Ex Parte Southern

Board of Patent Appeals and Interferences

Jun 2, 2010

10772467 (B.P.A.I. Jun. 2, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte EDWIN SOUTHERN
__________

Appeal 2009-0108291
Application 10/772,4672
Technology Center 1600
__________

Decided: June 2, 20103
__________

Before LORA M. GREEN, FRANCISCO C. PRATS, and
JEFFREY N. FREDMAN Administrative Patent Judges.

PRATS, Administrative Patent Judge.

1 Oxford Gene Technology Limited is the real party in interest (App. Br. 3).
2 This application has a significant and lengthy parentage, with priority
claims dating back to 1988 (App. Br. 4).
In particular, this application is a divisional of Ser. No. 09/422,803,
now abandoned, which is a divisional of Ser. No. 08/925,676, now U.S.
Patent No. 6,054,270, which in turn is a divisional of Ser. No. 08/230,012,
now U.S. Patent. No. 5,700,637 (id.).
The Appeal Brief states that both the ‘270 and ‘637 patents have been
involved in reexamination proceedings and infringement litigation (id. at 4-
5).
3 Oral argument was presented in this case on May 13, 2010.

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DECISION ON APPEAL
This appeal under 35 U.S.C. § 134 involves claims to an apparatus for
analyzing polynucleotides. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.
STATEMENT OF THE CASE
Claims 17-27, 86, and 87 stand rejected and are on appeal (App. Br.
6).4 Claim 17 is representative and reads as follows:
Claim 17. Apparatus for analysing a polynucleotide, the
apparatus comprising: a support having an impermeable
surface; porous material attached to the impermeable surface;
and an array of oligonucleotides with predetermined sequences
attached to the porous material, wherein the array comprises at
least two defined cells, the sequence of the oligonucleotides of
a first cell is different from the sequence of the oligonucleotides
of a second cell, and the oligonucleotides are shorter than the
polynucleotide.

The sole rejection before us for review is the Examiner’s rejection of
claims 17-27, 86, and 87 under 35 U.S.C. § 103(a) as being unpatentable
over Stavrianopoulos5 and Matkovich6 (Ans. 5-7).
OBVIOUSNESS
ISSUE
The Examiner cites Stavrianopoulos as disclosing an impermeable
substrate-bound array of oligonucleotides having predetermined sequences
(Ans. 5). To meet the claims’ requirement of a porous material attached to
the impermeable surface, the Examiner cites Matkovich as disclosing “the

4 Appeal Brief filed September 25, 2008.
5 U.S. Patent No. 4,994,373 (filed Jul. 20, 1989).
6 U.S. Patent No. 4,828,386 (filed Jun. 19, 1987).
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use of a microporous membrane on top of a support . . . which can be used to
bind biologically active substances including nucleic acids” (id. at 6-7).
Based on the references’ teachings, the Examiner concludes that an
ordinary artisan would have considered it obvious “to modify the apparatus
taught by Stavrianopoulos et al. to insert a porous membrane with covalently
attached oligonucleotides, as taught by Matkovich” (id. at 7). The Examiner
reasons that an artisan would have been prompted to make this modification
“because Matkovich et al. teach that a porous surface results in a better
binding capacity of biological substances” (id.).
Appellant contends that the Examiner erred in finding that an ordinary
artisan would have combined the two references because Stavrianopoulos is
directed to nucleic acid assays, whereas Matkovich is concerned with
antibody binding, and the references are therefore nonanalogous art (App.
Br. 12). Moreover, Appellant argues, Stavrianopoulos teaches that porous
materials are less desirable when practicing the invention described therein
(id. at 13).
Appellant further contends that the Examiner erred in finding that
Stavrianopoulos meets the requirement in claim 17 that the arrayed
oligonucleotides have “predetermined sequences” because the reasons for
allowance in one of patented divisional parent cases interpreted that
language as requiring that “‘the complete sequence of each and every
oligonucleotide probe on the array surface is known’” (id. at 14 (italicization
omitted)). Appellant contends that this interpretation is consistent with the
teachings in the Specification (id. at 15-16). In contrast, Appellant argues,
Stavrianopoulos’ methods involve attaching oligonucleotides of unknown
sequence to the substrate (id. at 15).
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Appellant further argues that the Examiner erred in finding that
Stavrianopoulos meets claim 17’s requirement that the array includes “‘at
least two defined cells, [in which] the sequence of the oligonucleotides of a
first cell is different from the sequence of the oligonucleotides of a second
cell’” (id. at 16).
Appellant argues further that the Examiner erred in concluding that
the cited references teach or suggest the limitations requiring covalent
attachment of the oligonucleotide to the porous substrate (claims 23 and 86),
attachment by a terminal nucleotide (claims 24 and 87), and in situ
attachment of the oligonucleotides (claim 25) (App. Br. 17-21).
In view of the positions advanced by Appellant and the Examiner, the
issue with respect to this rejection is whether the Examiner’s conclusion of
obviousness is supported by the evidence of record.
FINDINGS OF FACT (“FF”)
Stavrianopoulos
1. Stavrianopoulos discloses “a method for quantifiably detecting a
targeted polynucleotide sequence in a sample of biological and/or
nonbiological material employing a probe capable of generating a soluble
signal” (Stavrianopoulos, col. 1, ll. 15-18).
2. In Stavrianopoulos’ method, “[an] analyte [which] may be a DNA or
RNA molecule of small or high molecular weight” (id. at col. 1, ll. 29-30)
from a biological sample is “preferably denatured into single-stranded form,
and then directly fixed to a suitable solid support” (id. at col. 5, ll. 37-39).
3. Thus, “[f]or example, glass plates provided with an array of
depressions or wells would have samples of the various denatured analytes
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deposited therein, the single-stranded analytes being fixed to the surfaces of
the wells” (id. at col. 8, ll. 41-45).
4. To determine whether the immobilized nucleic acid from the
biological samples includes a particular sequence of interest,
“polynucleotide probes provided with a chemical label may be deposited in
each of the wells for hybridization to any complementary single-stranded
analyte therein. After washing to remove any non-hybridized probe, the
presence of any hybrid probe-analyte is then detectable” (id. at col. 8, ll. 45-
50).
5. Stavrianopoulos discloses:
It is preferred that the solid support to which the analyte is fixed
be non-porous and transparent, such as glass, or alternatively,
plastic, polystyrene, polyethylene, dextran, polypropylene and
the like. Conventional porous materials, e.g., nitrocellulose
filters, although less desirable for practice of the method of the
present invention, may also be employed as a support.

(Id. at col. 5, ll. 46-52.)
6. Stavrianopoulos discloses an example in which phage lambda DNA
is used as the analyte, with alkaline phosphatase/paranitrophenylphosphate
as the signaling moiety (see id., e.g., at col. 9, ll. 51-55), as well as an
example using adenovirus 2 DNA as the analyte (id. at col. 11, ll. 20-35).
7. Stavrianopoulos discloses that a technique useful for immobilizing the
sample nucleic acids involves functionalizing the glass substrate such that
the “treated glass surface will . . . have available alkylamine thereon suitable
for immobilizing or fixing any negatively charged polyelectrolytes applied
thereto” (id. at col. 8, ll. 32-35).
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8. Stavrianopoulos discloses that its invention “also encompasses
indirect fixation of the analyte, such as in situ techniques where the cell is
fixed to the support” (id. at col. 5, ll. 41-43).

Matkovich
9. Matkovich discloses a “multiwell plate . . . showing superior
characteristics in binding antibody and other substances of biological origin”
(Matkovich, col. 3, ll. 3-7).
10. Matkovich discloses that “[s]uperior capacity for the binding of
biological substances is obtained by providing a unitary insert comprising a
biochemically compatible microporous surface capable of binding antibody
and/or other substances of interest for carrying out binding assays that is
shaped to fit into at least one well of the plate” (id. at col. 3, ll. 13-19).
11. Matkovich discloses that its methods can involve the “use of a
backing material to support the microporous surface (the backing material
being either rigid or flexible, porous or non-porous)” (id. at col. 3, ll. 24-27).
12. Matkovich discloses that the “reactant, which may be of ionic,
molecular, or macromolecular nature, may be immobilized on the reaction
layer by strong physical forces or by being bonded in some manner, such as
covalent chemical coupling, to the surface of the reaction layer” (id. at col.
4, l. 64, through col. 5, l. 1).
13. Matkovich discloses:
Although the bound material is usually an antibody or antigen,
any reference herein to a binding surface capable of binding an
antibody (or similar language) is not limiting or to be
considered as indicating that only an antibody can be bound to
the surface. Specific examples of molecules that participate in
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binding interactions suitable for use in assays of the type
described here are set forth later in this specification.

(Id. at col. 3, l. 63, through col. 4, l. 2.)
14. Matkovich thus discloses, for example, that the “reagent or acceptor
molecule bound directly to the reaction substrate or the ligand being tested
for include such substances as immunoglobulins or antibodies, either
polyclonal or monoclonal, antigenic substances, apoproteins, receptors,
glycoproteins, lectins, carbohydrates, hormones, enzymes, carrier proteins,
heparin, coagulation factors, enzyme substrates, inhibitors, cofactors, nucleic
acids, etc.” (id. at col. 6, ll. 52-60 (emphasis added)).
PRINCIPLES OF LAW
In KSR Int’ l Co. v. Teleflex Inc., 550 U.S. 398, 415 (2007), the
Supreme Court emphasized “an expansive and flexible approach” to the
obviousness question, and in particular noted that the analysis “need not
seek out precise teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the inferences and creative
steps that a person of ordinary skill in the art would employ.” Id. at 418; see
also id. at 421 (“A person of ordinary skill is . . . a person of ordinary
creativity, not an automaton.”).
The Court also advised that “if a technique has been used to improve
one device, and a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the technique is
obvious unless its actual application is beyond his or her skill. Id. at 418.
Regarding claim interpretation, during examination the PTO must
interpret terms in a claim using “the broadest reasonable meaning of the
words in their ordinary usage as they would be understood by one of
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ordinary skill in the art, taking into account whatever enlightenment by way
of definitions or otherwise that may be afforded by the written description
contained in the applicant’s specification.” In re Morris, 127 F.3d 1048,
1054 (Fed. Cir. 1997).
ANALYSIS
Claim 17
We are not persuaded that the Examiner erred in concluding that an
ordinary artisan would have considered claim 17 obvious in view of the
cited references.
Claim 17 recites an apparatus for analyzing a polynucleotide. The
apparatus has a support with an impermeable surface, and a porous material
attached to the impermeable surface.
The apparatus of claim 17 also has an array of oligonucleotides
attached to the porous material. The array comprises at least two defined
cells, with the sequence of the oligonucleotides of a first cell being different
from the sequence of the oligonucleotides of a second cell.
Claim 17 recites that the “oligonucleotides [attached to the porous
surface] are shorter than the polynucleotide” analyzed by the apparatus. As
this feature is directed to the method by which the apparatus is used, we
conclude that it places essentially no structural limitation on the apparatus of
claim 17.
Claim 17 also recites that the oligonucleotides attached to the porous
surface have “predetermined sequences.” Appellant urges that this
limitation requires a practitioner to know the complete sequence of each and
every oligonucleotide attached to the apparatus (App. Br. 14).
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Even if we adopt this interpretation, however, a porous substrate
having two different oligonucleotides attached to it has the same structure
whether or not the practitioner knows the exact sequence of those
oligonucleotides. That is, the practitioner’s knowledge in no way affects the
actual structure of the array. The use of “predetermined” is an attempt to
incorporate a required process step into this product claim. We therefore
conclude that the recitation “predetermined sequences” in claim 17 does not
place any structural limitation on the claimed apparatus.
Accordingly, we interpret claim 17 as encompassing an apparatus
composed of an impermeable substrate with a porous material attached to it,
the porous material having two or more different oligonucleotides attached
to it, the different oligonucleotides being present in distinct defined cells.
We agree with the Examiner that the cited references suggest an
apparatus that has these features.
As noted above, Stavrianopoulos discloses that “glass plates provided
with an array of depressions or wells would have samples of the various
denatured analytes deposited therein, the single-stranded analytes being
fixed to the surfaces of the wells” (Stavrianopoulos, col. 8, ll. 41-45 (FF 3)).
We agree with the Examiner that this disclosure at the very least suggests
claim 17’s requirement of an array with at least two different
oligonucleotides attached to distinct defined cells.
Appellant argues that it is not reasonable to find that Stavrianopoulos
meets that feature because
One reasonable way of using the Stavrianopoulos assay in a
multiwell format would be to add the same analyte to separate
wells and then to add a different probe to each well. Thus each
well reveals whether a particular sequence is present in a single
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analyte. For instance, a single patient’s blood could be
screened for a dozen different mutations. In this format there
are “various denatured analytes” but each analyte is identical,
whereas claim 17 requires that “the sequence of the
oligonucleotides of a first cell is different from the sequence of
the oligonucleotides of a second cell”.

(Reply Br. 3.)
We are not persuaded by this argument. While it might be reasonable
to interpret Stavrianopoulos in the manner Appellant posits, we agree with
the Examiner that an ordinary artisan would have considered it at least
equally reasonable to interpret the disclosure of applying “various denatured
analytes” to an array of depressions or wells as suggesting that
oligonucleotides from different biological samples should be applied to the
different wells. Doing so would allow the various samples to be tested with
a single probe to determine if the samples, for example from different
individuals being tested, contained a particular nucleic acid sequence of
interest.
Accordingly, we are not persuaded that the Examiner erred in finding
that Stavrianopoulos teaches or suggests the requirement in claim 17 that the
array have two or more defined cells that contain oligonucleotides with
different sequences. Moreover, as discussed above, claim 17’s requirement
that the sequences be “predetermined” does not place any structural
limitation on the apparatus, and we are therefore not persuaded that the array
described by Stavrianopoulos is distinguishable from the array recited in
claim 17 on that basis.
We are also not persuaded that the cited references fail to suggest
adding a porous substrate to Stavrianopoulos’ apparatus for attachment of
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the oligonucleotides. Specifically, while Stavrianopoulos discloses that it is
“preferred that the solid support to which the analyte is fixed be non-porous
and transparent” (Stavrianopoulos, col. 5, ll. 46-48 (FF 5)), Stavrianopoulos
specifically states that “[c]onventional porous materials, e.g., nitrocellulose
filters, although less desirable for practice of the method of the present
invention, may also be employed as a support” (id. at col. 5, ll. 49-52 (FF
5)(emphasis added)).
Moreover, Matkovich discloses that, in assays involving binding of
substances contained in biological samples to immobilized molecules, the
use of a microporous immobilization substrate provides “[s]uperior capacity
for the binding of biological substances” (Matkovich col. 3, ll. 13-14 (FF
10)).
It may be true, as Appellant argues (App. Br. 12), that Matkovich
focuses on using the microporous support for attaching antibodies.
However, Matkovich explicitly states that its teachings are not limited to
antibodies, but instead are applicable to other “molecules that participate in
binding interactions” (Matkovich, col. 3, l. 68 through col. 4, l. 1 (FF 13)),
including “nucleic acids” (id. at col. 6, l. 60 (FF 14)).
Given the references’ teachings, we are not persuaded that the
Examiner erred in finding that an ordinary artisan would have prompted to
use a porous material as the oligonucleotide-immobilizing matrix on
Stavrianopoulos’ apparatus. For the reasons discussed above, we are not
persuaded that the Examiner otherwise erred in concluding that the
apparatus suggested by Stavrianopoulos and Matkovich would have been
obvious to an ordinary artisan.
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We therefore affirm the Examiner’s obviousness rejection of claim 17,
as well as the rejection of claims, 18-22, 26 and 27, which were not argued
separately. See 37 C.F.R. § 41.37(c)(1)(vii).

Claim 23
Claim 23 recites the “[a]pparatus of claim 17, wherein the
oligonucleotides are covalently attached to the porous material.” Appellant
contends that Stavrianopoulos and Matkovich do not teach or suggest this
limitation because Stavrianopoulos immobilizes oligonucleotides to its
substrate by ionic interaction (App. Br. 18).
Thus, Appellant argues, the Examiner has not provided a “reasonable
justification why a skilled person who looked to Matkovich would reject
Stavrianopoulos’[] choice of charged surfaces for and would instead use
covalent bonding” (id.). Moreover, Appellant urges, a “person of ordinary
skill would not arbitrarily select covalent attachment chemistry for an
analyte that is intrinsically ionic in nature and that had been deliberately
immobilized by Stavrianopoulos in a non-covalent manner” (id.).
We are not persuaded. We note that Stavrianopoulos functionalizes
its substrate to provide it with a positive charge that allows immobilization
of the negatively charged nucleic acids via ionic interaction (FF 7), which
undisputedly does not meet claim 23’s requirement of covalent attachment.
As discussed above, however, we agree with the Examiner that an
ordinary artisan would have been prompted by the references to use
Matkovich’s porous material as the oligonucleotide-immobilizing matrix on
Stavrianopoulos’ apparatus. We further agree with the Examiner that an
ordinary artisan using Matkovich’s porous material as an oligonucleotide-
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immobilizing matrix would have looked to Matkovich to determine suitable
methods of attaching substances to its porous material.
As noted above, Matkovich explicitly states that “covalent chemical
coupling” was a suitable method for attaching the immobilized reactants to
the porous matrix (Matkovich, col. 4, l. 68 (FF 12)). Accordingly, we are
not persuaded that an ordinary artisan would have covalently attached the
oligonucleotides to Matkovich’s porous substrate only through hindsight
reasoning, since an ordinary artisan following Matkovich’s explicit teaching
in that regard would have been advised of the suitability of covalent
attachment.
As we agree with the Examiner that the cited references suggest the
covalent attachment recited in claim 23, we affirm the Examiner’s
obviousness rejection of that claim, as well as claim 86, which was argued in
the same grouping. See 37 C.F.R. § 41.37(c)(1)(vii).

Claim 24
Claim 24 recites the “[a]pparatus of claim [17], wherein the
oligonucleotides are covalently attached by a terminal nucleotide.”
Appellant contends that the cited references lack disclosures regarding
this feature that are specific enough to render the claim obvious (App. Br.
20). The Examiner responds that, while Stavrianopoulos “does not
explicitly teach attachment via a terminal nucleotide, the Examiner
maintains that Stavrianopoulos et al. suggests such an attachment where he
teaches that oligonucleotides are attached such that they can still hybridize.
This teaching encompasses attachment via a terminal nucleotide. Matkovich
et al. teaches covalent attachment” (Ans. 14).
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We find that Appellant has the better position here. In contrast to the
situation above, where the prior art explicitly taught the suitability of
covalent attachment, in the instant case the Examiner points to no specific
teaching in either reference suggesting that attachment by the terminal
nucleotide would be suitable in, or even achievable by, the disclosed
methods. Thus, while we acknowledge Stavrianopoulos’ teaching regarding
the desirability of immobilizing the oligonucleotides in a manner that allows
hybridization to a probe, the Examiner has not provided evidence suggesting
that adequate hybridization was unattainable using the attachment methods
described in the references, nor has the Examiner pointed to any specific
evidence that of record suggesting that attachment of oligonucleotides
through the terminal nucleotide would have been desirable, or even suitable,
in the methods of Stavrianopoulos and Matkovich.
Accordingly, we reverse the Examiner’s obviousness rejection of
claim 24, as well as claim 87, which also requires the oligonucleotides to be
attached by a terminal nucleotide.

Claim 25
Claim 25 recites the “[a]pparatus of claim 17, wherein the
oligonucleotides are synthesized in situ.”
To meet that limitation the Examiner cites Stavrianopoulos’ disclosure
that its invention “also encompasses indirect fixation of the analyte, such as
in situ techniques where the cell is fixed to the support” (Stavrianopoulos,
col. 5, ll. 41-43 (FF 8)). Appellant contends that the cited portion of
Stavrianopoulos does not relate to in situ synthesis of the actual
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oligonucleotides, but instead relates to direct immobilization of the cell
containing the target oligonucleotide to the substrate (App. 21).
We agree with Appellant that the cited references do not teach or
suggest the apparatus recited in claim 25.
While we interpret claim 25 as a product-by-process claim, we note
the Specification’s disclosure that in situ synthesis of oligonucleotides
begins with the initial covalent attachment of a terminal nucleotide to the
substrate via a long aliphatic linker, after which reaction mixtures adding the
desired nucleotides via phosphoramidite chemistry are sequentially applied
to the covalently linked terminal nucleotide (Spec. 14-16). Thus, viewing
the claim in light of the Specification, the in situ synthesis method recited in
claim 25 essentially requires the claimed apparatus to have a terminal
nucleotide covalently attached to the substrate.
As noted above, we do not agree with the Examiner that the cited
references render obvious apparatuses in which the oligonucleotides are
attached to the porous substrate by one of the oligonucleotides’ terminal
nucleotides. Nor are we persuaded that Stavrianopoulos’ disclosure of
attaching cells containing the oligonucleotides, rather than the
oligonucleotides themselves, suggests the structure required in claim 25.
Accordingly, we reverse the Examiner’s obviousness rejection of
claim 25.
SUMMARY
We affirm the Examiner’s rejection of claims 17-23, 26, 27, and 86,
under 35 U.S.C. § 103(a) as being obvious in view of Stavrianopoulos and
Matkovich.
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However, we reverse the Examiner’s rejection of claims 24, 25, and
87 over those references.

TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED-IN-PART

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