Biocompatibles UK Limited

Patent Trials and Appeals Board

Aug 19, 2021

2020005983 (P.T.A.B. Aug. 19, 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.
13/981,706 10/10/2013 Koorosh Ashrafi 8150.0688 5973
121974 7590 08/19/2021
Kacvinsky Daisak Bluni PLLC (8150)
2601 Weston Parkway, Suite 103
Cary, NC 27513
EXAMINER
MATTISON, LORI K
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
08/19/2021 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):
docketing@kdbfirm.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte KOOROSH ASHRAFI, ANDREW LENNARD LEWIS, CLARE
HEAYSMAN, ANDREW LLOYD, and GARY PHILIPS
__________

Appeal 2020-005983
Application 13/981,706
Technology Center 1600
__________

Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and
ULRIKE W. JENKS, Administrative Patent Judges.

FREDMAN, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134(a) involving claims to
microspheres suitable for use in embolisation of a tumor. 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
Biocompatibles UK Limited (see Appeal Br. 3). We refer to the
Specification of July 25, 2013 (“Spec.”); Final Action of Sept. 19, 2019
(“Final Act.”); Appeal Brief of May 21, 2020 (“Appeal Br.”); Examiner’s
Answer of June 18, 2020 (“Ans.”); and Reply Brief of Aug. 18, 2020
(“Reply Br.”).
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Statement of the Case
Background
“[P]olymer microspheres can be useful in the treatment of
embolisation. Embolisation involves the introduction of embolic agents into
the arteries feeding a tumour to starve it of its nutrients and oxygen” (Spec.
4:29–31). “There is evidence from preclinical tumour models, that
embolisation alone may induce hypoxia in the tumour” (id. at 5:2–3).
“[H]ypoxic tumours are known to possess a reductive environment” (id. at
3:4). “Polymers that contain disulfide functionality can be considered both
redox and thiol responsive” (id. at 2:29–30). Prior art describes
microcapsules “cross-linked with disulfides by layer-by-layer deposition of
thiolated PMA” that were used “for loading doxorubicin and delivering the
drug to colon cancer cells in vitro” (id. at 4:1–3; 4:24–25).
The Claims
Claims 1, 5, 9–15, and 21–31 are pending.2 Independent claim 1 is
representative and reads as follows:
1. Microspheres suitable for use in embolisation of a tumor,
comprising a gel body, wherein the gel body comprises a
synthetic polymer and a drug, wherein the microparticles have
an average diameter in the range 40 to 1500 μm, wherein the
polymer comprises polyvinyl alcohol wherein the polymer is
cross-linked by a cross linking agent of the formula:
A-(CH2)n-S-S-(CH2)n'-A'
wherein A and A' are independently selected from groups
which can form a covalent bond with the polymer; n and n' are
integers ranging from 1 to 10; and wherein at least one of the -

2 We note that claims 16–19 and 32 were identified as withdrawn from
consideration by the Examiner in the Final Action.
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(CH2)n and -(CH2)n'- groups are substituted with groups which
are capable of electrostatically associating with the drug;
and wherein the polymer is in the form of a hydrogel, and
wherein the groups capable of electrostatically
associating with the drug are carboxyl groups.

The Issue
The Examiner rejected claims 1, 5, 9–15, and 21–32 under 35 U.S.C.
§ 103(a) as obvious over Lewis,3 Stein,4 Ilangovan,5 and Meng6 (Final Act.
5–11).
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 the claims obvious?
Findings of Fact
1. Lewis teaches microspheres
suitable for embolisation, comprises particles having a matrix
of water-swellable water-insoluble polymer and, absorbed in
the matrix, a water-soluble therapeutic agent, and is
characterised in that the polymer has an overall anionic charge
at a pH in the range 6 to 8, in that the particles, when swollen to
equilibrium in water have particle sizes in the range 40-1500
μm and in that the therapeutic agent is an anthracycline
compound having at least one amine group.
(Lewis ¶¶ 11, 40). Lewis teaches “composition is of use for embolising
tumours and delivering cytotoxic agents thereto” (Lewis ¶ 1).

3 Lewis et al., US 2004/0161466 A1, published Aug. 19, 2004.
4 Stein et al., US 2002/0076443 A1, published June 20, 2002.
5 Ilangovan et al., In vivo measurement of tumor redox environment using
EPR spectroscopy, 234/235 Mol. Cellular Biochemistry 393–98 (2002).
6 Meng et al., Reduction-sensitive polymers and bioconjugates for
biomedical applications, 30 Biomaterials 2180–98 (2009).
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2. Lewis teaches a “type of polymer which may be used to form
the water-swellable water-insoluble matrix is polyvinyl alcohol crosslinked
using aldehyde type crosslinking agents” (Lewis ¶ 13).
3. Lewis teaches the “the polymer will form a hydrogel.
Generally the polymer is covalently crosslinked” (Lewis ¶ 12).
4. The Examiner acknowledges that Lewis does “not teach
disulfide crosslinking of the polyvinyl alcohol” (Final Act. 6).
5. Stein teaches “cross-linked polymer matrices” (Stein ¶ 8)
including polyvinyl alcohol polymers (Stein ¶ 17) “such that an entrapped
therapeutic agent or agents is released from the matrix under zero order,
pseudo zero order or first order kinetics. The release characteristics are
adjustable by selection of the appropriate phases, polymer(s), cross-linking
agent(s), and excipients, among other factors” (Stein ¶ 11).
6. Stein teaches “[p]referably, the polymer comprises at least two
thiol groups, and may be a homopolymer or a copolymer” (Stein ¶ 18).
7. Stein teaches:
A matrix of the present invention may be prepared by cross-
linking the polymer on which at least two thiol groups are
present in the presence of the therapeutic agent. The cross-
linking of the polymer on which at least two thiol groups are
present may include disulfide bonds, thioether bonds, and
combinations thereof.
(Stein ¶ 64).
8. Stein teaches:
controlled release of the therapeutic agent from the matrix is
believed to occur as a consequence of the diffusion from and/or
biodegradation of the matrix by one or more in-vivo
degradation pathways. . . . degradation of the matrix is achieved
by local factors at the site of administration such as reducing
agents . . . The varied presence of these various degradation
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agents in particular compartments in the body provides further
guidance on selecting the appropriate site for administration,
and also in the preparation of a matrix to provide the desired
release kinetics in the presence of the particular degradative
machinery at the site.
(Stein ¶ 87).
9. Ilangovan teaches “[s]olid tumors are characterized by a
number of physiological properties such as occurrence of significant
hypoxia, large amounts of cellular reducing equivalents” (Ilangovan,
abstract).
10. Ilangovan teaches the “enhanced reduction of the nitroxide in
tumor compared to normal tissue, thus, may be due to lower oxygen
concentration as well as to the significantly enhanced GSH levels in the
tumor” (Ilangovan 396, col. 2).
11. Meng teaches “reduction-sensitive biodegradable polymers and
conjugates have emerged as a fascinating class of biomedical materials that
can be elegantly applied for the development of sophisticated delivery
systems for both biotherapeutics” (Meng 2180, col. 1).
12. Meng teaches:
These materials usually contain characteristic disulfide
linkage(s) in the main chain, at the side chain, or in the cross-
linker. The disulfide bonds, though sufficiently stable in the
circulation and in the extracellular milieu, may be prone to
rapid cleavage, at a time scale from minutes to hours, under a
reductive environment through thiol-disulfide exchange
reactions.
(Meng 2180, col. 1).
13. Meng teaches “of particular interest is that tumor tissues are
highly reducing and hypoxic compared with normal tissues, with at least 4-
fold higher concentrations of GSH in the tumor tissues over normal tissues,
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rendering the reducible bioconjugates valuable for tumor-specific drug and
gene delivery” (Meng 2180, col. 2 to 2181, col. 1).
14. Scheme I of Meng is reproduced below

“Scheme 1. Chemical structures of disulfide-containing cross-linking
agents” (Meng 2182; cf. Spec. 7).
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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
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 reasoning regarding the
scope and content of the prior art (Final Act. 5–11; FF 1–14) and agree that
claims 1, 22, and 23 are rendered obvious by Lewis, Stein, Ilangovan, and
Meng. We address Appellant’s arguments below.
Claim 1
Appellant contends “that polyvinyl alcohol is only one polymer
among a ‘large number’ of polymers in Stein that have at least two
functional or reactive groups, which include amino, carboxyl, thiol and
hydroxy groups, among others” (Appeal Br. 9). Appellant also contends
“that the controlled release of therapeutic agent occurring as a consequence
of biodegradation of the matrix by an in-vivo degradation pathway via
reducing agents, as described by Stein, is a completely different release
mechanism than that taught by Lewis” (id.).
We find these arguments unpersuasive because they fail to address the
references in combination. Lewis teaches particles composed of polyvinyl
alcohol polymers for embolization of tumors (FF 1–3) and Stein
demonstrates that polymers including polyvinyl alcohol may be cross-linked
using disulfide groups (FF 5–8). And as to the release mechanisms, Meng
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provides persuasive reasoning to utilize disulfide groups as taught by Stein
in the particles of Lewis because disulfide linking groups may be “elegantly
applied for the development of sophisticated delivery systems” (FF 11) such
as delivery to a hypoxic tumor making the “reducible bioconjugates valuable
for tumor-specific” delivery (FF 13). “Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references. . . . [The 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).
Appellant contends “the dithiobis(succinimydylpropionate)
crosslinker . . . of Meng, is distinct from the claimed crosslinker, A-(CH2)n-
S-S-(CH2)n'-A', in which at least one of the -(CH2)n- and -(CH2)n'- groups
are substituted with carboxyl groups which are capable of electrostatically
associating with a drug” (Appeal Br. 11).
We find that this argument is factually incorrect because it does not
address all of the crosslinkers taught by Meng. Meng teaches a set of
crosslinkers (FF 14) identical to those recited in the Specification (see Spec.
7). Indeed, Meng teaches an L-cystine bisacrylamide crosslinker having
carboxy groups that is structurally identical to the crosslinker recited in
claims 25 and 26 (FF 14, compound BACy). Thus, Meng teaches a
crosslinker substituted with carboxyl groups that, to the extent Appellant is
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correct, will inherently be capable of electrostatically associating with a drug
(cf. Appeal Br. 11).
Appellant contends
Turning to the L-cystine bisacrylamide (BACy)
crosslinker of Meng, it would not be obvious to select such a
crosslinker in order to produce a polyvinyl alcohol release
system containing disulfide linkages in its structure. First, the
L-cystine bisacrylamide (BACy) is described in conjunction
with bioreducible polyethylenimine (PEI) polymers and
networks in Meng, rather than polyvinyl alcohol. Moreover,
one of ordinary skill in the art would not have simply
“recognized from the structure of the L-cystine bisacrylamide
(BACy)” that it is suitable for crosslinking the Nelfilcon B of
Lewis et al. as the Nelfilcon B contains pendant ethylenically
unsaturated groups, as urged in the Office Action, because there
is no teaching or suggestion in the references to do so.
(Appeal Br. 11).
We are not persuaded because the prior art “is presumptively enabling
barring any showing to the contrary by a patent applicant.” In re Antor
Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012). Appellant has provided
no evidence that the crosslinkers of Meng would not function to crosslink
polyvinyl alcohol. Indeed, Appellant lacks any evidence showing any doubt
regarding the functionality of Meng’s crosslinkers. And “attorney 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).
As to whether the Meng’s crosslinkers would have been suitable for
Nelfilcon B, Meng teaches these are crosslinking agents and Appellant
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provides no evidence that the crosslinking agents would be ineffective
against any particular compound.
Appellant contends
one would not have been motivated to select one of the
crosslinkers taught by Meng and use it to crosslink the
Nelfilcon B of Lewis et al. because the crosslinked product
would not be expected to provide rapid degradation under a
reductive environment present in intracellular compartments
and one would not have been motivated to provide disulfide
linkage(s) in order to control the release of the drug, as argued
in the Office Action. This is true at least because the pendant
ethylenically unsaturated groups of the Nelfilcon B would be
expected to crosslink the polymer (as they had in Lewis), and
the resulting crosslinks would not contain a disulfide linkage
and thus would not be expected to be reduction-sensitive.
(Appeal Br. 11).
We find this argument unpersuasive for several reasons. First, claim 1
lacks any recitation regarding the rate of degradation and, therefore,
“appellant’s arguments fail from the outset because . . . they are not based on
limitations appearing in the claims.” In re Self, 671 F.2d 1344, 1348 (CCPA
1982). Second, Meng specifically teaches that “tumor tissues are highly
reducing and hypoxic” (FF 13) and “disulfide bonds, though sufficiently
stable in the circulation and in the extracellular milieu, may be prone to
rapid cleavage, at a time scale from minutes to hours, under a reductive
environment” (FF 12). Thus, Meng expressly suggests that rapid cleavage
would be expected to occur using the disulfide bonds in the hypoxic
environment of a tumor consistent with Lewis’ tumor embolization
treatment (FF 1). Third, Appellant’s discussion of the “expected” operation
of the prior art lacks any evidentiary support and fails to properly apply the
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crosslinkers of Meng (identical to that of claim 26). Geisler, 116 F.3d at
1470.
Claims 22 and 23
Appellant again contends that the “dithiobis(succinimydylpropionate)
crosslinker . . . of Meng comprises leaving groups that are susceptible to
nucleophilic attack. However, this crosslinker is distinct from the claimed
crosslinker” (Appeal Br. 12).
We again find this argument unpersuasive because Meng is not
limited to a single crosslinker, but teaches a variety of different functional
crosslinkers including an L-cystine bisacrylamide crosslinker that is
structurally identical to the crosslinkers recited in claims 25 and 26 (FF 14,
compound BACy). Moreover, Meng teaches a set of crosslinkers (FF 14)
identical to those shown in the Specification (see Spec. 7), where the
Specification acknowledges that the “chemical structures of some of the
more common disulfide-containing crosslinkers that may be used in the
invention are shown below” (Spec. 6:20–21). Consequently, Appellant’s
argument not only lacks evidentiary support but is actually inconsistent with
the direct teachings of Appellant’s own Specification, which suggests that
Meng’s crosslinkers may be used in the invention.
Conclusions of Law
A preponderance of the evidence of record support the Examiner’s
conclusion that the prior art renders the claims obvious.

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DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 5, 9–15,
21–31
103(a) Lewis, Stein,
Ilangovan, Meng
1, 5, 9–15,
21–31

No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED