Ex Parte Leung et al

Board of Patent Appeals and Interferences

Apr 22, 2009

10939988 (B.P.A.I. Apr. 22, 2009)

UNITED STATES PATENT AND TRADEMARK OFFICE
_________________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
_________________

Ex parte DAVID W. LEUNG, PHILIP A. BERGMAN, ALAN LOFQUIST,
GREGORY E. PIETZ, CHRISTOPHER K. TOMPKINS,
and DAVID W. WAGGONER, Jr.

Appellants
_________________

Appeal 2008-5749
Application 10/939,988
Technology Center 1600
_________________

Decided1: April 22, 2009
_________________

Before RICHARD TORCZON, SALLY GARDNER LANE and MICHAEL
P. TIERNEY, Administrative Patent Judges.

LANE, Administrative Patent Judge.

DECISION ON APPEAL

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).

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I. STATEMENT OF THE CASE
The appeal, under 35 U.S.C. § 134, is from a Final Rejection of claims
1, 3, 11, and 15. Claims 2, 4, 5, 9, 10, 12-14, 16-48, 54, 55, and 57-62 were
canceled. (App. Br. 6). Claims 6-8, 49-53, and 56 have been withdrawn for
claiming non-elected subject matter. (See Response to Restriction
Requirement, Oct. 11, 2005). We have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
Appellants claim a recombinant form of granulocyte colony
stimulating factor (“G-CSF”) that is attached to a polyglutamic acid or
polyaspartic acid of between 10 kD and 100 kD.
The Examiner relied on the following patent documents.
Number Name Date
5,977,163 (“US ’163”) Li et al. Nov. 2, 1999
6,180,084 (“US ’084”) Ruoslahti et al. Jan. 30, 2001
WO 99/33957 Deussen et al. Jul. 8, 1999

The Examiner also relied on the following publications.
• Tanaka et al., “Pharmacokinetics of Recombinant Human
Granulocyte Colony-stimulating Factor Conjugated to
Polyethylene Glycol in Rats,” Cancer Res., vol. 51, pp. 3710-
3714 (1991) (“Tanaka”).

• Suominen et al., “Enhanced recovery and purification of
Aspergillus glucoamylase from Saccharomyces cerevisiae by
the addition of poly(aspartic acid) tails,” Enzyme Microb.
Technol., vol. 15, pp. 593-600 (1993) (Suominen”).

• Li et al., “Complete Regression of Well-established Tumors
Using a Novel Water-soluble Poly(L-Glutamic Acid)-Paclitaxel
Conjugate,” Cancer Res., vol. 58, pp. 2404-09 (1998) (“Li”).

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• LeBorgne et al., “Experimental and theoretical analysis of the
chromatographic behaviour of protein purification fusions
carrying charged tails,” Bioseparation, vol. 5, pp. 53-64 (1995)
(“LeBorgne”).

The Examiner rejected claims 1 and 11 under 35 U.S.C. § 103(a) over
LeBorgne, Tanaka, US ‘163 and Li. The Examiner also rejected claims 1
and 11 under 35 U.S.C. § 103(a) over Suominen, Tanaka, US ‘163 and Li.
Finally, the Examiner rejected claims 1, 11, and 15 under 35 U.S.C. § 103(a)
over WO 99/33957 and Tanaka. Appellants did not argue for the
patentability of any of these claims separately. We review claim 1 as a
representative claim as to each rejection. See Bd. R. 37(c)(1)(vii).
In addition, the Examiner rejected claim 3 under 35 U.S.C. § 103(a)
over the each of the groups of references cited above, along with US ‘084.
II. REJECTIONS OVER LEBORGNE OR SOUMINEN TAKEN
WITH TANAKA, US ‘163, AND LI
1. Appellants’ claim 1 recites:
A recombinant fusion protein, comprising a polyanionic
polypeptide and a granulocyte colony stimulating factor
polypeptide at either one end or at both ends thereof,
wherein the size of the polyanionic polypeptide is
between 10 kD and 100 kD, and
wherein the polyanionic polypeptide is polyglutamic acid
or polyaspartic acid.2

(App. Br. 21, Claims Appx.).

2 Claim 1 has been reformatted, to add indentations. (See 37 C.F.R.
§ 1.75(i)).
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2. LeBorgne teaches that a “[p]oly(glutamic acid) tail consisting
of 6 glutamate residues was fused to the N-terminus of Escherichia coli β-
galactosidase (β-gal), by genetic engineering techniques.” (LeBrogne
abstract).
3. LeBorgne teaches that “[t]he use of such a charged fusion for
selective recovery of β-gal from cell extract using IEC [Ion Exchange
Chromatography] and Ion-Exchange Membrane Chromatography (IEMC)
was explored. The additional charges enabled the separation factor to be
increased about two-fold on both IEC and IEMC . . . .” (LeBorgne abstract).
4. Suominen teaches “[e]nhanced recovery and purification of
Aspergillus glucoamylase from Saccharomyces cerevisiae by the addition of
poly(aspartic acid) tails.” (Suominen title).
5. Suominen teaches that
[p]oly(aspartic acid) tails of different lengths were fused to the
glucoamylase (GA) of Aspergillus awamori by genetic
engineering techniques. Tails consisting of 5, 7, and 10
asparate residues were fused to the N-terminus of the full-
length mature GA (aa 1-616) downstream from the intact leader
peptide to produce fusion proteins designated GAND5,
GAND7, and GAND10, respectively.

(Suominen abstract).
6. Those of skill in the art would know that improved selection
and recovery is an advantage with any recombinant protein. (Suominen
at 593-94).
7. US ‘163 teaches that “[p]olymers with molecular mass larger
than 30 kDa do not readily diffuse through normal capillaries and glomerular
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endothelium, thus sparing normal tissue from irrelevant drug-mediated
toxicity [citations omitted].” (US ‘163 col. 3, ll. 16-19).
8. US ‘163 provides that “[t]he calculated molecular weight of
PG-paclitaxel [poly(L-glutamic acid)-paclitaxel conjugate] containing 15-
25% paclitaxel (w/w) is in the range of 45-55 kDa.” (US ‘163 col. 14, ll. 49-
51).
9. US ‘163 teaches PG-paclitaxel with a molecular weight
between 10 kD and 100 kD.
10. Tanaka discloses “recombinant human granulocyte colony-
stimulating factor conjugated to polyethylene glycol (PEG-rhG-CSF) . . . .”
(Tanaka abstract).
Legal Principles
The Supreme Court has noted that “[i]f a person of ordinary skill can
implement a predictable variation, § 103 likely bars its patentability.” KSR
Int’l Co. v. Teleflex, Inc., 127 S.Ct. 1727, 1740 (2007). Not all variations
that those of skill in the art might theoretically have predicted are barred
under 35 U.S.C. § 103. Absent a reason why the skilled artisan would have
made the variation, it may be patentable. See KSR Int’l v. Teleflex Inc., 127
S.Ct. 1727, 1740-41 (2007) (“Often, it will be necessary for a court to look
to interrelated teachings of multiple patents; the effects of demands known
to the design community or present in the marketplace; 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 by the patent at issue. To facilitate review,
this analysis should be made explicit.”).
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Issue
Would those of skill in the art have found a fusion between a
polyanionic domain of between 10 kD to 100 kD and G-CSF obvious from
the teachings of either LeBorgne or Suominen with the teachings of Tanaka,
US ‘163, and Li?
Analysis
Le Borgne (FFs3 2-3) and Suominen (FF 4-5) teach making fusions
for selective recovery of an attached recombinant protein. (FF 10). US ‘163
teaches polyglutamic acid fused to the drug paclitaxel with a molecular
weight between 10 kD and 100 kD. (FF 7-9). Tanaka teaches recombinant
hG-CSF attached to PEG as a carrier. (FF 10). According to the Examiner,
it would have been obvious to one of ordinary skill in the art at
the time the invention was made to recombinantly make any
fusion protein comprising a polyanionic polypeptide by fusing
any polyglutamic as taught by LeBorgne et al where
polyplutamic acid having the desired length or molecular
weight between 10 kD and 100 kD as taught by the ‘163 patent
or Li et al to any polypeptide or drug such as human
granulocyte colony-stimulating factor (rG-CSF) as taught by
Tanaka et al.

(Ans. 8). The Examiner makes a similar argument for the rejection over
Suominen. (See Ans. 10).
Appellants argue that the Examiner erred in assuming that
in the context of fusion proteins, either all polyanions are
interchangeable, or all therapeutic proteins are interchangeable,
regardless of what the conjugate is being used to accomplish.
That is, the Examiner . . . fails to given a reason why it would

3 Findings of fact.
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have been obvious to replace the prior art protein, e.g. β-
galactosidase, GAND5, GAND7, or GAND10, with Tanaka’s
GCSF protein. It is only by reading Appellants’ present
specification and implementing hindsight reconstruction that
the examiner could possibly conceive of the claimed
recombinant GCSF-polyglutamic/polyaspartic fusion protein.

(App. Br. 19). We are not persuaded by Appellants’ argument. Because
LeBorgne and Suominen teach that polyanions are useful for the selective
recovery of the different proteins β-galactosidase of E. coli (FFs 2-3) and
glucoamylase of A. awamori (FFs 4-5), it would seem, without evidence to
the contrary, that polyanions would be useful for selective recovery of
recombinant protein generally. Appellants have not directed us to evidence
to the contrary. Furthermore, those of skill in the art would have considered
selective recovery to be useful for any recombinant protein. (FF 6). Thus,
Appellants have not persuaded us that those of skill in the art would not have
considered the combination of the cited references to be obvious to achieve
selective recovery of G-CSF. See KSR, 127 S.Ct. at 1742 (“any need or
problem known in the field of endeavor at the time of invention and
addressed by the patent can provide a reason for combining the elements in
the manner claimed.”).
In their “Summary of the Argument,” Appellants note
that conventional techniques of chemical synthesis could not
accommodate production of larger polyanionic polymers.
Thus, “it is difficult to control the specificity and quality of
larger [>10 kD] molecular weight polyanionic polymers when
using chemical synthesis methods.” [Specification], paragraph
bridging pages 2 and 3.
To address this problem, Appellants invented a
recombinant method for reproducibly producing a
monodispersion of polyanionic polymer, between 10 kD and
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100 kD in size, that can be recombinantly fused to GCSF to
enhance the latter’s water-solubility, thereby modifying its
bioavailability and circulatory half-life in the body.

(App. Br. 10). To the extent that Appellants are arguing that the claimed
protein is not obvious because they have invented a way to make
polyanionic polymers of between 10 kD and 100 kD, we are not persuaded.
Appellants claim only a recombinant fusion protein, not a method of
producing a polyanionic polypeptide fused to G-CSF. Given the teaching in
US ‘163 of PG-paclitaxel with a molecular weight between 10 kD and 100
kD (FFs 15-17), Appellants have not directed us to sufficient evidence that
those of skill in the art would not have found a fusion between a polyanionic
polypeptide of the claimed size and G-CSF to be obvious from the teaching
of US ‘163 (FFs 7-9).
Conclusion of Law
Appellants have failed to convinced us that those of skill in the art
would not have found a polyanionic domain of between 10 kD and 100 kD
fused to G-CSF obvious from the teachings of either LeBorgne or Suominen
and Tanaka, US ‘163, and Li. Accordingly, the Examiner did not err in
rejecting claim 1 under 35 U.S.C. § 103(a) over LeBorgne or Suominen,
taken with Tanaka, US ‘163, and Li.
Claim 3
11. Appellants’ claim 3 recites:
The recombinant fusion protein of claim 1 further comprising a
targeting polypeptide.

(App. Br. 21, Claims Appx.).
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12. The term “targeting polypeptide” was not found in Appellants’
specification, but the term “targeting motif” is defined as “a targeting moiety
that comprises either an amino acid sequence or a small molecule that has
affinity with other proteins or biological structures.” (Spec. ¶ [0080]).
13. US ‘084 teaches that “the ability of tumor homing peptides of
the invention to target drugs into tumors was examined. As disclosed
herein, the linking of a cancer chemotherapeutic agent, doxorubicin, to a
tumor homing molecule reduced the systemic toxicity of the doxorubicin
and enhanced anti-tumor activity of the agent (see Examples VIII and XV).”
(US ‘084 col. 15, ll. 14-20).
Analysis
Appellants’ claim 3 adds a “targeting polypeptide” to the recombinant
fusion protein recited in claim 1 (FF 11), which we understand to be an
amino acid sequence or a small molecule that has affinity with other proteins
or biological structures.” (FF 12). US ‘084 teaches “tumor homing
peptides” that target drugs into tumors. (FF 13).
Appellants argue that “[t]he citation to prior art that teaches a fusion
protein that contains a ‘targeting peptide,’ for instance, does not remedy the
fatal deficiency that no combination of the prior art taught or suggested a
recombinant fusion protein comprising GCSF and polyglutamic acid or
polyaspartic acid.” (App. Br. 19). As explained above, we find no
deficiency in the teaching of a recombinant fusion protein comprising GCSF
and a polyanion by the prior art.
Accordingly, we are not persuaded that the Examiner erred in
rejecting claim 3 under 35 U.S.C. § 103(a) over LeBorgne or Suominen and
Tanaka, US ‘163, Li, and US ‘084.
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III. REJECTIONS OVER WO 99/33957 AND TANAKA
14. WO 99/33957 teaches that “anionic peptides might be used as
carriers of ligands to bone.” (WO 99/33957 p. 2, ll. 19-20).
15. WO 99/33957 describes “a modified enzyme comprising one or
more polyanionic domains [that] binds to hydroxylapatite in the teeth,
thereby allowing the enzyme in an oral care composition to exert a
prolonged enzymatic action.” (WO 99/33957 p. 2, ll. 26-29).
16. WO 99/33957 teaches that “[p]referred examples of
polyanionic peptide domains are polyglutamic acid and polyaspartic acid
. . . . (WO 99/33957 p. 4, ll. 16-17).
17. Tanaka teaches that G-CSF “induced differentiation in a murine
myelomonocytic leukemic cell line and stimulated granulocyte colony
formulation by normal progenitor cells.” (Tanaka 3710, left col.).
18. Those of skill in the art would have known that the progenitors
of granulocyte colonies reside in the bone marrow.
19. Tanaka teaches that “[c]onjugation of PEG to proteins increases
their size; the larger the protein, the slower is the clearance by the kidney.
This is an explanation for the decrease in clearance by PEG-modified
protein.” (Tanaka p. 3713, left col.).
20. Tanaka teaches that “[t]he serum rhG-CSF concentration
decreased steadily after injection with a terminal half-life of 1.79 h. The
PEG-rhG-CSF concentration after injection decreased much more slowly
with a half-life of 7.05 h.” (Tanaka abstract).
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Issue
Would those of skill in the art have had a reason to add a polyanionic
domain to G-CSF from the teachings of WO 99/33957 and Tanaka?
Analysis
The Examiner relied on WO 99/33957 as teaching that “[t]he
polyglutamic and/or polyaspartic acid domain of the fusion protein is
negative charge at pH 7, which is useful for binding hydroxylapatite on teeth
surface or bone and prolonged the enzyme action for an extended period of
time (see page 2, lines 15-29, page 21, lines 25-37, page 9, lines in
particular).” (Ans. 4; see FFs 14 and 16). Tanaka teaches the advantages of
extending the half-life of G-CSF. (FFs 19-20). Because those of skill knew
that G-CSF acts on cells in the bone marrow (FFs 17-18), those of skill in
the art would have had reason to combine WO 99/33957 and Tanaka to
prolong the activity of G-CSF by targeting it to the bone.
Appellants argue that “the proteins in question – oral enzymes versus
hormonal GCSF – are used in wholly unrelated fields, and the polyanionic
peptides to which each is attached perform different functions, namely,
binding to teeth versus slowing the rate by which GCSF is filtered from the
body via its kidney/renal system thereby prolonging its neutrophil-
stimulating activity.” (App. Br. 12). WO 99/33957 teaches that polyanionic
peptides bind to bone, as well as to teeth. Because G-CSF acts on bone
marrow cells, one skilled in the art would have had reason to look to
teachings relating to binding a compound to hydroxyapatite which would
allow for prolonged activity at the bone site
Appellants also argue that
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the Examiner’s reasoning is fundamentally and fatally flawed
because WO 99/33957 teaches away from using polyethylene
glycol as polyanionic conjugate of an oral enzyme. Rather, WO
99/33957 teaches only that PEG is useful for preventing the
loss of water from oral care products, such as toothpaste.
Thus WO 99/33957 refers to PEG only once in the specification
at page 19, lines 11-18, as a possible species of ‘humectants.’
A humectant is ‘employed to prevent loss of water from e.g.,
toothpastes. Suitable humectants for use in oral care products
. . . include . . . polyethylene glycol.’ Id.

(App. Br. 13 (emphasis in original)). “A reference may be said to teach away
when a person of ordinary skill, upon reading the reference, would be
discouraged from following the path set out in the reference, or would be led
in a direction divergent from the path that was taken by the applicant.” In re
Gurley, 27 F3d 551, 553 (Fed. Cir. 1994). Appellants fail to sufficiently
explain why the use of PEG as a humectant in oral care products would have
discouraged those in the art from using it in other ways, under different
circumstances.
Similarly, Appellants argue that “Tanaka does not teach or suggest
that something other than PEG could be conjugated to GCSF. . . . In light of
this background, common sense would have militated against replacing the
oral enzyme of WO 99/33957 with Tanaka’s non-oral cytokine, GCSF.”
(App. Br. 15-16). Again, Appellants fail to explain why the conjugation of
PEG to G-CSF would have discouraged those in the art from conjugating
other moieties to G-CSF.
Appellants also assert:
Nothing in WO 99/33957 or Tanaka teaches that the category of
chemicals that are used as humectants, such as PEG, is fungible
with the category of negatively charged polypeptides that are
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useful for binding enzymes to teeth. The function of the
polyanion in WO 99/339567 is to stick its partnering enzyme to
a tooth; the function of PEG in WO 99/33957 is to prevent
toothpaste from drying out.

(App. Br. 14). To the extent Appellants’ are arguing there is no reason to
combine WO 99/33957 and Tanaka, we find the common activity of
polyanion peptides and G-CSF at the bone to be a sufficient reason.
Appellants have not provided sufficient evidence to persuade us otherwise.
Finally, Appellants argue that “[w]ith nothing beyond the unfounded
generalization that polyglutamic acid and PEG are equivalent in this context,
the Examiner contends that the skilled artisan would have expected the
former to work at least as well as the latter.” (App. Br. 16). While we make
no determination that polyglutamic acid would work “at least as well as”
PEG we conclude that one skilled in the art would have had a reason to
select polyglutamic acid and would have expected it to allow the G-CSF to
attach to its site of action, i.e., the bone, and thus to allow for prolonged
activity.
Appellants also argue that the Examiner “has already acknowledged
the distinctness of GCSF in its 21-way restriction requirement dated
September 8, 2005.” (App. Br. 17 (emphasis in orginal)). According to
Appellants, the Examiner “is barred from advancing an obviousness
rationale” (App. Br. 17) because “this restriction requirement precludes a
rejection under 35 U.S.C. § 103 based on interchanging G-CSF with any
other protein. (App. Br. 18). The Examiner’s restriction requirement,does
not amount to a conclusion of nonobviousness of the claimed fusion protein
over the prior art. In re Weber, 580 F.2d 455, 458 (CCPA 1978) (“[I]t is
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recognized that the PTO must have some means for controlling such
administrative matters as examiner caseloads and the amount of searching
done per filing fee.”)
Conclusion of Law
Those of skill in the art would have had a reason to add a polyanionic
domain to G-CSF from the teachings of WO 99/33957 and Tanaka.
Accordingly, the Examiner did not err in rejecting claim 1 under 35 U.S.C.
§ 103(a) over WO 99/33957 and Tanaka.
Claim 3
Appellants argue that “[t]he citation to prior art that teaches a fusion
protein that contains a ‘targeting peptide,’ for instance, does not remedy the
fatal deficiency that no combination of the prior art taught or suggested a
recombinant fusion protein comprising GCSF and polyglutamic acid or
polyaspartic acid.” (App. Br. 19). As explained above, we find no
deficiency in the teaching of a recombinant fusion protein comprising GCSF
and a polyanion by the prior art.
Accordingly, we are not persuaded that the Examiner erred in
rejecting claim 3 under 35 U.S.C. § 103(a) over WO 99/33957 and Tanaka.
IV. ORDER
Upon consideration of the record and for the reasons given,
the rejection of claims 1, 11, and 15 under 35 U.S.C.
§ 103(a) over WO 99/33957 and Tanaka is AFFIRMED;
the rejection of claim 3 under 35 U.S.C. § 103(a) over WO 99/33957,
Tanaka, and US ‘084 is AFFIRMED;
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the rejection of claims 1 and 11 under 35 U.S.C. § 103(a) over
LeBorgne, Tanaka, US ‘163, and Li is AFFIRMED;
the rejection of claim 3 under 35 U.S.C. § 103(a) over LeBorgne,
Tanaka, US ‘163, Li, and US ‘084 is AFFIRMED;
the rejection of claims 1 and 11 under 35 U.S.C. § 103(a) over
Suominen, Tanaka, US ‘163, and Li is AFFIRMED; and
the rejection of claim 3 under 35 U.S.C. § 103(a) over Suominen,
Tanaka, US ‘163, Li, and US ‘084 is AFFIRMED.
No time period for taking any subsequent action in connection with
the appeal may be extended under 37 C.F.R. § 1.136(a).

AFFIRMED

MT

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