Jeffrey Zink et al.

Patent Trials and Appeals Board

Dec 20, 2021

2021001248 (P.T.A.B. Dec. 20, 2021)

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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/841,331 07/22/2010 Jeffrey I. Zink UCLAP160US/2008-374-2 1831
22434 7590 12/20/2021
WEAVER AUSTIN VILLENEUVE & SAMPSON LLP
P.O. BOX 70250
OAKLAND, CA 94612-0250
EXAMINER
WESTERBERG, NISSA M
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
12/20/2021 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
following e-mail address(es):
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte JEFFREY I. ZINK, JIE LU, FUYUHIKO TAMANOI, ANDRE
NEL, SARAH ANN HENSCHEID, FRASER STODDART, QIAOLIN
CHEN, TIAN XIA, KAUSHIK PATEL, and WILLIAM DICHTEL
__________

Appeal 2021-001248
Application 12/841,331
Technology Center 1600
__________

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims to a
nanodevice for drug delivery. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We affirm.

1 We use the word “Appellant” to refer to “applicant” as defined in 37
C.F.R. § 1.42. Appellant identifies the Real Party in Interest as The Regents
of the University of California (see Appeal Br. 1). We have considered the
Specification of July 22, 2010 (“Spec.”); Non-Final Office Action of Sept.
27, 2019 (“Non-Final Action”); Appeal Brief of Aug. 26, 2020 (“Appeal
Br.”); and Examiner’s Answer of Sept. 29, 2020 (“Ans.”).
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Statement of the Case
Background
“Mesoporous silica nanoparticles coated with molecular valves hold
the promise to encapsulate a payload of therapeutic compounds, to transport
them to specific locations in the body, and to release them in response to
either external or cellular stimuli” (Spec. ¶ 5). “Sequestering drug
molecules serves the dual purpose of protecting the payload from enzymatic
degradation, while reducing the undesired side-effects” (id.).
The Claims
Claims 32–35, 38–40, 42–50, and 70–72 are on appeal. Claim 32 is
the sole independent claim, is representative and reads as follows:
32. A nanodevice for drug delivery, said device comprising:
a mesoporous silica containment vessel defining a
storage chamber therein and defining at least one port to
provide transfer of a drug to or from said storage chamber,
wherein said storage chamber contains a drug selected from the
group consisting of a small molecule drug for anticancer
treatment, an siRNA, a small molecule antioxidant, and a small
molecule drug for immune suppression; and
a valve assembly attached to said containment vessel;
wherein said valve assembly comprises a [2]rotaxane or
[2]pseudorotaxane disposed on a triamine string comprising
PhNH(CH2)6NH(CH2)4NH2, and said valve assembly is
operable in an aqueous environment to at least one of open and
closed in response to a change of pH in a local environment of
said valve assembly, where said valve assembly is closed and
retains said drug in said chamber at a pH greater than 6.73 and
is open at a pH less than 6.73 and releases said drug from said
chamber, and is reversibly operable under physiological
conditions found in a person; and
wherein said nanodevice consists of biocompatible
materials and has a maximum dimension of less than about 1
μm and greater than about 50 nm.
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The Rejections
A. The Examiner rejected claims 32–35, 38–40, 42, 43, and 70–722 under
35 U.S.C. § 103(a) as obvious over Lin,3 CNSI,4 Kim,5 Mock,6 and
Fritzberg7 (Ans. 3–8).
B. The Examiner rejected claims 44–47 under 35 U.S.C. § 103(a) as
obvious over Lin, CNSI, Kim, Mock, Fritzberg, and Santra8 (Ans. 8–9).
C. The Examiner rejected claim 50 under 35 U.S.C. § 103(a) as obvious
over Lin, CNSI, Kim, Mock, Fritzberg, Kónya,9 and Paciotti10 (Ans. 9–10).
D. The Examiner rejected claims 48 and 49 under 35 U.S.C. § 103(a) as
obvious over Lin, CNSI, Kim, Mock, Fritzberg, Kónya, Paciotti, and
Zhang11 (Ans. 10–11).

2 We note that the Examiner failed to include claim 72 in the grounds of
rejection. Because dependent claim 72 selects a species from a Markush
group listed in claim 32, we treat this error as inadvertent.
3 Lin et al., US 2006/0154069 A1, published July 13, 2006.
4 Powered Artificial Nano-Machines: Molecular Valves and Impellers, CNSI
2005 Annual Research Report 51 (2005) (“CNSI”).
5 Kim, Mechanically interlocked molecules incorporating cucurbituril and
their supramolecular assemblies, 31 Chem. Soc. Rev. 96–107 (2002).
6 Mock et al., A Cucurbituril-based Molecular Switch, J. Chem. Soc., Chem.
Commun. 1509–11 (1990).
7 Fritzberg et al., US 6,767,531 B2, issued July 27, 2004).
8 Santra et al., Folate Conjugated Fluorescent Silica Nanoparticles for
Labeling Neoplastic Cells, 5 J. Nanoscience and Nanotechnology 899–904
(2005).
9 Kónya et al., Synthetic Insertion of Gold Nanoparticles into Mesoporous
Silica, 15 Chem. Mater. 1242–8 (2003).
10 Paciotti et al., Colloidal Cold Nanoparticles: A Novel Nanoparticle
Platform for Developing Multifunctional Tumor-Targeted Drug Delivery
Vectors, 67 Drug Development Research 47–54 (2006).
11 Zhang et al., US 2006/0216239 A1, published Sept. 28, 2006.
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A. 35 U.S.C. § 103(a) over Lin, CNSI, Kim, Mock, and Fritzberg
The Examiner finds Lin teaches “mesoporous silica-based delivery
system that provides for controlled release” (Ans. 3) but does not teach “the
use of rotaxanes or pseudorotaxanes” as releasing components (id. at 4), “the
particular triamine aminoalkane string of claim 32” (id. at 5), or “the specific
anticancer agents” (id. at 7).
The Examiner finds “CNSI and Kim disclose that rotaxanes or
pseudorotaxanes can serve as valve assemblies for molecular devices” (Ans.
5). The Examiner finds Mock teaches “cucurbituril exhibits a pH-contingent
bimodal binding pattern . . . in figure 2, the cucurbituril moves along the
backbone when the pH changes from above 6.7 to below 6.7 or vice versa”
(id.). The Examiner finds “CNSI 2005 discloses that reversible operable
ligands can be used to modulate the release from the nanodevices of Lin et
al. and that a variety of ‘strings’ such as those in Kim or Mock et al. can be
used to prepare the stoppers for these devices” (id. at 6). The Examiner
finds an artisan “would optimize the particular string for the uncapping to
occur at a pH value that is relevant for the desired drug delivery location
with a stopper” (id.). The Examiner also finds it obvious to select known
anti-cancer agents such as those of Fritzberg (see id. at 7).
Appellant contends
modification of the particles described by Lin et al. to produce
the presently claimed nanodevices, would change the principle
of operation of Lin et al. and therefore cannot support a prima
facie case of obviousness (see, MPEP §2143.0l(VI)). Kim et al.
offers no teaching whatsoever regarding valve assemblies and
modification of Lin et al. using the valve assemblies using the
teachings offered in CNSI (2005) would produce nanodevices
operated by changes in oxidation/reduction, not by changes in
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pH as required by the pending claims. Finally, Mock et al. does
not lead one of skill to modify the valve assemblies to pH
operably valve assemblies, because Mock et al. teaches
assemblies that are unstable at physiological pH (e.g., pH -7 or
– pH -4.5-5.0 in lysosomes). Additionally, the valve assemblies
taught by CNSI (2005) (as evidenced by Nguyen) uses
materials that are toxic and are not biocompatible.
Accordingly, the combination of Lin et al., CNSI (2005), Kim
(2002), Mock et al., and Fritzberg et al. simply does not lead
one of skill to the drug delivery nanodevices recited in the
pending claims.
(Appeal Br. 8).
The issue with respect to this rejection is: Does a preponderance of
the evidence of record support the Examiner’s conclusion that the prior art
renders a drug delivery nanodevice with the particular recited valve
assembly of claim 32 obvious?
Findings of Fact
1. Lin teaches a
mesoporous silica-based delivery system is provided which
provides the controlled release of one or more agents from
pores within its matrix. This delivery system is typically
stimuli-responsive and chemically inert to the matrix-entrapped
molecules. The pores of the mesoporous silica matrix act as
reservoirs that can be loaded with a variety of molecules, e.g.,
bioactive agents such as conventional therapeutic agents.
(Lin ¶ 6).
2. Lin teaches:
The openings of the loaded mesopores are then reversibly or
irreversibly capped (e.g. with semiconductor nanoparticles,
biodegradable dendritic polymers (dendrimers), or proteins) so
as to encapsulate the molecules within the pores of the silica
matrix. The loaded and capped delivery systems allow for the
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site specific controlled release of the loaded material from the
pores of the mesoporous matrix.
(Lin ¶ 6).
3. Lin teaches “[m]esoporous silicates typically have a particle
size of about 50 nm to about 1 μm” (Lin ¶ 41).
4. Lin teaches the caps can be associated with a linker group
which can comprise a “labile group that can selectively react with a
releasing agent to release the cap from the mesoporous silicate following
delivery to a target site . . . For example, the labile group can be . . . a pH
sensitive bond, . . . and the releasing agent can be . . . acid/base (local pH
changes)” (Lin ¶¶ 47–48).
5. Lin teaches “conventional chemotherapeutic agents useful to
treat cancer . . . immunosuppressive drugs . . . and RNA or DNA molecules
of any suitable length” (Lin ¶ 50).
6. CNSI teaches a “molecular valve uses as its moving part a
rotaxane consisting of a ring that is mechanically trapped on a dumbbell
shaped component. The motion is of ring is powered by chemical energy”
(CNSI 51).
7. CNSI teaches the molecular valve “is attached to the pore
openings in a solid silica support . . . each of which contains ordered arrays
of 2 nm diameter tubular pores” (CNSI 51).
8. CNSI teaches the “fully reversible trapping and releasing of
molecules from pores is an example of a molecular valve” (CNSI 51).
9. Kim teaches “the efficient synthesis of mechanically
interlocked molecules such as catenanes and rotaxanes, which have attracted
considerable attention arising from not only their aesthetic appeal but also
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their potential applications such as molecular machines or switches” (Kim
96, col. 1).
10. Kim teaches: “Rotaxanes have been successfully employed in
the construction of molecular machines. Here, translocation of the ring
along the linear component can be achieved by external chemical,
electrochemical or photochemical stimuli. In appropriately designed
systems, such mechanical movements can be made to occur between two
different well-defined states” (Kim 103, col. 2).
11. Kim teaches (pseudo)rotaxane-based molecular switch where
rotaxane includes cucurbituril (CB[6]) as a molecular bead, and where “the
[CB[6]] molecular bead in 22 resides predominantly at the (diprotonated)
diaminohexane site at a pH lower than its pKa (5.7), but translocates to
(diprotonated) diaminobutane site when the pH of the solution becomes
higher than the pKa” (Kim 103, col. 2).
12. Kim teaches “terminal pseudorotaxane units therefore can
potentially inhibit escape of guest(s) trapped in the interior . . . this threading
and dethreading of molecular ‘beads’ at the terminals may provide these
novel dendrimers with a mechanism for reversible encapsulation and release
of guest molecules, which may find useful applications including drug
delivery” (Kim 105, col. 2).
13. Mock teaches, with respect to engineering devices on the
organic molecular scale, that “the simplest component for such ultimate
reduction in machine size is a ‘molecular switch,’ a ligand-receptor system
which has the capability to exist in more than one state, contingent upon
some controlling element” (Mock 1509, col. 1).
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14. Mock teaches “Triamine ligand PhNH(CH2)6NH(CH2)4NH2 2
has been specifically designed and prepared so as to be capable of binding in
two distinct ways to 1[, i.e., cucurbituril,] . . . in the presence of one
moleequivalent of 1, this pKa increases to 6.73 (±0.02). Such behaviour was
quite predictable” (Mock 1510, col. 1).
15. Mock teaches:
In this “switch” a hydronium ion is functioning as a control
element, inducing translocation between the two ligation states,
so as to maintain the ion-dipole interactions. We note that the
exact pH at which the transition takes place ought to be
regulable by varying the nature of substituents on the aryl ring.
Tandem anchoring of modified 1 and 2 residues to suitable
substrates may provide a strategy for systematically varying
macroscopic dimensions of a material in response to pH.
(Mock 1511, col. 1–2).
16. Fritzberg teaches “[c]hemotherapeutic antineoplastic (‘anti-
cancer’) agents that are useful in practicing the present invention include but
are not limited to doxorubicin . . . paclitaxel” (Fritzberg 15:9–16).
Principles of Law
A prima facie case for obviousness “requires a suggestion of all
limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333,
1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of
ordinary skill in the relevant field to combine the elements in the way the
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claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398,
418 (2007).
Analysis
We adopt the Examiner’s findings of fact and conclusion of law (see
Ans. 3–8, FF 1–16) and agree that the combination of prior art renders the
rejected claims obvious. We address Appellant’s arguments below.
Appellant contends Lin
only teaches two mechanisms for drug release from the
mesoporous particles: 1) The [] cap attached to the particle by a
linking group comprising a labile group that can react with a
releasing agent to release the cap from the mesoporous silicate
following delivery to a target site (see, e.g., paragraph [0048]);
or 2) A biodegradable dendrimer (i.e., poly(amidoamine
dendrimer) which is simply degraded in a physiological system
(hence biodegradable) (see, e.g., paragraph [0047]).
(Appeal Br. 4).
A reference “must be read, not in isolation, but for what it fairly
teaches in combination with the prior art as a whole.” In re Merck & Co.,
800 F.2d 1091, 1097 (Fed. Cir. 1986).
Lin teaches a drug delivery device comprising a mesoporous silica
containment vessel with a storage chamber, a port for transfer of a drug, and
small molecule drugs for cancer treatment, among other diseases (FF 1, 2,
5). Lin teaches the device has dimensions of less than about 1 μm and
greater than about 50 nm (FF 3).
Lin teaches “the loaded mesopores are then reversibly or irreversibly
capped” and that this release may be based on “acid/base (local pH
changes)” (FF 2, 4). While Appellant is correct that Lin does not anticipate
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claim 32, Lin does directly suggest that the release mechanism may be
reversible and may rely on pH changes (FF 2, 4).
CNSI demonstrates that a third release mechanism of which ordinary
artisans would have been aware were molecular valves powered by chemical
changes (FF 6–8). Kim also teaches a valve-like release mechanism,
specifically teaching molecular switches composed of rotaxanes (FF 9)
useful for “reversible encapsulation and release of guest molecules, which
may find useful applications including drug delivery” (FF 12). Kim teaches
that the switch that opens and closes to release molecules (FF 12) may be
controlled by pH causing translocations of compounds that result in either
open and closed states (FF 10–11). Mock identifies a specific ligand for
molecular switches (FF 13), triamine ligand PhNH(CH2)6NH(CH2)4NH2 (FF
14), that binds in two different ways where the “behaviour was quite
predictable” (FF 14). And Mock recognizes that the pH of translocation is
optimizable, teaching “the exact pH at which the transition takes place ought
to be regulable by varying the nature of substituents on the aryl ring” (FF
15). Lastly, the Examiner points to Fritzburg to show specific anticancer
agents (FF 16).
We agree with the Examiner that replacing the reversible release
mechanism of Lin’s drug delivery device with the valve/switch mechanism
disclosed by CNSI, Kim, and Mock would have been obvious because Kim
teaches such “reversible encapsulation and release of guest molecules, which
may find useful applications including drug delivery” (FF 12). We further
agree that following the guidance of Lin, Kim, and Mock to reversibly
release using changes in pH would have been obvious as a known alternative
valve/switch (FF 4, 11, 14, 15) and selecting the triamine ligand of Mock to
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control such pH reversible release at an optimized pH would have been
obvious because it allows for “the exact pH at which the transition takes
place . . . to be regulable” (FF 15). We are mindful that the Supreme Court
has clearly stated that the “combination of familiar elements according to
known methods is likely to be obvious when it does no more than yield
predictable results.” KSR, 550 U.S. at 416. Appellant does not identify any
unexpected results.
Appellant contends Kim “offer no[] teaching whatsoever regarding
valve assemblies”; that “the nanovalves described in CNSI (2005) involve a
tether attached to a pore of a mesoporous silica nanoparticle that can be
opened and closed by reduction/oxidation of a cyclobis(paraquat-p-
phenylene) moiety of a [2]rotaxane”; and that Mock “leads one of skill to
conclude that the structures described therein are unsuitable for use as
effective nanovalves in drug delivery nanodevice” (Appeal Br. 5; emphasis
omitted).
We find these arguments unpersuasive as they fail to address the
combination of references but rather identify ways in which each of the
references fails to anticipate claim 32. But the rejection is for obviousness,
not anticipation. See In re Keller, 642 F.2d 413, 425 (CCPA 1981) (“The
test for obviousness is not whether the features of a secondary reference may
be bodily incorporated into the structure of the primary reference; nor is it
that the claimed invention must be expressly suggested in any one or all of
the references. Rather, the test is what the combined teachings of the
references would have suggested to those of ordinary skill in the art.”)
Appellant contends that “one of skill would have no reasonable
expectation of success that the structures described by Mock et al. could
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retain a drug in the chamber recited in claim 32, particularly at the pH found
in a person (generally -pH 7, and in lysosomes pH-4.5-5.0)” (Appeal Br. 6).
We find this argument unpersuasive for several reasons. First,
Appellant provides no evidence or persuasive argument explaining why
there would not be a reasonable expectation of success. “[A]ttorney
argument [is] 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). Second, Kim specifically teaches that switches are suitable for
drug delivery (FF 12) and provides a reasonable expectation of success using
such molecular switches. And “[o]bviousness does not require absolute
predictability of success . . . all that is required is a reasonable expectation of
success.” In re Kubin, 561 F.3d 1351, 1360 (Fed. Cir. 2009).
Appellant contends “Fritzberg et al. offers no teaching regarding drug
delivery nanodevices. Accordingly, the combination of Lin et al., CNSI
(2005), Kim (2002) Mock et al., and Fritzberg et al., at best, produces a
nanodevice that operates according to fundamentally different mechanism
than the presently claimed nanodevices” (Appeal Br. 7).
We are not persuaded by this argument as Fritzberg is simply relied
upon by the Examiner to establish that some of the compounds recited in
claim 71 are known anti-cancer agents (FF 16) that would be obvious agents
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to use in the drug delivery device of Lin containing anti-cancer agents (FF 5)
as rendered obvious by the entirety of the cited prior art (FF 1–16).
Appellant cites the Zink Declaration12 to contend the
nanovalves described in CNSI (2005) (also in Nguyen et al.)
include materials that are not biocompatible. For example, the
rotaxanes used in Nguyen et al. include a paraquat moiety.
Paraquat is used as an herbicide and is toxic to human and
animals. Furthermore, Nguyen uses iron(III) perchlorate (i.e.,
Fe(ClQ4)3) as an oxidant to operate the nanovalve. Perchlorate
salts such as iron(III) are also toxic to humans.
(Appeal Br. 8).
We find this argument unpersuasive because, as the Examiner notes,
“Nguyen et al. is not relied upon [] in any of the current rejections” (Ans.
15). In addition, CNSI is simply cited to evidence that rotaxanes are a
component of molecular valves and that such valves were known. And Kim,
who teaches switches that may be useful in drug delivery (FF 12), also
teaches that these switches can be composed of rotaxanes (FF 10). As
Nguyen is not cited in this obviousness rejection, there is no reason the cited
prior art would use iron(III)perchlorate but rather would use the triamine
ligand of Mock to operate the obvious switch using pH regulation (FF 14–
15). Thus, the entire line of reasoning does not address the rejection as it
currently stands.
Conclusion of Law
A preponderance of the evidence of record support the Examiner’s
conclusion that the prior art renders a drug delivery nanodevice with the
particular recited valve assembly of claim 32 obvious.

12 Declaration of Dr. Jeffrey I. Zink, dated May 20, 2014.
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B.–D. 35 U.S.C. § 103(a) rejections
Appellant does not substantively separately argue these obviousness
rejections, instead relying upon their arguments to overcome the first
obviousness rejection from which these depend. The Examiner provides
sound fact-based reasoning for combining the remaining prior art (see Ans.
8–9). Having affirmed the obviousness rejection over Lin, CNSI, Kim,
Mock, and Fritzberg for the reasons given above, we also find that the
further combinations render the rejected claims obvious for the reasons
given by the Examiner.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§ 
Reference(s)/Basis Affirmed Reversed
32–35, 38–
40, 42, 43,
70–72
103  Lin, CNSI, Kim,
Mock, and Fritzberg
32–35, 38–
40, 42, 43,
70–72

44–47 103  Lin, CNSI, Kim,
Mock, Fritzberg,
Santra
44–47
50 103 Lin, CNSI, Kim,
Mock, Fritzberg,
Kónya, Paciotti
50
48, 49 103 Lin, CNSI, Kim,
Mock, Fritzberg,
Kónya, Paciotti, Zhang
48, 49
Overall
Outcome
32–35, 38–
40, 42–50,
70–72

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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