Ex Parte Roberts et al

Board of Patent Appeals and Interferences

Mar 8, 2010

10398845 (B.P.A.I. Mar. 8, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
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BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
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Ex parte MICHAEL J. ROBERTS and ANTONI KOZLOWSKI
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Appeal 2009-004682
Application 10/398,845
Technology Center 1600
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Decided: March 9, 2010
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Before TONI R. SCHEINER, LORA M. GREEN, and
MELANIE L. McCOLLUM, Administrative Patent Judges.

McCOLLUM, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a polymer
conjugate preparation method. The Examiner has rejected the claims as
obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.
STATEMENT OF THE CASE
Claims 57-79 are on appeal. Claims 80 and 81 are also pending but
have been withdrawn from consideration by the Examiner. (App. Br. 5.)
We will focus on claims 57, 66, and 74, which read as follows:
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57. A method for preparing a bioactive agent hydroxyapatite-
targeting polymer conjugate, said method comprising the steps of:
a. providing an isolated water-soluble polymer comprising, at a first
terminus, a hydroxyapatite-targeting moiety, and at a second terminus, a
reactive group suitable for reacting with a functional group of a biologically
active agent, and
b. reacting said isolated water-soluble polymer from step (a) with a
biologically active agent comprising said functional group under conditions
effective to form a covalently bonded biologically active agent -water-
soluble polymer-hydroxyapatite targeting conjugate.
66. The method of claim [57, wherein said biologically active agent
comprises multiple functional groups suitable for reacting with said reactive
group, and said reacting step is carried out under conditions effective to form
a mixture of biologically active agent -water-soluble polymer-
hydroxyapatite targeting conjugates, wherein said mixture comprises
different conjugate multimer species each having a different number of
hydroxyapatite-targeting-water-soluble polymers covalently attached to said
biologically active agent], wherein said mixture is purified to separate each
of the conjugate multimer species.
74. The method of claim 57, wherein said water-soluble polymer has
a molecular weight ranging from about 100 daltons to about 100,000
daltons.
Claims 57-79 stand rejected under 35 U.S.C. § 103(a) as obvious over
Bentz et al. (EP 0 512 844 A1, Nov. 11, 1992) (Ans. 3).
The Examiner relies on Bentz for substantially disclosing the instant
method (Ans. 4). In particular, the Examiner relies on the embodiment
disclosed in Bentz Example 1 (id. at 6). The Examiner finds that “Bentz
[does] not specifically state that isolated water[] soluble polymer is used,”
but argues that “[o]ne having ordinary skill in the art would have been
motivated to purify the PEG before use in order to remove materials that
may be toxic to the biological system” (id. at 7 & 4).
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Appellants argue:
Nowhere does Example I teach or suggest the step of isolating
the product of tetracycline with bis-epoxy PEG prior to reaction
with an active agent, nor describe the characteristics of such
product, nor would it be obvious or even likely that an
intermediate product such as that embodied by the
Appellant[s’] step (a) would even be formed. Moreover, Bentz
fails to even recognize the insufficiencies of Example I with
respect to providing a useful, characterizable, reproducibly
prepared TGF-β-PEG-bone targeting conjugate.
(App. Br. 15.)
Appellants also argue that Bentz fails to disclose the limitation of
claim 74 because the disclosure of a molecular weight of 5K relates to
mPEG, which does not “meet the limitation of a polymer having a reactive
group at one terminus” (id. at 19).
With regard to claim 66, Appellants argue that “purification of a final
conjugate product, e.g., separation of various multimer species is nowhere
described or suggested in Bentz” (id. at 20).
ISSUES
Did the Examiner err in concluding that Bentz suggests providing an
isolated water-soluble polymer comprising, at a first terminus, a
hydroxyapatite-targeting moiety and, at a second terminus, a reactive group
suitable for reacting with a functional group of a biologically active agent?
Did the Examiner err in concluding that Bentz suggests a water-
soluble polymer having a molecular weight ranging from about 100 daltons
to about 100,000 daltons, as recited in claim 74?
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Did the Examiner err in concluding that Bentz suggests purifying a
mixture to separate each of the conjugate multimer species, as recited in
claim 66?
FINDINGS OF FACT
1. The term “isolated” is defined as “[s]eparated from others;
solitary or singular” (The American Heritage® Dictionary of the English
Language, Houghton Mifflin, Boston, MA, 2007, viewed March 3, 2010,
).
2 The Specification states:
The term “isolatable” is intended to mean that the activated
polymers can be isolated or separated from other compounds
prior to attachment to a biologically active agent. The
acceptable level of isolation or purity will depend on various
factors, such as the difficulty of purification, the type of
contaminating compounds present, etc. . . . As exemplified in
the examples below, the activated polymer derivatives are
generally isolated and purified by precipitation followed by
solvent extraction and/or chromatography techniques, such as
ion-exchange chromatography.
(Spec. 6-7.)
3. The Specification also states:
By isolating or separating the hydroxyapatite-targeting
activated polymers prior to attachment to the biologically active
agent, better yield and purity is achieved. In addition, isolation
of the polymer derivatives allows qualitative and quantitative
analysis of the polymer prior to incorporation of the
biologically active agent, which, in turn, increases the overall
quality of the biologically active product. Having an isolatable
hydroxyapatite-targeting activated polymer available for
attachment to biologically active agents can result in a
conjugate with a well-defined composition that can easily be
conveyed to regulatory authorities.
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(Id.)
4. In addition, the Specification discloses: “The hydroxyapatite-
targeting moiety may comprise any moiety capable of binding to, or
otherwise exhibiting a chemical affinity for, hydroxyapatite surfaces (i.e.
calcium phosphate), such as bone. . . . In one embodiment, the
hydroxyapatite-targeting moiety is . . . tetracycline.” (Id. at 8.)
5. Bentz discloses “a composition comprising a bone growth
factor and a targeting molecule having affinity for a tissue of interest, where
the bone growth factor and targeting molecule are chemically conjugated to
a crosslinker,” the crosslinker preferably being a synthetic hydrophilic
polymer (Bentz, col. 4, ll. 29-34).
6. Bentz discloses that the “bone growth factor is preferably
TGF-β” (id. at col. 4, l. 35).
7. Bentz discloses that the “[t]argeting molecules preferably have
an affinity for bone, such as tetracycline” (id. at col. 4, ll. 36-38).
8. Bentz discloses that “preferred hydrophilic polymers are . . .
polyethylene glycols (PEG) having an average molecular weight between
about 200 and about 10,000” (id. at col. 6, ll. 55-58).
9. Bentz also discloses that the “resulting bone growth factor-
targeting molecule conjugates may be purified by standard techniques,
preferably by reverse-phase HPLC (RP-HPLC), size-exclusion HPLC (SEC-
HPLC . . . ) or ion-exchange chromatography” (id. at col. 9, ll. 34-38).
10. In Example 1, Bentz discloses the preparation of a TGF-β-PEG-
tetracycline conjugate (id. at col. 11, ll. 1-3).
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11. In the method of Bentz Example 1: “Tetracycline (2 µmol . . . )
is dissolved in 1 µmol bis-epoxy-PEG . . . and reacted at 90°C under
nitrogen for 24 hr with gentle stirring. The resulting tetracycline-PEG
conjugate is then reacted with TGF-β2. . . . The resulting TGF-β-PEG-
tetracycline conjugates are then purified by molecular sieve chromatography
and C18-RP-HPLC.” (Id. at col. 11, ll. 5-15.)
12. In Example V, Bentz also discloses the formation of a
tetracycline-PEG conjugate. In forming this product, Bentz discloses
forming a precipitate, which is purified by acetone extraction and “can be
further purified by ion exchange and size exclusion chromatography.” Bentz
additionally discloses that, “[a]fter activation, the tetracycline-PEG
conjugate can then be coupled to the TGF-β.” (Id. at col. 12, ll. 20-44.)
13. In addition, Bentz discloses an embodiment in which
“monomethylpolyethylene glycol (mPEG) (mw 5,000) is reacted with
glutaric anhydride to form mPEG glutarate,” the “glutarate derivative is then
reacted with N-hydroxysuccinimide to form a succinimidyl
monomethylpolyethylene glycol glutarate,” and the “succinimidyl ester is
then capable of reacting with free amino groups present on a bone growth
factor (lysine residues) to form a bone growth factorPEG conjugate, which
may then be further conjugated to a targeting molecule” (id. at col. 9, ll. 12-
21).
PRINCIPLES OF LAW
“In rejecting claims under 35 U.S.C. § 103, the examiner bears the
initial burden of presenting a prima facie case of obviousness. Only if that
burden is met, does the burden of coming forward with evidence or
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argument shift to the applicant.” In re Rijckaert, 9 F.3d 1531, 1532 (Fed.
Cir. 1993) (citation omitted).
“‘[I]t is elementary that the mere recitation of a newly discovered
function or property, inherently possessed by things in the prior art, does not
cause a claim drawn to those things to distinguish over the prior art.’” In re
Best, 562 F.2d 1252, 1254-55 (CCPA 1977) (quoting In re Swinehart, 439
F.2d 210, 212-13 (CCPA 1971)). “[W]hen the PTO shows sound basis for
believing that the products of the applicant and the prior art are the same, the
applicant has the burden of showing that they are not.” In re Spada, 911
F.2d 705, 708 (Fed. Cir. 1990).
“Attorney’s argument in a brief cannot take the place of evidence.” In
re Pearson, 494 F.2d 1399, 1405 (CCPA 1974). “An assertion of what
seems to follow from common experience is just attorney argument and not
the kind of factual evidence that is required to rebut a prima facie case of
obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997).
In addition, “it is well settled that unexpected results must be
established by factual evidence. ‘Mere argument or conclusory statements
in the specification does not suffice.’” Id. (quoting In re De Blauwe, 736
F.2d 699, 705 (Fed. Cir. 1984)). “[W]hen unexpected results are used as
evidence of nonobviousness, the results must be shown to be unexpected
compared with the closest prior art.” In re Baxter-Travenol Labs., 952 F.2d
388, 392 (Fed. Cir. 1991).
ANALYSIS
The term “isolated” is not specifically defined in the Specification. A
general dictionary definition of the term is “[s]eparated from others; solitary
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or singular” (Finding of Fact (FF) 1). However, based on how the term
“isolated” and other forms of the word “isolate” are used in the Specification
(see FF 2), we do not interpret the term “isolated” to require complete
separation from other compounds.
In Example 1, Bentz discloses reacting tetracycline with bis-epoxy-
PEG to form a tetracycline-PEG conjugate (FF 11). Appellants argue that it
would not be “obvious or even likely that an intermediate product such as
that embodied by the Appellant[s’] step (a) would even be formed” (App.
Br. 15). In particular, Appellants argue:
The reagent, bis-epoxy PEG, reacts with amino, hydroxyl, and
thiol groups. Due to the lack of site selective and/or protecting
group chemistry, the use of a bifunctional PEG reagent, the
molar ratios described, absence of solvent, and reaction
temperature described, it is likely that this reaction leads to a
mixture of cross-linked and disordered networks of PEG-
tetracy[c]line compositions. Further, due to the tendency
towards degradation of the tetracycline ring system under
alkaline conditions, one would expect significant degradation of
the tetracycline molecule. Thus, it is highly unlikely that a
discrete, isolable tetracycline-PEG conjugate comprising a
reactive group could even be obtained from this intermediate
synthesis step, even if such were described or suggested - which
it is not.
(Id. at 15-16 (footnotes omitted).)
We are not persuaded. As noted by Appellants, in Bentz Example 1,
the tetracycline-PEG conjugate is formed without solvent (FF 11). Thus, it
is not clear that the tetracycline-PEG conjugate is not already isolated. In
addition, in another embodiment, Bentz discloses isolating and purifying the
intermediate tetracycline-PEG conjugate (FF 12). Therefore, if the
tetracycline-PEG conjugate in Example 1 is not already isolated, we agree
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with the Examiner that it would have been obvious to isolate this
intermediate.
Furthermore, whether or not a mixture of cross-linked and disordered
networks of PEG-tetracycline compositions is formed, given the 2:1 molar
ratio of tetracycline to PEG (FF 11), we find that there is sound basis for the
Examiner to conclude that a PEG polymer with tetracycline on at least one
end is being formed. In addition, given that the method of Example 1 results
in a TGF-β-PEG-tetracycline conjugate (FF 10), we find that there is also
sound basis for the Examiner to conclude that a reactive group suitable for
reacting with a functional group of TGF-β is at the other end. Appellants’
attorney arguments do not persuade us to the contrary.1
Appellants also argue that “Bentz fails to even recognize the
insufficiencies of Example I with respect to providing a useful,
characterizable, reproducibly prepared TGF-β-PEG-bone targeting
conjugate” (App. Br. 15). In particular, Appellants argue:
The recited method is based, at least in part, in the Appellant[s’]
recognition that prior attempts to provide a bioactive agent
having a bone targeting agent attached thereto (such as
described in Bentz) result in compositions that are poorly
characterized, and contain multiple chemical species, due to the
multiple reactive sites typically present on biologically active
agents such as proteins (page 6, line 27 to page 7, line 5). The
numerous species contained in such compositions often possess

1 We note that Example 1 does not disclose that the tetracycline-PEG
conjugate is formed under alkaline conditions. Example 1 does state that the
tetracycline-PEG conjugate is reacted with TGF-β “by adding 100 µg
TGF-β2 dissolved in 0.02 M sodium borate, . . . pH 9.0 to 52 µl of the
tetracycline-PEG conjugate” (Bentz, col. 11, ll. 8-12). However, this occurs
after the tetracycline-PEG conjugate is formed.
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different bioactivi[ti]es and hydroxyapatite-binding
characteristics - due [to] differences in numbers and positions
of attached polymer (Example 9, Example 10).
(Id. at 10.)
We are not persuaded. The Specification states that isolating the
hydroxyapatite-targeting activated polymer provides benefits (FF 3).
However, Appellants have not provided sufficient evidence that isolation
provides benefits as compared to the closest prior art, nor have they provided
evidence that such benefits would have been unexpected.
With regard to claim 74, we recognize that the disclosure in Bentz of
mPEG having a molecular weight of 5,000 is in the context of an
embodiment that is different from the method of claim 57 (see FF 13).
However, we agree with the Examiner that this disclosure renders obvious
the use of PEG having a molecular weight of 5,000 in other embodiments of
Bentz. Furthermore, Bentz generally discloses “polyethylene glycols (PEG)
having an average molecular weight between about 200 and about 10,000”
(FF 8), which is within the range recited in claim 74 and therefore discloses
PEG having a molecular weight within this range.
With regard to claim 66, the Examiner states that “Bentz suggests
purification of the product and since the presence [of] multimers results
[from] the reaction itself, purification of the product would also separate side
products from the desired product. Purification includes isolation of the
desired product from any unwanted by-products.” (Ans. 9.) We do not
agree that the Examiner has set forth a prima facie case that claim 66 would
have been obvious. Bentz Example 1 discloses that the “resulting TGF-β-
PEG-tetracycline conjugates are then purified by molecular sieve
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chromatography and C18-RP-HPLC” (FF 11). In addition, Bentz generally
discloses that the “resulting bone growth factor-targeting molecule
conjugates may be purified by standard techniques, preferably by reverse-
phase HPLC (RP-HPLC), size-exclusion HPLC (SEC-HPLC . . . ) or ion-
exchange chromatography” (FF 9). However, the Examiner has not set forth
a prima facie case that these techniques would necessarily result in the
separation of each conjugate multimer species.
CONCLUSION
Appellants have not shown that the Examiner erred in concluding that
Bentz suggests providing an isolated water-soluble polymer comprising, at a
first terminus, a hydroxyapatite-targeting moiety and, at a second terminus, a
reactive group suitable for reacting with a functional group of a biologically
active agent. We therefore affirm the obviousness rejection of claim 57.
Claims 58-65, 68-73, and 76-79 have not been argued separately and
therefore fall with claim 57. 37 C.F.R. § 41.37(c)(1)(vii).
In addition, Appellants have not shown that the Examiner erred in
concluding that Bentz suggests a water-soluble polymer having a molecular
weight ranging from about 100 daltons to about 100,000 daltons, as recited
in claim 74. We therefore affirm the obviousness rejection of claim 74.
Claim 75 is argued with and therefore falls with claim 74. Id.
However, the Examiner did err in concluding that Bentz suggests
purifying a mixture to separate each of the conjugate multimer species, as
recited in claim 66. We therefore reverse the obviousness rejection of
claim 66 and of claim 67, which depends from claim 66.
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TIME PERIOD FOR RESPONSE
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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