Ex Parte Kester et al

Patent Trial and Appeal Board

Dec 15, 2014

10835520 (P.T.A.B. Dec. 15, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte MARK KESTER, THOMAS STOVER,
TAO LOWE, JAMES ADAIR, and YOUNG SHIN KIM
__________

Appeal 2012-006971
Application 10/835,520
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
ROBERT A. POLLOCK, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a
resorbable unagglomerated nanoparticle drug delivery vehicle. The
Examiner rejected the claims as indefinite and as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part.

1 Appellants identify the Real Party in Interest as The Penn State
Research Foundation (see Br. 1).
Appeal 2012-006971
Application 10/835,520

2
Statement of the Case
Background
“[T]he present invention provides nanoscale assembly systems for
systemic delivery of therapeutic bioactive lipid compounds and/or
hydrophobic chemotherapeutic agents and/or nucleotide/gene agents to
individuals in need of such therapy” (Spec. 1 ¶ 2).
The Claims
Claims 53, 54, 56, 57, 78, 79, 81, 83, 85, 86, and 89–92 are on appeal.
Independent claim 53 is representative and reads as follows:
53. A resorbable unagglomerated nanoparticle drug
delivery vehicle for delivering a growth-arresting lipid-
derived bioactive compound and/or a hydrophobic
chemotherapeutic agent and/or gene therapy agent to an
animal or human in need of such delivery, comprising a
dispersant attached to a calcium phospho-silicate shell
encapsulating the lipid-derived compound, hydrophobic
chemotherapeutic agent or gene therapy agent, wherein the
lipid-derived compound is selected from the group
consisting of C2 – C10 ceramides and C18 – C24 ceramides
dimethyl sphingosine, trimethyl sphingosine, ether-linked
diglycerides, ether-linked phosphatidic acids, sphingosines
and sphinganines; and the gene therapy agent is selected
from the group consisting of oligonucleotides, ribozymes,
DNA-zymes, plasmids, antisense or Si-RNA therein.

The issues
A. The Examiner rejected claims 91 and 92 under 35 U.S.C. § 112,
second paragraph as indefinite (Ans. 5).
B. The Examiner rejected claims 53, 54, 78, 79, 81, and 83 under
Appeal 2012-006971
Application 10/835,520

3
35 U.S.C. § 103(a) as obvious over Schmidt,2 Ducheyne,3 Brunner,4
Labhasetwar,5 Charles,6,7 Wei,8 and Wiesner9 (Ans. 6–8).
C. The Examiner rejected claims 53, 56, 78, 85, 89, 91, and 92 under
35 U.S.C. § 103(a) as being obvious over Schmidt, Ducheyne, Brunner,
Labhasetwar, Charles, Wei, Wiesner, and Dobson10 (Ans. 9–10).
D. The Examiner rejected claims 53, 56, 57, 78, 85, 86, and 90 under
35 U.S.C. § 103(a) as being obvious over Schmidt, Ducheyne, Brunner,
Labhasetwar, Charles, Wei, Wiesner, Weimer11 and Soltys12 (Ans. 10–11).

2 Hartley T. Schmidt & Agnes E. Ostafin, Liposome Directed
Growth of Calcium Phosphate Nanoshells, 14 ADVANCED
MATERIALS 532–535 (2002).
3 Ducheyne et al., US 5,591,453, issued Jan. 7, 1997.
4 Tovar et al., WO 03/020320 A2, published Mar. 13, 2003 (This
reference is called Brunner by the Examiner. Hereafter, further
references will be to Tovar et al., US 2004/0265392 A1, published
Dec. 30, 2004 for the English translation) (see Ans. 4)).
5 Labhasetwar et al., Nanoparticle drug delivery system for
restenosis, 24 ADVANCED DRUG DELIVERY REVIEW 63–85 (1997).
6 Charles et. al., Ceramide-Coated Balloon Catheters Limit
Neointimal Hyperplasia After Stretch Injury in Carotid Arteries,
87 CIRCULATION RESEARCH 282–288 (2000).
7 The Examiner inadvertently omitted Charles from the statement
of rejection, but relied upon Charles in the Answer (see Ans. 7).
8 Wei et al., US 5,681,589, issued Oct. 28, 1997.
9 Wiesner et al., US 2004/0101822 A1, published May 27, 2004.
10 Tan et al., WO 01/88540 A1, published Nov. 22, 2001.
(Hereafter, we will refer to this reference by the fifth named
inventor, “Dobson” for consistency with the Examiner).
11 Weimer et al., Influence of a poly-ethylene glycol spacer on
antigen capture by immobilized antibodies, 45 J. BIOCHEM.
BIOPHYS. METHODS 211–219 (2000).
Appeal 2012-006971
Application 10/835,520

4
A. 35 U.S.C. § 112, second paragraph
Appellants do not argue this rejection, instead stating that “the change
in claim dependency of rejected claims 91–92 (and removing the
amendments made to claims 89–90) can easily be alleviated by an
Examiner’s amendment upon receipt of a decision of the Board.” (Br. 7.)
We therefore summarily affirm the indefiniteness rejection based
upon the Examiner’s explanation and reasoning (Ans. 5). See In re Berger,
279 F.3d 975, 984 (Fed. Cir. 2002) (in which the Board affirmed an
uncontested rejection of claims under 35 U.S.C. § 112, second paragraph,
and on appeal the Federal Circuit affirmed the Board’s decision and found
that the appellant had waived his right to contest the indefiniteness rejection
by not presenting arguments as to error in the rejection on appeal to the
Board).
B. 35 U.S.C. § 103(a) over Schmidt, Ducheyne, Brunner, Labhasetwar,
Charles, Wei, and Wiesner
The issue with respect to this rejection is: Does the evidence of record
support the Examiner’s conclusion that Schmidt, Ducheyne, Brunner,
Labhasetwar, Wei, and Wiesner render the claims obvious?
Findings of Fact
1. Schmidt teaches that “nanoscale liposomes can be used as a
nanoscale template for the deposition of silica, to create a hollow silica

12 Paul J. Soltys & Mark R. Etzel, Equilibrium adsorption of LDL
and gold immunoconjugates to affinity membranes containing
PEG spacers, 21 BIOMATERIALS 37–48 (2000).
Appeal 2012-006971
Application 10/835,520

5
nanoshell. These silicate materials have been used to encapsulate
fluorescent dyes, enzymes” (Schmidt 532, col. 2).
2. Schmidt teaches that “[c]alcium and phosphate are precipitated
on the exterior of the liposome forming the completed shell with a
liposome/solvent core. This method can be altered to produce shells of 45
nm to greater than 100 nm in diameter, with thicknesses ranging from 2 nm
to greater than 10 nm” (Schmidt 533, col. 1).
3. Schmidt teaches a suspension “containing monodisperse and
aggregated nanoshells as well as some nanocrystallites of calcium
phosphate. . . . The supernatant had a very high percentage of smaller shells
on the order of 30–50 nm that were stable in suspension” (Schmidt 533, col.
2).
4. Ducheyne teaches that “[c]arriers comprising silica-based glass
providing for the controlled release of biologically active molecules . . . are
disclosed. . . . Biologically active molecules are incorporated within the
matrix of the glass during production” (Ducheyne, abstract).
5. Ducheyne teaches that a “sol-gel derived silica-based glass
containing Ca and P was synthesized by mixing the three alkoxides TMOS,
CME, and TEP” (Ducheyne, col. 23, l. 66 to col. 24, l. 1).
6. Brunner teaches “nanoparticles with tumor necrosis factor
(TNF) or cytokine immobilized thereon” (Brunner, abstract).
7. Brunner teaches “compact or hollow nanoparticles with sizes
between 5 and 500 nm. These consist either of organic or inorganic particle
materials” (Brunner 4 ¶ 28).
Appeal 2012-006971
Application 10/835,520

6
8. Brunner teaches that the “nanoparticle of the invention
consists of an inorganic carrier material such as silicon, SiO2, SiO, a silicate,
Al2O3, SiO2·Al2O3, ZrO2, Fe2O3, Ag2O, Zr2O3, Ta2O5, zeolite, TiO2, glass,
indium tin oxide, hydroxyapatite, calcium phosphate, calcium carbonate, Au,
Fe3O4, ZnS, CdSe or a mixture thereof” (Brunner 7 ¶ 59).
9. Labhasetwar teaches that:
Nanoparticles possess several advantages as a carrier system
for the intra-arterial localization of therapeutic agents.
These advantages include their subcellular size, targeted
surfaces, good suspensibility, and uniform dispersity for a
catheter-based delivery, and an easy penetration into the
arterial wall without causing trauma. In various studies we
have demonstrated an efficient intra-arterial localization of
nanoparticles, biocompatibility in the arterial wall, and
effectiveness for the inhibition of experimental restenosis.

(Labhasetwar, abstract.)
10. Charles teaches that “ceramide-coated balloon catheters
significantly reduced neointimal hyperplasia induced by balloon angioplasty
in rabbit carotid arteries in vivo. This ceramide treatment decreased the
number of vascular smooth muscle cells entering the cell cycle without
inducing apoptosis” (Charles, abstract).
11. The Examiner finds that “Wei teaches liposomes that include
C6-ceramide, demonstrating that the production of liposomes containing the
hydrophobic compound were possible and known at the time of the
invention” (Ans. 7; see Wei, col. 19, ll. 20–22).
12. Wiesner teaches that:
Surface functional groups, especially ionizable groups,
provide other desirable properties to the nanoparticles, such
Appeal 2012-006971
Application 10/835,520

7
as charge stabilization in buffered media. Charged
carboxylate surface groups can maintain the nanoparticles as
single particle colloidal dispersions which avoid or minimize
nanoparticle agglomeration. Nanoparticle surface
functionalization procedures are known

(Wiesner 13 ¶ 151).
13. The Adair Declaration13 teaches that the “Schmidt reference
does not provide any teaching or other indication that its nanoparticle
synthesis method can be used to create nanoparticles with calcium phospho-
silicate shells. And following the teaching of the reference would not result
in such particles” (Adair Decl. 3 ¶ 7).
14. The Adair Declaration teaches that “[o]nly in the case where
reverse micelles are used and the calcium phosphosilicate particles are
created within the confinement provided by the reverse micelle does the
silicate become incorporated within the calcium phosphate matrix in a
reliable manner” (Adair Decl. 3 ¶ 8).
15. The Adair Declaration teaches that
Experiments in our laboratory to prepare caclium [sic]
phospho-silicate nanoparticles based on either the deposition
methods taught by Scmidt [sic] et al. or co-precipitation
approches [sic] have failed to give the calcium, phosphate,
and silicate in solid solution with one another with either the
colloidical [sic?] stability or amorphous phase stability as
currently claimed. Trying to incorporate the silicate by
synthetic methods other than that of the present invention
results in silicon dioxide and transient amorphous calcium
phosphate that eventually forms hydroxyapatite. Thus, the
calcium phosphate deposition approach on nanoliposomes

13 Second Declaration of James Adair, filed Dec. 28, 2010.
Appeal 2012-006971
Application 10/835,520

8
used by Schmidt et al. does not provide two important
features for an encapsulation system as claimed

(Adair Decl. 3–4 ¶ 8).
16. The Adair Declaration teaches that “one skilled in the art
following the teaching of Schmidt would not have arrived at the claimed
nanoparticles and adapting the method taught in Schmidt would have
produced unstable nanoparticles” (Adair Decl. 4 ¶ 10).
Principles of Law
“In proceedings before the Patent and Trademark Office, the
Examiner bears the burden of establishing a prima facie case of obviousness
based upon the prior art.” In re Fritch, 972 F.2d 1260, 1265 (Fed. Cir.
1992).
Analysis
The Examiner reasons that because Brunner teaches that a
nanoparticle may be comprised of “an inorganic carrier material such as
silicon . . . calcium phosphate . . . or a mixture thereof” (Brunner 7 ¶ 59; FF
8), “it would have been obvious to one of ordinary skill in the art at the time
of the invention to use calcium phosphosilicate for the shell in the
nanoparticles of Schmidt et al. instead of calcium phosphate as a functional
equivalent” (Ans. 8).
Appellants contend that “techniques known at the time of the
invention in the applicable art could not arrive at the claimed nanoparticles”
(Br. 16). Appellants contend that “the synthesis methods taught by Schmidt
et al. provide no indication that the methods could be used to create calcium
phospho-silicate shells for nanoparticles” (Br. 17).
Appeal 2012-006971
Application 10/835,520

9
In this case, the Examiner’s logic to combine the references is based
on “functional equivalence.” “Functional equivalence” is a reason which
may support a prima facie case of obviousness, and the Examiner reasonably
relies upon Brunner to demonstrate that both silicon and calcium phosphate
were known materials useful in forming nanoparticles, including in mixtures
(FF 8).
However, we find Appellants’ position more persuasive because the
Adair Declaration demonstrates that there is no reasonable expectation of
success in forming unagglomerated calcium phospho-silicate shell
nanoparticles based on the teachings of the prior art (FF 13–16). “Evidence
that the variables interacted in an unpredictable or unexpected way could
render the combination nonobvious.” In re Applied Materials, Inc., 692
F.3d 1289, 1298 (Fed. Cir. 2012). Here, Appellants have provided such
evidence in the Adair Declaration, stating that neither the Schmidt nor co-
precipitation method provided the calcium phosphor-silicate shells in
unagglomerated form as required by the claims (see Adair Decl. 3 ¶ 8; FF
15). We recognize that “[o]bviousness does not require absolute
predictability of success . . . all that is required is a reasonable expectation of
success.” In re O’Farrell, 853 F.2d 894, 903–04 (Fed. Cir. 1988).
However, the Examiner has not explained why, in light of the Adair
Declaration, there would have been a reasonable expectation of success in
forming unagglomerated calcium phospho-silicate shells as required by the
claims.
Appeal 2012-006971
Application 10/835,520

10
The Examiner contends that “[n]o data or experimental evidence
describing the work that was conducted or the results it achieved was
provided in this declaration” (Ans. 15).
While the Examiner is correct that expert opinions expressed without
disclosing the underlying facts or data upon which the opinion is based may
be given little or no weight, Rohm & Haas Co. v. Brotech Corp., 127 F.3d
1089, 1092 (Fed. Cir. 1997), here the Adair Declaration makes a specific
factual statement that experiments resulted in a negative, the inability to
prepare the desired nanoparticles using the Schmidt or co-precipitation
approaches (FF 15). The underlying data would therefore simply show the
negative result.
The Examiner also contends that “the claims do not recite any amount
of colloidal stability or amorphous stability as a requirement of the product”
(Ans. 15).
We do not find this argument persuasive because the instant
Specification defines “non-aggregating is the state of ‘dispersed’
bioparticulates” (Spec. 9 ¶ 44). Thus, aggregated or agglomerated
bioparticulates do not fall within the scope of the claims.
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that Schmidt, Ducheyne, Brunner, Labhasetwar, Wei, and Wiesner render
the claims obvious.
C–D. 35 U.S.C. § 103(a) rejections
These rejections rely upon the underlying obviousness rejection over
Schmidt, Ducheyne, Brunner, Labhasetwar, Wei, and Wiesner. Having
Appeal 2012-006971
Application 10/835,520

11
reversed this rejection, we also necessarily reverse the further obviousness
rejections because none of Dobson, Weimer, and Soltys is relied upon to
teach a calcium phospho-silicate shell as required by the claims.

SUMMARY
In summary, we affirm the rejection of claims 91 and 92 under
35 U.S.C. § 112, second paragraph as indefinite.
We reverse the rejection of claims 53, 54, 78, 79, 81, and 83 under
35 U.S.C. § 103(a) as obvious over Schmidt, Ducheyne, Brunner,
Labhasetwar, Charles, Wei, and Wiesner.
We reverse the rejection of claims 53, 56, 78, 85, 89, 91, and 92 under
35 U.S.C. § 103(a) as being obvious over Schmidt, Ducheyne, Brunner,
Labhasetwar, Charles, Wei, Wiesner, and Dobson.
We reverse the rejection of claims 53, 56, 57, 78, 85, 86, and 90 under
35 U.S.C. § 103(a) as being obvious over Schmidt, Ducheyne, Brunner,
Labhasetwar, Charles, Wei, Wiesner, Weimer, and Soltys.

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

cdc