Ex Parte Hsieh

Board of Patent Appeals and Interferences

Nov 24, 2008

11173635 (B.P.A.I. Nov. 24, 2008)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte HUANGPIN BEN HSIEH
__________

Appeal 2008-5237
Application 11/173,635
Technology Center 1600
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Decided: November 24, 2008
__________

Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and
FRANCISCO C. PRATS, Administrative Patent Judges.

PRATS, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to an
oligonucleotide-protein conjugate. The Examiner has entered two rejections
for anticipation. We have jurisdiction under 35 U.S.C. § 6(b). We affirm
one of the Examiner’s anticipation rejections and reverse the other.

Appeal 2008-5237
Application 11/173,635

STATEMENT OF THE CASE
Claims 1-15 are pending and on appeal (App. Br. 1). Claims 1, 2, 4,
7, 8, 10, and 13 are illustrative and read as follows:
1. An oligonucleotide-protein conjugate produced by
coupling an albumin protein to an oligonucleotide while the
oligonucleotide is attached to a support media.

2. The oligonucleotide-protein conjugate of claim 1
wherein the albumin protein is bovine serum albumin (BSA).

4. The oligonucleotide-protein conjugate of claim 2
wherein the ratio of oligonucleotide to BSA ranges from about
1 to about 50.

7. A protein conjugated oligonucleotide produced by
passing a first solution including an oligonucleotide through a
support media thereby coupling said nucleotide to said support
media, passing a second solution including an albumin protein
adapted to form a conjugate with said oligonucleotide through
said support media, thereby conjugating said protein with said
oligonucleotide while said oligonucleotide is coupled to said
support media.

8. The protein conjugated oligonucleotide of claim 7
wherein the albumin protein is bovine serum albumin (BSA)[.]

10. The protein conjugated oligonucleotide of claim 8
wherein the ratio of oligonucleotide to BSA ranges from about
1 to about 50.

13. A conjugate of an oligonucleotide and bovine serum
albumin (BSA) wherein the ratio of oligonucleotide to BSA
ranges from about 1 to about 50.
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The Examiner relies on the following documents to show
unpatentability:
Manoharan US 6,656,730 B1 Dec. 2, 2003

A. Bidaine et al., THE PHOTOTRITYL GROUP.
PHOTOCROSSLINKING OF OLIGONUCLEOTIDES TO BSA,
6 Bioorganic & Medicinal Chemistry Letters 1167-1170 (1996).

The following rejections are before us for review:
Claims 1, 2, 4-8, and 10-15 stand rejected under 35 U.S.C. § 102(b) as
being anticipated by Bidaine (Ans. 4-8).
Claims 1, 3, 7, and 9 stand rejected under 35 U.S.C. § 102(b) as being
anticipated by Manoharan (Ans. 8-11).
ANTICIPATION -- BIDAINE
ISSUE
The Examiner cites Bidaine as disclosing “an oligonucleotide-BSA
complex that is formed on a membrane of cutoff 30,000 from Millipore and
photocrosslinking of oligonucleotides to BSA” (Ans. 4). The Examiner
reasons that, “[a]lthough independent claim 1 requires coupling an albumin
protein to an oligonucleotide while the oligonucleotide is attached to a
support media, claim 1 does not require that an oligonucleotide-protein
conjugate recited in claim 1 must contain support media” (id. at 5).
Rather, the Examiner contends, claim 1 is a product-by-process claim
(id.). Thus, the Examiner argues, “[i]f the product in the product-by-process
claim is the same as or obvious from a product of the prior art, the claim is
unpatentable even though the prior product was made by a different process”
(id.) (citing In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985).
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Appellant argues that the Examiner erred in finding that Bidaine
anticipates claims 1, 7, and 13 because Bidaine does not disclose that its
oligonucleotide-protein conjugate is linked by covalent bonds (App. Br. 5-
7). Appellant further argues that Bidaine does not disclose preparing the
oligonucleotide-protein conjugate using support media attached to the
oligonucleotide (id. at 7-10).
Moreover, Appellant argues, language directed to the method of
making a product can be used to characterize the claimed product, and, as
shown in the Specification, the claimed conjugates are distinguishable from
Bidaine’s (id. at 10-11). Appellant further argues that the oligonucleotide to
conjugation ratios recited in claims 4-6 and 10-15, are not disclosed by
Bidaine (id. at 12-13).
The issue with respect to this rejection, then, is whether the Examiner
erred in finding that Bidaine describes an oligonucleotide-protein conjugate
that meets the structural requirements of the claims.
FINDINGS OF FACT (“FF”)
1. Bidaine discloses that “a photoactivatable trityl cap was used to
immobilize an oligonucleotide on BSA (bovine serum albumin)” (Bidaine
1167).
2. Specifically, Bidaine discloses synthesizing an oligonucleotide linked
to a trityl functional group through 1,2-dideoxy-D-ribofuranose (see Bidaine
1167-68). The tritylated oligonucleotide had the following structure:

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The tritylated oligosaccharide (compound 7), as shown above, “was
acylated by N-hydroxysuccinimidyl p-benzoylbenzoate, to give 8” (id. at
1167). Thus, compound 8 differs from compound 7 in that compound 8 has
the hydrophobic crosslinking group “X” hooked to the trityl group at the
primary amine moiety (id.)
3. Bidaine discloses that “[a]lbumin is well known for its capacity to
bind hydrophobic drugs” (Bidaine 1167). Bovine serum albumin has a
molecular weight of about 66,000 Daltons (see Spec. 2).
Bidaine also discloses that when a mixture of the tritylated
oligonucleotide compound 8 and excess BSA (“2 molar equivalents, or
more”) were ultrafiltered against a membrane having a 30,000 Dalton cutoff,
“the oligonucleotide was more than 90% retained by BSA. Without BSA, it
passed through the membrane” (Bidaine 1167).
Thus, Bidaine showed that BSA was capable of adsorbing tritylated
oligonucleotide compound 8.
4. Bidaine discloses that a complementary filtration experiment was run,
showing that compound 7 was also adsorbed onto BSA (Bidaine 1170 n.
17). The experiment used oligonucleotide:BSA ratios of 1:0.5, 1:1, 1:2, 1:5,
1:20, and 1:50 (id.).
5. Bidaine also discloses covalently binding tritylated oligonucleotide
compound 8 to BSA (Bidaine 1169).
Specifically, Bidaine discloses that tritylated oligonucleotide
compound 8 was dissolved along with “a large excess of BSA (25:1 molar
ratio), [and] was irradiated in a small glass tube by a slide projector for 7
hours (i.e. the time necessary for its complete disappearance). A conjugate
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BSA-oligonucleotide was isolated by preparative anion exchange FPLC and
dialyzed against water (membrane cutoff 12000)” (id. (citation omitted)).
Bidaine calculated that 1 mole of compound 8 yielded “0.4 μmole of
conjugate” (id.).
6. Bidaine discloses that the BSA-oligonucleotide conjugate was able to
capture an oligonucleotide having the complementary sequence, thus
showing that the sequence of compound 8 “was accessible and not
extensively degraded by photolysis” (Bidaine 1169).
PRINCIPLES OF LAW
It is well settled that “[t]o anticipate a claim, a prior art reference
must disclose every limitation of the claimed invention, either explicitly or
inherently.” In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997).
It is also “well settled that the presence of process limitations in
product claims, which product does not otherwise patentably distinguish
over the prior art, cannot impart patentability to that product.” SmithKline
Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1318 (Fed. Cir. 2006)
(quoting In re Stephens, 345 F.2d 1020, 1023 (CCPA 1965). As stated in In
re Thorpe, 777 F.2d at 697 (citations omitted):
[E]ven though product-by-process claims are limited by and
defined by the process, determination of patentability is based
on the product itself. The patentability of a product does not
depend on its method of production. If the product in the
product-by-process claim is the same as or obvious from a
product of the prior art, the claim is unpatentable even though
the prior product was made by a different process.

Also, once the Examiner establishes that a product recited in terms of
its process of making is prima facie unpatentable due to anticipation,
Appellant bears the burden of proving “that the prior art products do not
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necessarily or inherently possess the characteristics of his claimed product.”
Id. at 698 (quoting In re Fitzgerald, 619 F.2d 67, 70 (CCPA 1980); In re
Best, 562 F.2d 1252, 1255 (CCPA 1977)).
ANALYSIS
Appellant’s arguments do not persuade us that the Examiner erred in
finding that Bidaine describes an oligonucleotide-protein conjugate that
meets the structural requirements of the claims. Claims 1 and 7 require the
recited compound to be either an “oligonucleotide protein conjugate” (claim
1), or a “protein conjugated oligonucleotide” (claim 7), the protein in both
cases being an albumin.
Contrary to Appellant’s argument, Bidaine discloses that the tritylated
oligonucleotide compound 8 was in fact covalently linked to BSA by
photocrosslinking, to form a “conjugate” (see FF 5). Because Bidaine’s
oligonucleotide-BSA conjugate meets all of the structural limitations in
claims 1 and 7, we agree with the Examiner that it was reasonable to
conclude that Bidaine’s conjugate is encompassed by those claims.
Given this reasonable finding that claims 1 and 7 are prima facie
anticipated by Bidaine, the burden shifted to Appellant to show non-
anticipation. In re Thorpe, 777 F.2d at 698. We find that Appellant has not
met the burden of adequately rebutting the Examiner’s prima facie case of
anticipation.
Specifically, Appellant argues that claims 1 and 7 require the use of
“support media” to prepare the claimed compound, and that the filter
membrane used by Bidaine in the filtration experiments is not the same
medium disclosed in the Specification as being used to prepare the claimed
conjugates (App. Br. 7-8). Moreover, Appellant urges, claims 1 and 7
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require linkage of the oligonucleotide to the support, which is not disclosed
in Bidaine (id. at 8-10). Appellant further urges that the claimed process
limitations impart a structural difference to the claimed product because the
process limitations result in higher conjugation ratios as compared to other
methods of producing oligonucleotide-BSA conjugates (id. at 11-12).
We are not persuaded by these arguments. Appellant does not point
to, nor explain, any structural difference between a conjugate produced
using the asserted media and the conjugate of Bidaine. Moreover, neither
claim 1 nor claim 7 requires any specific conjugation ratio.
Therefore, because Appellant has not met the burden of showing that
Bidaine’s conjugate is structurally different from the conjugates recited in
claims 1 and 7, we affirm the Examiner’s anticipation rejection of those
claims. Because they were not argued separately, claims 2 and 8 fall with
claims 1 and 7. See 37 C.F.R. § 41.37(c)(1)(vii).
Appellant argues that the Examiner erred in finding that Bidaine
meets the limitations in claims 4-6 and 10-15 requiring the conjugates to
have specific oligonucleotide to BSA ratios. Specifically, Appellant notes
that the Examiner relied on note 17 in Bidaine to meet this limitation (see FF
4), but argue:
A close review of note 17 in the paper to Bidaine et al.
reveals that the ratios of oligonucleotide to BSA are merely the
relative amounts of oligonucleotide that is adsorbed on BSA.
These amounts of oligonucleotide and BSA are not amounts of
each in a conjugated product as called for in the claims at issue.
This is yet another significant distinction between the pending
claims and the limited disclosure by Bidaine et al.

(App. Br. 13.)
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We select claim 4 as representative of the argued claims. See 37
C.F.R. § 41.37(c)(1)(vii). Claim 4 recites “[t]he oligonucleotide-protein
conjugate of claim 2 wherein the ratio of oligonucleotide to BSA ranges
from about 1 to about 50.”
Claim 2, in turn, recites “[t]he oligonucleotide-protein conjugate of
claim 1 wherein the albumin protein is bovine serum albumin (BSA).”
Thus, claim 4 recites an oligonucleotide-BSA conjugate in which the
oligonucleotide:BSA ratio ranges from about 1:1 to about 50:1.
Bidaine’s tritylated oligonucleotide compound 8 contains a single
hydrophobic crosslinking moiety “X” that allows conjugation of the
oligonucleotide to the BSA (see FF 2). Thus, when Bidaine reacted the
oligonucleotide compound 8 with an excess of BSA to produce conjugated
molecules (FF 5), each oligonucleotide moiety could, at most, carry only a
single BSA molecule.
Given the excess of BSA used in Bidaine’s conjugation reaction, and
the oligonucleotide contruct’s capacity to bind at most a single BSA
molecule to the hydrophobic crosslinking moiety “X”, we agree with the
Examiner that it was reasonable to conclude that the conjugates produced by
Bidaine’s conjugation reaction had at least a 1:1 oligonucleotide:BSA ratio,
which is encompassed by claim 4’s ratio of from about 1:1 to 50:1.
Appellant’s argument therefore does not persuade us that the Examiner erred
in concluding that Bidaine meets the oligonucleotide:BSA ratio recited in
claim 4.
We therefore affirm the Examiner’s rejection of claim 4 as anticipated
by Bidaine. Because they were not argued separately, claims 5, 6, and 10-15
fall with claim 4. See 37 C.F.R. § 41.37(c)(1)(vii).
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ANTICIPATION -- MANOHARAN
ISSUE
Claims 1, 3, 7, and 9 stand rejected under 35 U.S.C. § 102(b) as being
anticipated by Manoharan (Ans. 8-11).
The Examiner cites Manoharan as disclosing “an oligonucleotide-
albumin complex on membranes” in which “the synthesized oligonucleotide
is attached to 3'-amino modified controlled pore glass . . . and the
conjugation reaction is performed with the oligonu[cle]otide still bound to
the solid support” (id. at 8 (citations omitted)). The Examiner reasons that
claim 1 encompasses Manoharan’s oligonucleotide-albumin complex
because Appellant’s Specification does not define the claim term
“conjugate” and therefore “the claims do not require a protein conjugated
oligonucleotide formed by covalent bonds” (id. at 9).
Appellant contends the Examiner erred in finding that Manoharan
anticipates the cited claims because Manoharan merely discloses a test of the
efficiency of the oligonucleotides’ binding to human serum albumin (App.
Br. 15-16). Appellant argues that the disclosed easily reversible binding is
not a covalent bond, and that Manoharan therefore “fails to disclose a
procedure to make a ‘conjugated’ oligonucleotide-protein product” (id. at
16; see also Reply Br.16).
The issue with respect to this rejection, then, is whether the Examiner
erred in interpreting the claims as encompassing Manoharan’s membrane-
bound oligonucleotide-albumin complex.
FINDINGS OF FACT
7. Manoharan discloses methods for increasing the concentration of
therapeutic or diagnostic oligonucleotides, such as antisense
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oligonucleotides, in serum (Manoharan, col. 10, l. 60, through col. 12, l. 1).
To accomplish this, “a drug moiety that is known to bind to a serum protein
is selected and conjugated to an oligonucleotide” (id. at col. 10, ll. 62-64).
8. Manoharan discloses examples in which oligonucleotides were
covalently bound to a variety of drugs, including ibuprofen (Manoharan, col.
38, l. 50 through col. 42, l. 8), penicillin (id. at col. 44, l. 20 through col. 45,
l. 9), and aspirin (id. at col. 45, l. 54 through col. 46, l. 3). The covalently
bound drug-oligonucleotide constructs are referred to as being
“[c]onjugated” (id. at col. 44, ll. 24 and 52; col. 45, l. 55).
9. Manoharan discloses a test of the capacity of its drug-oligonucleotide
conjugates to bind to human serum albumin (Manoharan, col. 46, l. 4
through col. 47, l. 45).
Specifically, mixtures of human serum albumin and radioactively
labeled oligonucleotide-drug conjugates, or unconjugated oligonucleotides,
were placed on ultrafiltration membranes having a 30,000 Dalton cutoff, and
gently spun until about 20% of the sample had passed through the filter,
after which the binding efficiencies were determined based on the amounts
of bound and free label present (id. at col. 46, ll. 21-40). Manoharan
discloses that binding of the “unconjugated” oligonucleotide controls was
“very weak,” whereas “[a]ddition of the ibuprofen conjugate increased the
affinity substantially” (id. at col. 46, ll. 58-60).
10. Manoharan does not refer to the binding of the drug-oligonucleotide
constructs to the albumin as “conjugation,” nor does Manoharan disclose
that the drug-oligonucleotide conjugates became covalently bound to the
albumin. Rather, Manoharan discloses that “[b]inding of drugs to albumin is
usually rapidly reversible” (Manoharan, col. 4, ll. 35-36).
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11. Appellant’s Specification uses the term “conjugation” to refer to a
covalent linkage between the oligonucleotide and albumin. For example, the
Specification discloses that “[c]onjugation between BSA and an
oligonucleotide generally occurs by introducing an amino linker to the
oligonucleotide and then conjugating the BSA to the linker. One example of
an amino linker is a C-12 amino linker” (Spec. 8).
12. The Specification discloses an example of “conjugation” of an
oligonucleotide to BSA through a C-12 amino linker (id. at 14), and
designates the product as having the structure “oligo-NH-BSA” (id. at 15).
The Specification discloses determining the molecular weight of the C-12
amino-linked oligonucleotide-BSA construct (id.) The Specification
designates the conjugate’s structure as “Oligo-C12-NH-BSA,” and refers to
the construct as “conjugated oligonucleotide-BSA” (id.).
PRINCIPLES OF LAW
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 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).
Thus, while “the PTO must give claims their broadest reasonable
interpretation, this interpretation must be consistent with the one that those
skilled in the art would reach.” In re Cortright, 165 F.3d 1353, 1358 (Fed.
Cir. 1999).

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ANALYSIS
We agree with Appellant that the Examiner erred in interpreting the
claims as encompassing Manoharan’s membrane-bound oligonucleotide-
albumin complex. The independent claims subject to this ground of
rejection, 1 and 7, recite that the claimed compound is an “oligonucleotide
protein conjugate” (claim 1), or a “protein conjugated oligonucleotide”
(claim 7).
We note, as the Examiner argues,1 that a generic dictionary defines
“conjugate” as merely meaning “to rejoin together” (Ans. 12). We do not
agree, however, that the generic definition advanced by the Examiner
governs the claim interpretation in this case. Rather, we agree with
Appellant that the claims require some type of covalent linkage between the
oligonucleotide and the protein.
While it is true that claims must be given their broadest reasonable
interpretation consistent with the Specification, Morris, 127 F.3d at 1054,
claim terms must also be interpreted as they would by one of ordinary skill
in the pertinent art. See Cortright, 165 F.3d at 1358.
In the instant case, the prior art cited by the Examiner consistently
uses the term “conjugate” to refer only to covalently linked moieties, and

1 The Examiner also presents a significant amount of argument in the
Response to Reply Brief mailed July 24, 2007. This document, in essence,
is a Supplemental Examiner’s Answer.
The Examiner may furnish a Supplemental Examiner’s Answer in
response to new issues raised in a Reply Brief. MPEP § 1207.05. However,
“[e]very supplemental examiner’s answer must be approved by a
Technology Center (TC) Director or designee.” Id. Because the document
mailed July 24, 2007, does not evidence the required approval, we do not
consider the arguments presented therein.
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does not use that term to refer to non-covalently associated species. For
example, Manoharan only uses “conjugate” to refer to the covalently linked
drug-oligonucleotide construct (FF 7, 8), but does not use that term to refer
to the oligonucleotide construct when it is reversibly bound to the albumin
(FF 9, 10). Similarly, Bidaine only uses “conjugate” to refer to the
covalently bound oligonucleotide-BSA construct, but does not use that term
to refer to the oligonucleotide when it is merely adsorbed to BSA in
filtration experiments (see FF 3-5).
Moreover, consistent with the cited prior art’s usage of the term,
Appellant’s Specification uses “conjugate” to refer only to covalently linked
species (FF 11, 12). Thus, there is no evidence that Appellant sought to
diverge from the art-accepted meaning of the term evidenced by Manoharan
and Bidaine. We therefore agree with Appellant that, when given their
broadest reasonable interpretation consistent with the Specification and the
prior art, the claims require some type of covalent linkage between the
oligonucleotide and the protein moieties.
Manoharan discloses binding experiments between
drug-oligonucleotide conjugates and human serum albumin (FF 9).
Manoharan does not refer to the albumin-oligonucleotide association as
being a “conjugate” nor does Manoharan state that the oligonucleotide
construct is covalently bound to the albumin (FF 10). Rather, Manoharan
states that drugs usually bind reversibly to albumin (FF 10).
Because the Examiner does not point to, nor do we see, any evidence
that Manoharan’s oligonucleotide construct is covalently bound to albumin,
as required by claims 1 and 7, we reverse the Examiner’s rejection of those
claims, and their dependent claims 3 and 9, as anticipated by Manoharan.
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SUMMARY
We affirm the Examiner’s rejection of claims 1, 2, 4-8, and 10-15
under 35 U.S.C. § 102(b) as anticipated by Bidaine.
We reverse the Examiner’s rejection of claims 1, 3, 7, and 9 under
35 U.S.C. § 102(b) as anticipated by Manoharan.

AFFIRMED-IN-PART

lp

MARK S. SVAT, ESQ.
FAY, SHARPE, FAGAN, MINNICH & McKEE, LLP
1100 SUPERIOR AVENUE, SEVENTH FLOOR
CLEVELAND OH 44114-2579
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