RAMOT AT TEL-AVIV UNIVERSITY LTD.

Patent Trials and Appeals Board

Oct 26, 2021

2021001022 (P.T.A.B. Oct. 26, 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.
14/770,096 08/25/2015 Rafael ISCHAKOV 63243 9038
67801 7590 10/26/2021
PRTSI Inc.
232 NW 42nd Ter
Plantation, FL 33317
EXAMINER
WESTERBERG, NISSA M
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
10/26/2021 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):
usptomail@ipatent.co.il
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RAFAEL ISCHAKOV, LUDMILA BUZHANSKY,
LIHI ADLER-ABRAMOVICH, and EHUD GAZIT 1
Appeal 2021-001022
Application 14/770,096
Technology Center 1600
Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and
JAMIE T. WISZ, Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
composition comprising hydrogel particles, which have been rejected based
on obviousness and obviousness-type double patenting. We have jurisdiction
under 35 U.S.C. § 6(b).
We REVERSE.

1 Appellant identifies the real party in interest as Ramot at Tel-Aviv
University Ltd.. Appeal Br. 2. “Appellant” refers to “applicant” as defined in
37 C.F.R. § 1.42.
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Application 14/770,096

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STATEMENT OF THE CASE
“Polymer-based hydrogel nanoparticles (HNPs) have been recently
described as effective drug delivery vehicles.” Spec. 1:28–29. “Natural or
synthetic self-assembled peptides represent an additional type of gel forming
molecules.” Id. at 2:12–13. “Orbach . . . reported that aromatic dipeptides
such as N-fluorenylmethoxycarbonyl-diphenylalanine (Fmoc-FF), self-
assemble in aqueous solutions to form nano-scale ordered hydrogels of
remarkable mechanical rigidity.” Id. at 2:15–19.
The Specification describes a “methodology in which . . . hydrogel
nanoparticles (HNPs), were prepared by utilizing mechanical
homogenization and inverse-emulsion methods, with the aim of serving as
nanocarriers for controlled drug delivery.” Id. at 9:16–20. More specifically,
“Fmoc-FF based and Fmoc-FRGD based nanoparticles were formed using
inverse (or inverted) emulsion technique. In order to stabilize those NPs in
aqueous solutions, D-α-tocopheryl, polyethylene glycol 1000 succinate
(vitamin E-TPGS), as a biocompatible and biodegradable surfactant, was
applied.” Id. at 9:21–25.
Claims 1, 4, 6, 8, 10, 16–18, 23, 26, and 28–30 are on appeal. Claim
1, the only independent claim, is illustrative and is reproduced below:
1. A composition comprising a plurality of physically
discrete hydrogel particles, each hydrogel particle comprising a
three-dimensional network made of a plurality of self-
assembled peptides and an aqueous medium, wherein each
peptide in the plurality of peptides is Phe-Phe, Phe-Gly,
naphthylalanine-naphthylalanine (Nal-Nal) or Phe-Arg-Gly-
Asp (SEQ ID NO:1),
and wherein each peptide in the plurality of peptides
comprises an aromatic end-capping moiety substituting the
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N-terminus thereof, said end-capping moiety being
9-fluorenylmethyloxycarbonyl (Fmoc),
wherein an average diameter of each of the hydrogel
particles ranges from 10 nm to 1000 nm, or from 10 nm to 500
nm,
and wherein the composition further comprises an
emulsion stabilizer being in association with the hydrogel
particles.

The claims stand rejected as follows:
Claims 1, 4, 6, 8, 10, 16–18, 23, 26, 28, and 30 under 35 U.S.C.
§ 103(a) as obvious based on Orbach,2 Thayumanavan,3 and Martin4 (Non-
Final Action5 4);
Claim 29 under 35 U.S.C. § 103(a) as obvious based on Orbach,
Thayumanavan, Martin, and Altman6 (Non-Final Action 9);
Claims 1, 4, 6, 8, 10, 16–18, 23, 26, and 28–30 for obviousness-type
double patenting based on claims 1–36 of U.S. Patent 9,074,095 in view of
Thayumanavan and Martin, and optionally also in view of Orbach or Altman
(Non-Final Action 12);
Claims 1, 4, 6, 8, 10, 16–18, 23, 26, and 28–30 for obviousness-type
double patenting based on claims 1–23 of U.S. Patent 9,610,353 in view of

2 Orbach et al., “Self-Assembled Fmoc-Peptides as a Platform for the
Formation of Nanostructures and Hydrogels,” Biomacromolecules 10:2646–
2651 (2009).
3 Thayumanavan, US 2011/0200675 A1, published Aug. 18, 2011.
4 Martin et al., “The release of model macromolecules may be controlled by
the hydrophobicity of palmitoyl glycol chitosan hydrogels,” Journal of
Controlled Release 80:87–100 (2002).
5 Office Action mailed Apr. 1, 2020.
6 Altman et al., US 2011/0008406 A1, published Jan. 13, 2011.
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Thayumanavan and Martin, and optionally also in view of Orbach or Altman
(Non-Final Action 14); and
Claims 1, 4, 6, 8, 10, 16–18, 23, 26, and 28–30 for obviousness-type
double patenting based on claims 1–34 of U.S. Patent 10,245,351 in view of
Thayumanavan and Martin, and optionally also in view of Orbach or Altman
(Non-Final Action 15).
OPINION
Obviousness
Claims 1, 4, 6, 8, 10, 16–18, 23, 26, 28, and 30 stand rejected as
obvious based on Orbach, Thayumanavan, and Martin. Claim 29 stands
rejected as obvious based on Orbach, Thayumanavan, Martin, and Altman.
The same issue is dispositive for both rejections.
The Examiner finds that Orbach teaches that “Fmoc-protected . . .
dipeptides such as Fmoc-Phe-Phe . . . form hydrogels.” Non-Final Action 4.
The Examiner finds that Orbach also teaches that “Fmoc-FG [Fmoc-Phe-
Gly], Fmoc-FRGD [Fmoc-Phe-Arg-Gly-Asp] and Fmoc-RGDF formed
hydrogels.” Id. The Examiner finds that Orbach teaches that its
“nanostructured material . . . can be used in different biomedical applications
including drug delivery.” Id. at 4–5.
The Examiner finds that “Thayumanavan discloses hydrogels drug
delivery vehicles that release entrapped drug in response to changes in
carbon dioxide partial pressure with the gels prepared from polymerization
of meth(acrylate) monomers.” Id. at 5. The Examiner also finds that
Thayumanavan teaches that its “hydrogels can be prepared as nanoparticles
(nanogels) that are suitable for parenteral (e.g., intravenous injection) with
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diameter of the nanogel particles being less than 500 nm,” and exemplifies
“particles with diameters in the range of 10 – 150 nm.” Id.
The Examiner concludes that it would have been obvious “to prepare
hydrogel particles using the hydrogel materials of Orbach . . . because the
self-assembling, Fmoc-peptide hydrogels of Orbach can be formed into
blocks of hydrogels and used in such forms or can be prepared as particles
comprising a drug but can also be used for controlled drug delivery as a
particulate form as disclosed by Thayumanavan.” Id. at 5–6.
The Examiner acknowledges that Orbach and Thayumanavan do not
teach “[i]nclusion of a stabilizer such as the vitamin E derivative TPGS in
the final particles.” Id. at 6. The Examiner finds that Martin “discloses
hydrogel based on palmitoyl glycol chitosan” and states that “[g]els
comprising TPGS had a high speed of hydration . . . and altered the time to
erosion onset.” Id. at 6–7.
The Examiner concludes that it would have been obvious “to
incorporate a material such as TPGS into the hydrogel particles disclosed by
Orbach et al. and Thayumanavan . . . because Martin et al. discloses that
inclusion of ingredients like TPGS in hydrogels alters the hydrophilicity and
other properties of the obtained hydrogels.” Id. at 7. The Examiner reasons
that “such ingredients can be used by the person of ordinary skill in the art to
further control the release of the bioactive agent included in the particles to
achieve the desired hydration and drug release profile.” Id. at 7.
Appellant argues that “it is an error of fact for the Examiner to allege
that Chen[7] and Thayumanavan ‘establish that there are numerous methods

7 See infra, pages 8–9.
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by which nanoparticles of hydrogels can be prepared.’” Appeal Br. 8
(quoting Non-Final Action 9). Appellant argues that “Chen is not concerned
with nanoparticles but rather with considerably larger microparticles, as
Chen teaches that the formed particles described therein have diameters
ranging from 15 to 105 microns.” Id.
Appellant also argues that “[t]he Examiner does not appear to have
even mentioned any method of preparing nanoparticles supposedly
established by Thayumanavan, except for ‘with the gels prepared from
polymerization of meth(acrylate) monomers.’” Id. at 9 (quoting Non-Final
Action 5). Appellant therefore concludes that “Chen and Thayumanavan
together provide evidence of only a single method of preparing hydrogel
nanoparticles, namely polymerization of meth(acrylate) monomers; and the
Examiner has not disputed that this method is not applicable to forming
hydrogels from self-assembling peptides.” Id.
We agree with Appellant that the Examiner has not shown, by a
preponderance of the evidence, that the cited references would have
provided a skilled artisan with a reasonable expectation of successfully
making hydrogel particles in the nanometer size range recited in claim 1
using Orbach’s self-assembling peptides.
Orbach states that Fmoc-Phe-Phe (Fmoc-FF) had been shown to self-
assemble “into a rigid hydrogel.” Orbach 2646, right col. Orbach states that
“Fmoc-FG forms a hydrogel” and “Fmoc-FRGD . . . formed hydrogels.” Id.
at 2647, right col. Orbach also states that “[a]ll of the Fmoc-peptides were
first dissolved in DMSO and then diluted in water to their final
concentration. The dilution of the DMSO solutions into water leads to
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substantial self-assembly of these peptides.” Id. Orbach states that “[a]ll
Fmoc-peptides that formed hydrogels were arranged as branching, flexible
fibrous structures.” Id. at 2648, left col. Finally, Orbach states that, “[i]n
most cases, their properties enable the utilization in different biomedical
applications including drug delivery.” Id. at 2650, left col.
Thus, Orbach teaches that most of the peptides recited in Appellant’s
claim 1 will self-assemble into hydrogels if they are dissolved in DMSO and
then diluted in water. As the Examiner noted, however, Orbach does not
teach particles of the size recited in claim 1. For this characteristic, the
Examiner cites Thayumanavan. Non-Final Action 5–6.
Thayumanavan discloses
a drug delivery vehicle comprises a first hydrogel comprising
an opioid antagonist, wherein release of the opioid antagonist
from the first hydrogel is stimulated by an increase in the
concentration of CO2 in the environment of the drug delivery
vehicle; and a second hydrogel comprising an opioid, wherein
release of the opioid from the second hydrogel is substantially
CO2-independent, or is decreased by an increase in the
concentration of CO2 in the environment of the drug delivery
vehicle.
Thayumanavan ¶ 8.
Thayumanavan discloses that its hydrogels can be “prepared as
nanoparticles (nanogels) that are suitable for parenteral administration (e.g.,
intravenous injection” and have “diameters of less than 500 nm.” Id. ¶ 99.
Thayumanavan’s Example 4 describes a method of making “nanogels with
diameters of 10–150 nm.” Id. ¶ 129. Thayumanavan describes making those
nanogels using an inverse emulsion polymerization of the monomer HEMA
(2-hydroxyethyl methacrylate) with a bisacrylamide acetal crosslinker, both
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of which were dissolved in an aqueous phase that also included the free
radical initiator ammonium peroxodisulfate. Id. ¶ 126. The aqueous phase
was mixed with an organic phase made up of hexane, Span 80 (sorbitan
monooleate) and Tween 80 (polyethyleneglycol-sorbitan monooleate). Id.
The mixture was then sonicated and polymerization was initiated by adding
N,N,N',N'-tetramethylethylene diamine, and polymerization was allowed to
proceed. Id.
The Examiner cites Thayumanavan as providing a skilled artisan with
a reason to make Orbach’s hydrogel in nanoparticulate form, and points to
Thayumanavan’s Example 4 as showing nanoparticles with sizes in the
range recited in claim 1, but the Examiner does not point to any evidence or
provide sound technical reasoning to show that a skilled artisan would have
considered Thayumanavan’s method—which used the monomer HEMA,
which was covalently cross-linked—to be applicable to Orbach’s self-
assembling peptides. The Examiner does not, in fact, assert that
Thayumanavan’s method could successfully be used with Orbach’s peptides.
See Non-Final Action 5–6. Nor does the Examiner cite Martin as disclosing
a method of making hydrogel nanoparticles. See id. at 6–7.
Rather, the Examiner states that
[r]eferences such as Chen et al. and Thayumanavan establish
that there are numerous methods by which nanoparticles of
hydrogels can be prepared. Moya-Ortega et al. discloses that
nano-, micro- and macro-hydrogels can be prepared by top-
down or bottom up approaches, [with] the top down method
generating nanoparticles by physical, chemical or mechanical
grinding of large particles or clusters.
Id. at 9.
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The Examiner did not provide citations for either Chen or Moya-
Ortega, but noted in the Answer that Chen was “cited on PTO-892 mailed
July 13, 2018” and Moya-Ortega was “cited on PTO-892 mailed April 1,
2020.” Ans. 12. We understand the cited references to be Chen et al.,
Formation of supramolecular hydrogel microspheres via microfluidics, Lab
on a Chip 9:2947–2951 (2009), and Moya-Ortega et al., Cross-linked
hydroxypropyl-β-cyclodextrin and γ-cyclodextrin nanogels for drug delivery:
Physicochemical and loading/release properties, Carbohydrate Polymers
87:2344–2351 (2012). Both references are of record.
The Examiner states that “Chen and Moya-Ortega are not relied upon
to reject the instant claims but to rebut Appellant’s arguments by providing
evidence as to the state of the art and the knowledge of the person of
ordinary skill in the art.” Ans. 13. These references are therefore relevant to
the issue of whether a person of ordinary skill in the art would have had a
reasonable expectation of successfully making Appellant’s composition,
based on the disclosures of Orbach, Thayumanavan, and Martin.
Chen states that “[s]upramolecular hydrogel microspheres are
hydrogel particles formed by the self-assembly of hydrogelators in water.”
Chen 2947, abstract. Chen describes a “strategy to prepare supramolecular
hydrogel microspheres with diameters ranging from 15 to 105 microns by
using microfluidics.” Id. Thus, as Appellant has pointed out (Appeal Br. 8),
Chen does not describe a method of making hydrogel particles with an
average diameter of 1000 nm (1 micron) or less, and the Examiner has not
persuasively shown that Chen’s teachings could successfully be applied to
make the claimed composition.
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Moya-Ortega describes a “technique to prepare cyclodextrin (CD)
nanogels, in which the cross-linking takes place simultaneously with an
emulsification/solvent evaporation process.” Moya-Ortega 2344, abstract.
Moya-Ortega states that “[n]ano-, micro- and macro-hydrogels can be
created according to either the ‘bottom-up’ or the ‘top-down’ approaches.
. . . The ‘top-down’ method generates nanoparticles by physical, chemical or
mechanical grinding of large particles or clusters.” Id. at 2344, right col.
Moya-Ortega, however, does not use the “top-down” approach to
make its nanogels. Instead, its method is similar to Thayumanavan’s: Moya-
Ortega prepared an aqueous phase containing the cyclodextrin monomer
(γCD or HPβCD) and the cross-linker (ethylene glycol diglycidyl ether,
EGDE), along with either hydroxypropyl methylcellulose (HPMC) or agar;
this solution was then mixed with an organic phase containing Span 80 in
dichloromethane, and the mixture was homogenized and stirred at 60°C for
30 minutes. Id. at 2345, right col.
In summary, none of the references cited by the Examiner—either
those cited as the basis of the rejection or those cited as evidence of the
knowledge of those skilled in the art—describes making hydrogel particles
of the size required by Appellant’s claims from self-assembling peptides,
and the Examiner has not persuasively shown that Moya-Ortega’s passing
reference to “top-down” methods of making nanogels would have provided
those skilled in the art with a reasonable expectation of successfully
converting Orbach’s macro-scale hydrogels into particles with an average
size of 1000 nm or less.
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We therefore conclude that the Examiner has not supported, by a
preponderance of the evidence, a prima facie case of obviousness based on
Orbach, Thayumanavan, and Martin. The Examiner cites Altman only as a
basis for including a cryoprotectant in the claimed composition (Non-Final
Action 10), and does not point to any disclosure that makes up for the
deficiency in Orbach, Thayumanavan, and Martin.
We reverse the rejection of claims 1, 4, 6, 8, 10, 16–18, 23, 26, 28,
and 30 under 35 U.S.C. § 103(a) based on Orbach, Thayumanavan, and
Martin and the rejection of claim 29 under 35 U.S.C. § 103(a) based on
Orbach, Thayumanavan, Martin, and Altman.
Obviousness-type double patenting
All of the claims stand rejected for obviousness-type double patenting
based on the claims of U.S. Patent 9,074,095, U.S. Patent 9,610,353, or U.S.
Patent 10,245,351, each taken in view of Thayumanavan and Martin, and
optionally also in view of Orbach or Altman.
With regard to each of the double patenting rejections, the Examiner
finds that the patented claims are drawn to a fibrous network made up of
self-assembling peptides that form a hydrogel. Non-Final Action 12, 14, 15.
The Examiner finds that “[d]iscrete particles or the inclusion of additional
ingredients such as . . . vitamin E derivative are not claimed.” Id. at 12, 14,
16.
The Examiner concludes, however, that the claimed composition
would have been an obvious modification of the previously patented claims:
It would have been obvious . . . to prepare discrete hydrogel
particles that contain a vitamin E derivative to alter the
hydration and release properties. . . . The person of ordinary
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skill in the art would have been motivated to make those
modifications and reasonably would have expected success
because Thayumanavan discloses that hydrogels can be
prepared as particles such as nanogels for the administration of
biologically active ingredients while Martin et al. and Altman et
al. disclose that various additives can be added to hydrogels.
Id. at 13, 14–15, 16 (emphasis added). The Examiner relies on Orbach only
with regard to the Fmoc-FRGD peptide recited in Appellant’s claims. Id. at
13, 15, 16.
We agree with Appellant that the double patenting rejections rely on
“the same errors discussed [above with respect to the § 103 rejections],
primarily regarding the interpretation of Thayumanavan, Chen and Moya-
Ortega.” Appeal Br. 16. See also id. at 18, 20 (same). We therefore reverse
all of the rejections for obviousness-type double patenting.
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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1, 4, 6, 8,
10, 16–18,
23, 26, 28,
30
103(a) Orbach,
Thayumanavan, Martin
1, 4, 6, 8,
10, 16–18,
23, 26, 28,
30
29 103(a) Orbach,
Thayumanavan, Martin,
Altman
29
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
U.S. Patent 9,074,095,
Thayumanavan, Martin,
Orbach, Altman
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
U.S. Patent 9,610,353,
Thayumanavan, Martin,
Orbach, Altman
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
U.S. Patent 10,245,351,
Thayumanavan, Martin,
Orbach, Altman
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
Overall
Outcome
1, 4, 6, 8,
10, 16–18,
23, 26, 28–
30
REVERSED