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10. A method of producing an addressable array of biopolymers, said
method comprising:

(a) producing a first volume of a fluid activator in at least two
different regions of a substrate surface, wherein each of said at
least two different regions comprises a functional moiety;
(b) depositing a second volume of a fluid biomonomer onto said
first volume in each of said at least two different regions so that
said biomonomer bonds to said functional moiety, wherein said
second volume is smaller than said first volume; and
(c) repeating steps (a) and (b) to produce a biopolymer in each of
said at least two different regions to produce said addressable
array of biopolymers.

15. The method according to Claim 10, wherein said second volume is at
least about five-fold less than said first volume.

The Examiner relies on the following evidence:
Blanchard US 6,028,189 Feb. 22, 2000
Heyneker et al. US 6,264,891 B1 Jul. 24, 2001
Butler et al. US 6,589,726 B1 Jul. 8, 2003

Dean Tsou et al., Large scale synthesis of oligoribonucleosides on
high-loaded polystyrene (HLP) support, 14 NUCLEOSIDES &
NUCLEOTIDES 1481-1492 (1995).

Francine Wincott et al., Synthesis, deprotection, analysis and purification of
RNA and ribozymes, 23 NUCLEIC ACIDS RESEARCH 2677-2684 (1995).

Appellants rely on the following additional evidence:

Jer-Kang Chen et al., Synthesis of oligodeoxyribonucleotide N3´→P5´
phosphoramidates, 23 NUCLEIC ACIDS RESEARCH 2661-2668 (1995).

Tomasz Skorski et al., Antileukemia effect of c-myc N3´→P5´
phosphoramidate antisense oligonucleotides in vivo, 94 PROC. NATL. ACAD.
SCI. USA 3966-3971 (1997).
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The Examiner rejected the claims as follows:
Claims 1, 2, 5, 6, and 9 under 35 U.S.C. § 102(b) as anticipated by
Tsou.

Claims 1-6 and 8-17 under 35 U.S.C. § 103(a) as unpatentable over
Heyneker and Wincott.

Claims 7, 18, and 19 under 35 U.S.C. § 103(a) as unpatentable over
Heyneker, Wincott, and Butler.

Claims 32-34 under 35 U.S.C. § 103(a) as unpatentable over
Heyneker, Wincott, and Blanchard.

Claim 15 under 35 U.S.C. § 112, second paragraph, as indefinite.

ANTICIPATION
The Issue
The issue raised by this appeal is whether the Examiner has provided
an adequate factual basis to support the conclusion that Tsou discloses a
method of covalently bonding a monomer to a functional moiety on a
substrate, where a first volume of a fluid activator is deposited onto the
substrate, and a second, smaller volume of fluid monomer is deposited onto
the first, larger volume of fluid activator.
Findings of Fact
FF1 Appellants invented a method of covalently bonding a
monomer to a functional moiety on a substrate, where a first volume of a
fluid activator is deposited onto the substrate, and a second, smaller volume
of fluid monomer is deposited onto the first, larger volume of fluid activator
(claim 1). Successive iterations of these steps are used to build substrate-
bound polymers (e.g., claim 2).
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FF2 Claim 1 requires the second volume of fluid monomer to be
deposited onto the first volume of fluid activator to activate the monomer.
In other words, the first volume of fluid activator is not washed or drained
from the substrate before the second volume of fluid monomer is deposited.
FF3 The Examiner rejected claims 1, 2, 5, 6, and 9 under 35 U.S.C.
§ 102(b) as anticipated by Tsou.
FF4 Tsou describes synthesis of substrate-bound oligoribonucleotide
polymers on two different polystyrene supports using phosphoramidite
nucleoside monomers (Tsou 1482).
FF5 Tsou discloses that the synthesis was carried out “on Applied
Biosystems Models 390Z and 394 DNA/RNA synthesizers” (Tsou 1490),
but does not describe a complete synthesis protocol.
FF6 According to Tsou, each cycle of synthesis involved
detritylation (removal of acid-labile dimethoxytriyl (DMT) protecting
groups from a nucleoside), coupling of an activated phosphoramidite
nucleoside monomer to the detritylated nucleoside, capping, and oxidation
(id. at 1482).
FF7 Tsou discloses that “[a]ctivation of phosphoramidites was
effected with a 0.75 M solution of 5-ethylthio-1H-tetrazole in acetonitrile”
(Tsou 1483). Tsou further discloses that “[t]he quality of the syntheses on
the 390Z was markedly enhanced by a DMF wash before and after the
detritylation . . . [and] DMF was found to be very effective in removing
traces of iodine and acids still retained on the support after acetonitrile
washes” (id.).
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FF8 Tsou’s Table 2, reproduced below, compares reagent
consumption per synthesis cycle on the ABI 390Z large scale DNA/RNA
synthesizer:

Table 2 shows that the volume of activator (tetrazole in acetonitrile) used in
each cycle is greater than the volume of phosphoramidite monomer used.
Table 2 also shows the volume of acetonitrile used in each synthesis cycle.
FF9 Skorski, a 1997 reference made of record by Appellants,
discloses that “[o]ligonucleotide N3´→P5´ phosphoramidates were prepared
on an Applied Biosystems model 390Z or 394 automated synthesizers as
reported” (Skorski 3966, col. 2). Skorski cites Chen, a 1995 reference made
of record by Appellants, for the synthesis protocol.
FF10 Chen discloses that “[o]ligodeoxyribonucleotides and
oligoribonucleotides were prepared on an ABI 380B synthesizer using
standard DNA or RNA assembly protocols via the phosphoramidite method”
(Chen 2662, col. 1). “Oligonucleotide N3´→P5´ phosphoramidates were
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synthesized . . . using an ABI 394 synthesizer and 5´-O- and N-protected 3´-
amino-2´,3´-dideoxynucleosides as monomeric building blocks according to
the following protocol” (id.):
(i) detritylation, 5% dichloroacetic acid in CH2CH2, 60 s; (ii)
wash, acetonitrile, 30 s; (iii) phosphitylation, 0.2 M 2-cyano-
ethoxy-(N,N-diisopropylamino)chlorophosphoramidite and 0.2
M diisopropylethylamine in CH2Cl2, 15 min; (iv) wash,
acetonitrile, 10 s; (v) hydrolysis, 0.5 M tetrazole in
acetonitrile:H2O, 9:1 v/v, 5min; (vi) wash, acetonitrile, 60 s;
(vii) coupling, 0.2 M 3´-aminonucleoside in 3% triethylamine
in acetonitrile:carbon tetrachloride, 2:1 v/v, 60 min; (viii) wash,
acetonitrile, 30 s.

(Id.) According to Chen, “[t]his cycle, repeated several times, results in an
N3´→P5´ phosphoramidate oligonucleotide after final detritylation and
deprotection” (id.).
FF11 Thus, Chen discloses “standard DNA or RNA assembly
protocols via the phosphoramidite method” (Chen 2662, col. 1), performed
on the same synthesizers used by Tsou, where the protocols include an
acetonitrile wash step after tetrazole activation and before coupling with
monomer.
Principles of Law
“A claim is anticipated only if each and every element as set forth in
the claim is found, either expressly or inherently described, in a single prior
art reference.” Verdegaal Bros., Inc. v. Union Oil Co. of California, 814
F.2d 628, 631 (Fed. Cir. 1987).
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The Examiner’s rejections must be supported by a preponderance of
the evidence. See, e.g., Ethicon, Inc. v. Quigg, 849 F.2d 1422, 1427 (Fed.
Cir. 1988).
The Patent Office has the initial duty of supplying the factual
basis for its rejection. It may not, because it may doubt that the
invention is patentable, resort to speculation, unfounded
assumptions or hindsight reconstruction to supply deficiencies
in its factual basis. To the extent the Patent Office rulings are
so supported, there is no basis for resolving doubts against their
correctness. Likewise, we may not resolve doubts in favor of
the Patent Office determination when there are deficiencies in
the record as to the necessary factual bases supporting its legal
conclusion . . . .

In re Warner, 379 F.2d 1011, 1017 (CCPA 1967)(emphasis added). Warner
concerned the factual basis of an obviousness rejection, but its central
premise is equally appropriate here.
Extrinsic evidence may be considered in the context of anticipation
“when it is used to explain, but not expand, the meaning of a reference.” In
re Baxter Travenol Labs, 952 F.2d 388, 390 (Fed. Cir. 1991). “The role of
extrinsic evidence is to educate the decision-maker to what the reference
meant to persons of ordinary skill in the field of the invention, not to fill
gaps in the reference.” Scripps Clinic & Research Foundation v. Genentech,
Inc., 927 F.2d 1565, 1576 (Fed. Cir. 1991).
Analysis and Conclusion of Law
The Examiner concludes that “Tsou deposits the monomer volume
onto the activator volume as claimed” (Ans. 7), without an intervening wash
step. The basis for the Examiner’s conclusion is that “Tsou provides the
acetonitrile within the activator solution” and “describes a wash step before
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and after detritylaction [sic]” (id.) and “after monomer addition”3 (id.), but
“does not teach a wash step prior to monomer deposit” or “at any other step
in the synthesis reaction” (id.). In addition, the Examiner asserts that Tsou’s
Table 2 “clearly teaches reagent loading of tetrazole/acetonitrile followed by
phosphoramides” (id. at 8).
The Examiner’s conclusion is not supported by a preponderance of the
evidence. The mere fact that Tsou does not explicitly describe a wash step
between depositing the activator on the support and depositing the monomer
solution is not persuasive evidence that no wash step is performed, given the
fact that Tsou explicitly refers to “acetonitrile washes” (FF7), but provides
no further information about them. Clearly, Tsou does not describe a
complete step-by-step synthesis protocol. Moreover, Tsou’s Table 2, which
the Examiner relies on as evidence that phosphoramidite monomers are
added immediately after the tetrazole/acetonitrile activation solution, is not a
protocol. It is simply a list of reagents consumed during each cycle, and
does not indicate whether the reagents (e.g., tetrazole/acetonitrile,
phosphoramidites, acetonitrile) are added in the order listed, or that a listed
reagent is added only once in each cycle.
Finally, Chen provides extrinsic evidence that weighs against the
Examiner’s conclusion that Tsou’s protocol necessarily lacks a wash step
after activation, but before monomer deposition. Chen discloses a step-by-
step oligonucleotide synthesis protocol (i.e., “the phosphoamidite method”)

3 The Examiner asserts that Tsou describes a wash step “after monomer
addition,” but does not point to anything in the reference which supports this
assertion.
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using the same synthesizers used by Tsou (FF5, 10), and many of the same
reagents (FF8, 10). Chen’s protocol clearly includes an acetonitrile wash
step after tetrazole activation and before coupling with monomer (FF10, 11).
Thus, the Examiner has not provided an adequate factual basis to
support the conclusion that Tsou discloses a method of covalently bonding a
monomer to a functional moiety on a substrate, where a first volume of a
fluid activator is deposited onto the substrate, and a second, smaller volume
of fluid monomer is deposited onto the first, larger volume of fluid activator.
Accordingly, we reverse the rejection claims 1, 2, 5, 6, and 9 under 35
U.S.C. § 102(b) as anticipated by Tsou.
OBVIOUSNESS
The Issue
There are three separate obviousness rejections, but they all turn on the
same issue: whether the Examiner has established that covalently bonding a
monomer to a functional moiety on a substrate, where a first volume of a fluid
activator is deposited onto the substrate, and a second, smaller volume of fluid
monomer is deposited onto the first, larger volume of fluid activator would
have been obvious over the combined teachings of Heyneker and Wincott.
Additional Findings of Fact
FF12 The Examiner rejected Claims 1-6 and 8-17 under 35 U.S.C.
§ 103(a) as unpatentable over Heyneker and Wincott; claims 7, 18, and 19 as
unpatentable over Heyneker, Wincott, and Butler; and claims 32-34 under as
unpatentable over Heyneker, Wincott, and Blanchard.
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FF13 Heyneker describes an apparatus and protocol for synthesizing
oligonucleotides on a substrate support, using phosphoramadite monomers.
The apparatus performs the following physical steps:

(Heyneker, col. 14, l. 50 to col. 15, l. 11). There is no wash station or step
disclosed between Station 9, where 10 μL of tetrazole activator is dispensed,
and Station 10, where an equal volume (10 μL) of amidite is dispensed.
FF14 Wincott describes automated small scale synthesis of RNA on
an ABI 394 synthesizer, wherein a “6.5-fold excess (163 μl, 0.1 M = 16.3
μmol) of phosphoramidite and a 24-fold excess of S-ethyltetrazole
[activator] (238 μl, 0.25 M = 59.5 μmol) relative to polymer-bound 5´-
hydroxyl was used in each coupling cycle” (Wincott 2678, col. 1). Wincott
also describes automated large scale synthesis of RNA on an ABI 390Z
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synthesizer, wherein a “6-fold excess (1.5 ml, 0.1 M = 150 μmol) of
phosphoramidite and a 45-fold excess of S-ethyltetrazole [activator] (2.25
ml, 0.5 M = 1125 μmol) relative to polymer-bound 5´-hydroxyl was used in
each coupling cycle” (id.).
FF15 Wincott teaches that “RNA phosphoramidite coupling
efficiency is dependent on activator, activator concentration and time”
(Wincott 2677, col. 2). In particular, “[t]he use of S-ethyltetrazole as the
coupling activator reduces the reaction time by one-half” (id. at 2684).
Principles of Law
[T]he Examiner bears the burden of establishing a prima facie
case of obviousness based upon the prior art. “[The Examiner]
can satisfy this burden only by showing some objective
teaching in the prior art or that knowledge generally available to
one of ordinary skill in the art would lead that individual to
combine the relevant teachings of the references.”

In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir. 1992) (citations omitted,
bracketed material in original). “Often, it will be necessary . . . to look to
interrelated teachings of multiple [references] . . . and the background
knowledge possessed by a person having ordinary skill in the art, all in order
to determine whether there was an apparent reason to combine the known
elements in the fashion claimed[.]” KSR Int'l Co. v. Teleflex Inc., 127 S. Ct.
1727, 1740-41 (2007). “[T]his analysis should be made explicit” (id. at
1741), and it “can be important to identify a reason that would have
prompted a person of ordinary skill in the relevant field to combine the
elements in the way the claimed new invention does” (id.).

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Analysis and Conclusion of Law
The Examiner finds that Heyneker discloses a method of covalently
binding a monomer to a substrate by depositing a first volume of an activator
(10 µl tetrazole) on the substrate, and a second volume of monomer (10 µl
amidite) onto the activator (Ans. 9). The Examiner acknowledges that the
first and second volumes in Heyneker’s method are equal, but cites Wincott
as evidence that “activators in volumes excess to that of the monomers was
well known in the art” (id.). The Examiner concludes that “it would have
been obvious . . . to modify the activator volume of Heynecker . . . by
providing a volume in excess of the monomer . . . for the expected benefit of
optimizing the coupling reaction while reducing coupling/synthesis time as
taught by Wincott” (id. at 9-10).
Appellants contend that one skilled in the art would have no reason to
combine the teachings of Heyneker and Wincott in the first place because
Wincott uses ABI synthesizers, which “employ an acetonitrile wash step
between the activator and monomer depositing steps” (App. Br. 21), as
established by evidence of record.4 Nevertheless, Appellants contend that
even if one were to combine the teachings of Heyneker and Wincott, one
would simply adjust the relative concentrations of the activation and
monomer solutions, rather than adjusting their volumes, because “Wincott
teaches the benefit of optimizing concentration, not volume” (id. at 22), but
“volume is never discussed other than incidentally” (id. at 23).

4 This is an apparent reference to the Skorski and Chen articles, which have
been discussed in the context of the anticipation rejection over Tsou.
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Appellants have the better argument. Wincott uses a larger volume of
activator solution than monomer solution in the examples, but the reference
makes no other mention of volume, and explicitly teaches that coupling
efficiency is dependent on the particular activator used, as well as the
concentration of activator (FF15). We agree with Appellants that Wincott, at
best, would have given one skilled in the art a reason to optimize the
coupling/synthesis times of Heyneker’s method by using S-ethyltetrazole as the
activator, and adjusting the relative concentrations of activator and amidite
monomer solutions to the ratios taught by Wincott.
The Examiner has not established that covalently bonding a monomer to
a functional moiety on a substrate, where a first volume of a fluid activator is
deposited onto the substrate, and a second, smaller volume of fluid monomer is
deposited onto the first, larger volume of fluid activator would have been
obvious over the combined teachings of Heyneker and Wincott.
Butler and Blanchard, cited by the Examiner in the second and third
obviousness rejections to address certain limitations of the dependent claims,
do nothing to cure the underlying deficiency in the Examiner’s proposed
combination of Heyneker and Wincott.
Accordingly, all three rejections of the claims under 35 U.S.C. § 103(a)
are reversed.
INDEFINITENESS
The Issue
The issue raised by this appeal is whether the phrase “at least about five-
fold less” renders claim 15 indefinite.
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Additional Findings of Fact
FF16 The Examiner rejected claim 15 under 35 U.S.C. § 112, second
paragraph, asserting that the phrase “at least about five-fold less” renders the
claim indefinite.
FF17 According to the Specification,
at each monomeric residue addition or coupling step in the
synthesis protocol of a given ligand . . . a first volume of a fluid
activator is produced at a surface location and then a second
volume of activatable monomer is deposited onto the first
volume, where the first volume exceeds the second volume,
such that the second volume of fluid is smaller than the first
volume.

(Spec. ¶ 47.)
FF19 “In the subject methods, the first volume typically exceeds the
second volume by at least about 1.5 , usually by at least about 2 and more
usually by at least about 5 fold” (Spec. ¶ 47).
Principles of Law
“The definiteness inquiry focuses on whether those skilled in the art
would understand the scope of the claim when the claim is read in light of
the rest of the specification.” Union Pacific Resources Co. v. Chesapeake
Energy Corp., 236 F.3d 684, 692 (Fed. Cir. 2001).
Analysis and Conclusion of Law
We agree with Appellants that when claim 15 is read in light of the
Specification, one of skill in the art would understand that “the phrase about
five-fold provides for tolerances above and below five-fold, and the phrase at
least means that those tolerances provide the minimum values” (App. Br.
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14), and “[t]here is nothing indefinite in the juxtaposition of those two
phrases to form the phrase at least about” (id.).
Accordingly, the rejection of claim 15 under 35 U.S.C. § 112, second
paragraph, as indefinite, is reversed.
SUMMARY
We REVERSE:
the rejection of claims 1, 2, 5, 6, and 9 under 35 U.S.C. § 102(b) as
anticipated by Tsou;
the rejection of claims 1-6 and 8-17 under 35 U.S.C. § 103(a) as
unpatentable over Heyneker and Wincott;
the rejection of claims 7, 18, and 19 under 35 U.S.C. § 103(a) as
unpatentable over Heyneker, Wincott, and Butler;
the rejection of claims 32-34 under 35 U.S.C. § 103(a) as unpatentable
over Heyneker, Wincott, and Blanchard; and
the rejection of claim 15 under 35 U.S.C. § 112, second paragraph.

REVERSED

cdc

AGILENT TECHNOLOGIES INC.
INTELLECTUAL PROPERTY ADMINISTRATION, LEGAL DEPT.
MS BLDG. E P.O. BOX 7599
LOVELAND, CO 80537
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