Ex Parte Saraf et al

Patent Trial and Appeal Board

Feb 27, 2017

12563181 (P.T.A.B. Feb. 27, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O.Box 1450
Alexandria, Virginia 22313-1450
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/563,181 09/21/2009 Anita Saraf 13-21034-US 5882
98820 7590 03/01/2017
ReeH Smith T T P
EXAMINER
P.O. Box 488 POPA, ILEANA
Pittsburgh, PA 15230
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
03/01/2017 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ANITA SARAF,
MICHAEL C. HACKER, and ANTONIOS G. MIKOS
Appeal 2016-005280
Application 12/563,181
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
ADAMS, Administrative Patent Judge.
DECISION ON APPEAL1
This appeal under 35 U.S.C. § 134(a) involves claims 1—4 and 21—24
(App. Br. 2). Examiner entered rejection under 35 U.S.C. § 103(a). We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
STATEMENT OF THE CASE
Appellants’ “disclosure generally relates to gene delivery vectors” and
“[mjore specifically [] provides compositions and methods related to gene
delivery vectors that interact with human mesenchymal stem cells” (Spec.
1 Appellants identify the real party in interest as “William Marsh Rice
University” (App. Br. 2).
Appeal 2016-005280
Application 12/563,181
13). Claims 1 and 24 are representative and reproduced in the Claims
Appendix of Appellants’ Brief.
1. A composition comprising a plurality of hyaluronic acid
hexamers covalently attached to a branched polyethylenimine
[(bPEI)], wherein the plurality of hyaluronic acid [(HA)]
hexamers are covalently attached to terminal primary amine
groups on the branched polyethylenimine at anomeric carbons
on the hyaluronic acid hexamers.
(App. Br. 26.)
24. The composition of claim 1, wherein a degree of
substitution at the primary amine groups of bPEI with HA is in
the range of from about 12% to about 14%.
(Id. at 29.)
The claims stand rejected as follows:
Claims 1—4 and 21—24 stand rejected under 35 U.S.C. § 103(a) as
unpatentable over the combination of Zanta,2 Kircheis,3 Turley,4 and
Knudson.5
ISSUE
Does the preponderance of evidence relied upon by Examiner support
a conclusion of obviousness?
2 Maria-Antonietta Zanta et al., In Vitro Gene Delivery to Hepatocytes with
Galactosylated Polyethylenimine, 8 Bioconjugate Chem. 839—844 (1997).
3 R. Kircheis et al., Coupling of cell-binding ligands to polyethylenimine for
targeted sene delivery, 4 Gene Therapy 409—418 (1997).
4 Turley et al., US 2003/0036525 Al, published Feb. 20, 2003.
5 Warren Knudson et al., HYALURONAN OLIGOSACCHARIDES
PERTURB CARTILA GE MA TRIXHOMEOSTASIS AND IND UCE
CHONDROCYTIC CHONDROLYSIS, 43 ARTHRITIS & RHEUMATISM
1165-1174 (2000).
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Application 12/563,181
FACTUAL FINDINGS (FF)
FF 1. Zanta discloses that “the versatile cationic polymer polyethylenimine
(PEI) was found to be among the most efficient polycationic gene transfer
vectors to date” and “constitutes per se an outstanding core for the design of
more sophisticated devices” (Zanta 839: col. 2,11. 22—24 and 29—31; see
Ans. 3).
FF 2. Zanta discloses “a 5% galactose-bearing polyethylenimine (PEI—gal)
polymer which is condensed with plasmid DNA to neutrality,” which results
in “[a] hepatocyte-directed vector,” wherein “the asialoglycoprotein receptor
is involved in the transfection of hepatocytes with neutral PEI—gal/DNA
complexes” (Zanta, Abstract; see id. at 840: col. 1, first paragraph; see also
id. at 842: Figure 4, legend (“Neutral galactose-bearing complexes deliver
genes selectively to hepatocytes”); Ans. 3).
FF 3. Zanta’s Figure 1 is reproduced below:
Zanta’s Figure 1 illustrates an “[ijdealized scheme for the conjugation of
galactose to polyethylenimine via imine formation with lactose, and
subsequent condensation of PEI—gal with plasmid DNA into neutral
f
snine
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Application 12/563,181
galactose bearing complexes” (Zanta 841: Figure 1, Legend; see also id. at
840: col. 2,11. 28—32 (citation omitted) (“The most straightforward way to
link galactose to PEI is via imine formation of lactose (galactosyl-a 1,4-
glucose, see Figure 1) with the amine functions of PEI, followed by in situ
reduction back to a substituted amine”); Ans. 3).
FF 4. Zanta discloses that “[t]he percentage of derivatization is an
important factor to consider, too. A rough preliminary screening led to 5%
of the total amine functions being a good choice” (Zanta 840: col. 2,11. 35—
37; see Ans. 3; see also Ans. 20 (“Zanta [discloses that] “the degree of
substitution [is] a result effective variable with respect to transfection
efficiency and this provides [] motivation to vary the degree of
substitution”)).
FF 5. Examiner finds that Zanta fails to suggest an “HA-derived
oligosaccharide[] with a minimum length of 6 monosaccharides (HA
hexamers or HAe)” (Ans. 3).
FF 6. Kircheis discloses that “[a] major goal to be reached in gene therapy
protocols is the efficient and specific delivery of therapeutic genes into the
desired target cells” (Kircheis 409: col. 1,11. 1—3).
FF 7. Turley “relates to the use of forms of hyaluronic acid (hyaluronan)
... as a targeting agent in gene therapy to target active agents which ablate
the function of targeted genes in the control or treatment of disease and/or
conditions” (Turley 11; Ans. 4).
FF 8. Turley discloses that “[c]ell surface receptors specific for HA have
been identified, including the histocompatibility antigen CD44 and receptor
for hyaluronan-mediated motility (RHAMM)” (Turley 17; Ans. 4).
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Application 12/563,181
FF 9. Turley discloses:
The use of HA in [Turley’s] invention transports the gene
therapy agent to the cells which express HA receptors into the
cell, and thus, into the cytoplasm and into the nucleus. This is
because effective amounts of the forms of HA will bind cell
membranes and other molecules simultaneously and penetrate
into the nucleus taking the effective amount of gene therapy
into the cells.
(Turley 1118; Ans. 4.)
FF 10. Knudson discloses that “binding of HA to CD44 can be effectively
competed with through the use of small HA oligosaccharides, more
specifically, oligosaccharides with a minimum length of 6 monosaccharides
(HA6)” (Knudson 1166: col. 1,11. 6-9; Ans. 4).
FF 11. Appellants disclose that “[i]n certain embodiments, the bPEI-HA
conjugates of the present invention have a degree of substitution at the
primary amine groups of bPEI with HA in the range of from about 12% to
about 14%” (Spec. 127).
FF 12. Appellants disclose that “one advantage [of Appellants’ claimed
invention] may be that bPEI-HA conjugates may demonstrate reduced
cytotoxicity compared to unconjugated bPEI” and bPEI-HA “interactions
. . . are not limited to, the uptake of the bPEI-HA conjugate through
endocytosis via matrix receptors (e.g., CD44 receptors)” (Spec. 128
(emphasis added); see also id. 138 (“One possible advantage of using bPEI-
HA conjugates as gene delivery vectors is that the conjugates may be less
toxic to cells than unconjugated bPEI”) (emphasis added)).
FF 13. Appellants disclose that
the reduced cytotoxicity of bPEI-HA conjugates may persist
even when the bPEI-HA conjugates are complexed are [sic]
with different concentrations of DNA. It is believed that
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Application 12/563,181
reduced cytotoxicity of bPEI-HA conjugates compared to
unconjugated bPEI is observed because covalent bonds between
HA and bPEI mitigate some of the bPEI’s cationic charge
density by introducing anionic groups, and/or by reducing the
total number of primary amines (e.g., when bPEI is complexed
to HA through a reductive amination reaction, approximately
12% of the bPEI’s primary amines may be changed to
secondary amines).
(Spec. 138; see generally id. 1 66 (Appellants’ Example 8, wherein, “[t]he
toxicity of [] synthesized bPEI-HA [conjugates] was compared to the
toxicity of [unconjugated] bPEI on hMSCs [(human mesenchymal stem
cells)]”).
ANALYSIS
Based on the combination of Zanta, Kircheis, Turley, and Knudson,
Examiner concludes that, at the time Appellants’ invention was made, it
would have been prima facie obvious
to modify the composition of Zanta [] by replacing their
galactose-containing disaccharide with HA6 to achieve the
predictable result of obtaining a composition suitable to deliver
DNA to CD44-expressing cells[]. By doing so, one of
[ordinary] skill in the art would have obtained a composition
comprising a plurality of HA6 coupled to the terminal primary
amine groups on the side chains of the branched PEI via their
anomeric carbons[]. With respect to claim 24, Zanta [discloses
that] the degree of substitution [is] a result effective variable
with respect to transfection efficiency[]. [Therefore,] [i]t would
have been [further] obvious to one of [ordinary] skill in the art,
at the time [Appellants’] invention was made, to vary the
degree of substitution with the purpose of optimizing the PEI
conjugate for transfection [as a PEI-HA6 conjugate].
(Ans. 4.)
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Claim 1:
Zanta discloses that “the versatile cationic polymer polyethylenimine
(PEI) was found to be among the most efficient polycationic gene transfer
vectors to date” and “constitutes per se an outstanding core for the design of
more sophisticated devices” (FF 1). Zanta further discloses a “galactose­
bearing polyethylenimine” that “delivers] genes selectively to hepatocytes”
(FF 2). Kircheis discloses that “[a] major goal to be reached in gene therapy
protocols is the efficient and specific delivery of therapeutic genes into the
desired target cells” (FF 6). Turley discloses that CD44 has “[c]ell surface
receptors specific for HA” and Knudson discloses that “small HA
oligosaccharides, more specifically oligosaccharides with a minimum length
of 6 monosaccharides (HAe)” bind CD44 more effectively than HA (FF 8
and 10 (“binding of HA to CD44 can be effectively competed with through
the use of small HA oligosaccharides, more specifically, oligosaccharides
with a minimum length of 6 monosaccharides (HAe)”)). Thus, when Zanta,
Kircheis, Turley, and Knudson are viewed in combination, we are not
persuaded by Appellants’ contention that
one of ordinary skill in the art would not have been motivated
by Turley to modify the delivery system of Zanta considering
that Turley demonstrates efficient targeted delivery to cells
expressing the CD44 receptor through the use of large HA
molecules (not HA hexamers) in the absence of any additional
carrier such []as PEL
(App. Br. 6; see also id. at 7—9.) See DePuy Spine, Inc. v. Medtronic
Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009) (“A reference
does not teach away ... if it merely expresses a general preference for an
alternative invention but does not ‘criticize, discredit, or otherwise
discourage’ investigation into the invention claimed.”) (citing In re Fulton,
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Application 12/563,181
391 F.3d 1195, 1201 (Fed. Cir. 2004). Stated differently, Turley’s
alternative to Zanta’s construct, does not render Appellants’ claimed
invention non-obvious over the combination of references relied upon by
Examiner. For the foregoing reasons, we are not persuaded by Appellants’
contention that Examiner’s conclusion of obviousness is based in hindsight
(App. Br. 6—7 and 13—19).
As discussed above, Kircheis discloses that “[a] major goal to be
reached in gene therapy protocols is the efficient and specific delivery of
therapeutic genes into the desired target cells,” Turley discloses that CD44 is
a “[c]ell surface receptor[] specific for HA,” and Knudson discloses that
“small HA oligosaccharides, more specifically oligosaccharides with a
minimum length of 6 monosaccharides (HAe),” bind CD44 more effectively
than HA (FF 6, 8, and 10). Thus, even assuming Knudson is not within the
field of inventor’s endeavor, Knudson’s disclosure of HAe’s ability to
effectively bind CD44, a cell surface receptor that specifically binds HA, is
reasonably pertinent to the particular problem; specifically, the specific
targeting of gene therapy to a desired target cell (FF 6, 8, and 10; cf. App.
Br. 7. See In re Clay, 966 F.2d 656, 658—9 (Fed. Cir. 1992) (one of the two
criteria that has evolved for determining whether prior art is analogous is
whether the reference, if not within the field of the inventor’s endeavor, is,
nonetheless, reasonably pertinent to the particular problem with which the
inventor is involved). Therefore, we are not persuaded by Appellants’
contention that “Knudson is non-analogous art” (App. Br. 7; see also id. at
9-13).
Appellants fail to provide persuasive evidence or argument to support
their contention that “Knudson does not teach that HA hexamers effectively
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bind CD44 receptors” (App. Br. 7; see also id. at 11 (“Nowhere in Knudson
is a disclosure, teaching or suggestion of the internalization of HA
hexamers—or any HA oligosaccharide for th[at] matter—nor is gene therapy
or cell-targeting mentioned or implicated here”); cf. FF 10; see also Ans. 6
(“Based on the[] [combination of Zant[a], Kircheis, Turley, and Knudson],
one of skill in the art would have understood that HA and HA6 are functional
equivalents with respect to binding to CD44 and thus, also with respect to
targeting the CD44-expressing cells”)). See In re Pearson, 494 F.2d 1399,
1405 (CCPA 1974) (“Attorney’s argument in a brief cannot take the place of
evidence”). On this record, when the evidence relied upon by Examiner is
viewed as a whole and, wherein Appellants admit that HA is an effective
gene targeting agent for cells carrying CD44 receptors, we find no
persuasive evidence or argument that rebuts Examiner’s finding “that HA
and HA6 are functional equivalents” (see App. Br. 6; cf. Ans. 6).
As Examiner explains, Appellants’ claim 1 does not require “reduced
toxicity” (Ans. 15; see also FF 11 ([i]n certain embodiments, [of Appellants’
disclosure,] the bPEI-HA conjugates . . . have a degree of substitution at the
primary amine groups of bPEI with HA in the range of from about 12% to
about 14%”) (emphasis added)). Therefore, we are not persuaded by
Appellants’ contention that “the claimed invention can reduce toxicity of
bPEI regardless of the concentration or density of primary amines in the
composition which is contrary to the prior art and[,] therefore, a surprising
result” (App. Br. 7; see also id. at 19—21; see Reply Br. 2-4). Objective
evidence of non-obviousness must be commensurate in scope with the
claims which the evidence is offered to support. See, e.g., In re Boesch, 617
F.2d 272, 277 (CCPA 1980).
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Further, as discussed above, Zanta expressly discloses that “[t]he
percentage of derivatization is an important factor to consider” (FF 4).
Thus, when preparing a bPEI-HA6 conjugate, as suggested by the
combination of Zanta, Kircheis, Turley, and Knudson, a person of ordinary
skill in this art would have found it obvious to optimize the percentage of
derivatization of the bPEI- HA6 conjugate. “In determining whether the
subject matter of a patent claim is obvious, neither the particular motivation
nor the avowed purpose of the patentee controls. What matters is the
objective reach of the claim. If the claim extends to what is obvious, it is
invalid under § 103.” KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 419
(2007).
Claim 24\
Zanta discloses a “galactose-bearing polyethylenimine” conjugate that
targets hepatocytes (FF 2). Zanta further discloses that “[t]he percentage of
derivatization is an important factor to consider” and, through screening,
found that “[t]he percentage of derivatization[, for Zant[a]’s PEI-gal
conjugate,] 5% of the total amine functions [is] a good choice” (FF 4).
When this disclosure of Zanta is taken with Zanta’s disclosure that PEI
“constitutes per se an outstanding core for the design of more sophisticated
devices,” a skilled artisan would have recognized that when PEI is
derivatized with agents other than galactose the percentage of derivatization
of the PEI would require some degree of routine optimization (see FF 1 and
4). Therefore, we are not persuaded by Appellants’ contention that, on this
record, “[i]t is improper to reject a claim on the basis that it recites a result-
effective variable where the result sought in the prior art is different from the
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result sought in the present application” (App. Br. 23). “[W]here the general
conditions of a claim are disclosed in the prior art, it is not inventive to
discover the optimum or workable ranges by routine experimentation.” In re
Aller, 220 F.2d 454, 456 (CCPA 1955).
Appellants’ claim 24 does not require reduced toxicity, therefore, for
the reasons set forth above, we are not persuaded by Appellants’ contentions
regarding toxicity (App. Br. 23; see also Reply Br. 2—4).
Further, with respect to Appellants’ asserted unexpected result, the
combination of prior art relied upon by Examiner suggests bPEI- HA6
conjugates, not unconjugated bPEI. Appellants’ disclosure compares bPEI-
HA conjugates to unconjugated bPEI and concludes that the conjugated
form of bPEI is less toxic than the unconjugated form of bPEI (see FF 12—
13). Appellants do not, however, identify a disclosure in their Specification
that supports a conclusion that any particular degree of substitution is
necessary to reduce, by some degree, the toxicity of unconjugated bPEI. For
the foregoing reasons, we are not persuaded by Appellants’ contentions
regarding toxicity.
CONCLUSION OF LAW
The preponderance of evidence relied upon by Examiner supports a
conclusion of obviousness. The rejection of claims 1 and 24 under
35 U.S.C. § 103(a) as unpatentable over the combination of Zanta, Kircheis,
Turley, and Knudson is affirmed. Claims 2-4 and 21—23 are not separately
argued and fall with claim 1.
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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
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