Ex Parte Richard

Patent Trial and Appeal Board

Nov 6, 2017

12195806 (P.T.A.B. Nov. 6, 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
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/195,806 08/21/2008 Robert E. Richard 06-00112US2 (4010/218) 9168
121974 7590 11/08/2017
K AC VINSKY DAISAK BLUNI PLLC
America's Cup Building
50 Doaks Lane
Marblehead, MA 01945
EXAMINER
HELM, CARALYNNE E
ART UNIT PAPER NUMBER
1615
NOTIFICATION DATE DELIVERY MODE
11/08/2017 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
following e-mail address(es):
bbonneville @ kdbfirm .com
docketing @ kdbfirm. com
ndeane @ kdbfirm.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ROBERT E. RICHARD
Appeal 2016-004425
Application 12/195,8061
Technology Center 1600
Before FRANCISCO C. PRATS, JOHN G. NEW, and
TAWEN CHANG, Administrative Patent Judges.
PRATS, Administrative Patent Judge.
DECISION ON APPEAL
This appeal under 35 U.S.C. § 134(a) involves claims to injectable
medical compositions composed of hydrogel particles. The Examiner
rejected the claims for failure to comply with the written description
requirement, and for obviousness.
We have jurisdiction under 35 U.S.C. § 6(b). We reverse the written
description rejection. We also reverse each of the obviousness rejections,
except for one.
1 Appellant states that the “real party in interest in this Appeal is Boston
Scientific Scimed, Inc.” Appeal Br. 3.
Appeal 2016-004425
Application 12/195,806
STATEMENT OF THE CASE
The Specification discloses “hydrogel particles that swell in vivo upon
injection.” Spec. ^ 2. The Specification explains that such particles are
useful in “the technique of embolization [which] involves the therapeutic
introduction of particles into the circulation to occlude vessels, for example,
to either arrest or prevent hemorrhaging or to cut off blood flow to a
structure or organ.” Id. ^3. The Specification explains that microspheres
useful in therapeutic embolization may also be used for localized delivery of
therapeutic agents, such as doxorubicin. Id. ^5.
The Specification discloses, in one embodiment, “injectable
compositions . . . which contain temperature-sensitive hydrogel particles.”
Id. 7. The Specification explains that “[tjemperature-sensitive hydrogels
are able to swell or shrink in aqueous fluids as a result of a change in
temperature of the surrounding fluid. Negative temperature sensitive
hydrogels have a lower critical solution temperature (LCST). They contract
when heated above the LCST and expand when cooled below the LCST.”
Id. T| 39.
Thus, by preparing “hydrogel particles having an LCST above body
temperature, . . . and by injecting the particles into a subject above the
LCST, the particles will have self-expanding character, thereby increasing,
for example, their embolic or bulking effect, or thereby modulating the
release of therapeutic agent from the particles.” Id. ^ 70.
The Specification discloses that, in certain embodiments, “hydrogels
may be created, for example, from polymers whose LCST rises over time in
vivo after having been injected (e.g., from homopolymers and copolymers of
pHPMAm-dilactate [poly(N-(2-hydroxypropyl)methacrylamide lactate)], . . .
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Application 12/195,806
among others).” As to that embodiment, the Specification
explains, in particular:
By selecting an LCST value for the hydrogel particles (e.g., by
selecting a suitable ratio of dilactate monomer to monolactate
monomer) that is both below injection temperature (e.g., room
temperature) and below body temperature, such hydrogel
particles may be injected into the body of a subject at a
temperature where the particles are above their LCST value and
are thus in a contracted state. As the LCST value of the
particles rises over time to body temperature and above (such
that the temperature experienced by the particles is now below
their LCST value), the particles will expand.
Id.
Claims 21 and 22, the independent claims on appeal, are illustrative
and read as follows (Appeal Br. 19 (indentation added)):
21. A method of treatment comprising injecting an injectable
medical composition into a subject,
said injectable medical composition comprising
temperature sensitive hydrogel particles suspended in an
aqueous fluid,
said hydrogel particles comprising a crosslinked polymer
and a therapeutic agent,
said hydrogel particles having a lower critical solution
temperature (LCST) that is above normal body temperature,
wherein 95 vol% of the hydrogel particles have a longest
linear cross-sectional dimension between 30 pm and 5000 pm,
wherein the injectable medical composition is injected
into the subject at a temperature that is above the LCST of the
hydrogel particles, and
wherein said method of treatment is a tissue bulking
treatment or an embolization treatment.
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22. An injectable medical composition comprising
temperature sensitive hydrogel particles that comprise a
crosslinked polymer and a therapeutic agent,
said hydrogel particles having an ex vivo LCST that is
below normal body temperature and whose LCST increases in
vivo after injection into a subject from below normal body
temperature to above body temperature,
wherein 95 vol% of the hydrogel particles have a longest
linear cross-sectional dimension between 30 pm and 5000 pm.
The Examiner entered the following rejections:
(1) Claims 22, 23, 26-29, and 33^10, under 35 U.S.C. § 112, first
paragraph, as failing to comply with the written description requirement
(Final Act. 2-3 (entered November 20, 2014));
(2) Claim 21, under 35 U.S.C. § 103(a), as being unpatentable over
Escobar,2 D’Emanuele,3 Reb,4 Sawhney,5 and Barker6 (id. at 3-6);
(3) Claims 22-26, 33, 36, and 38, under 35 U.S.C. § 103(a) as
being unpatentable over Hennink,7 D’Emanuele, Nagaoka,8 and Flirt9 (id. at
6-9);
2 J.L. Escobar, et al., Cephazoline Sodium Release from Poly(N-isopropyl
acrylamide-co-N,N-dimethylacrylamide) Hydrogels, 91 J. Appl. Polym. Sci.
3433-3437 (2004).
3 A. D’Emanuele & R. Dinarvand, Preparation, characterisation, and drug
release from thermoresponsive microspheres, 118 Int. J. Pharm. 237-242
(1995).
4 US 2006/0251582 Al (published Nov. 9, 2006).
5 US 2001/0046518 Al (published Nov. 29, 2004).
61.C. Barker, et al., Studies of the “Smart” Thermoresponsive Behavior of
Copolymers of N-Isopropylacrylamide and N,N-Dimethylacrylamide in
Dilute Aqueous Solution, 36 Macromolecules 7765-7770 (2003).
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(4) Claims 27, 35, and 39, under 35 U.S.C. § 103(a) as being
unpatentable over Hennink, D’Emanuele, Nagaoka, and Hirt, and Soga B10
{id. at 9-11);
(5) Claims 28, 29, and 40, under 35 U.S.C. § 103(a) as being
unpatentable over Hennink, D’Emanuele, Nagaoka, Hirt, Soga B, Sawhney,
and Reb {id. at 11-13);
(6) Claim 37, under 35 U.S.C. § 103(a) as being unpatentable over
Hennink, D’Emanuele, Nagaoka, Hirt, Soga B, Sawhney, Reb, and Warren11
{id. at 13-14); and
(7) Claim 34, under 35 U.S.C. § 103(a) as being unpatentable over
Hennink, D’Emanuele, Nagaoka, Hirt, Soga B, and Ramstack12 (id. at 13-
14)
WRITTEN DESCRIPTION
The Examiner’s Prima Facie Case
In rejecting claims 22, 23, 26-29, and 33^40 for failing to comply
with the written description requirement, the Examiner finds that claim 22
recites “hydrogel particles with an ex vivo lower critical solution temperature
7 WO 01/09198 A1 (published Feb. 8, 2001).
8 Noriyasu Nagaoka et al., Synthesis of Poly(N-
isopropylacrylamide)Hydrogels by Radiation Polymerization and Cross-
Linking, 26 Macromolecules 7386-7388 (1993).
9 US 2008/0260833 Al (published Oct. 23, 2008).
10 Osamu Soga, Biodegradable thermosensitive polymers: synthesis,
characterization, and drug delivery applications, (March 2006) (Ph.D. thesis,
Utrecht University).
11 US 6,610,841 B1 (issued Aug. 26, 2003).
12 US 6,495,164 B1 (issued Dec. 17, 2002).
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(LCST) that is below normal body temperature and whose LCST increases
in vivo after injection into a subject from below body temperature to above
body temperature.” Final Action 2-3.
As to those particles, the Examiner finds that the Specification
“details that homopolymers and copolymers of
poly(hydroxypropylmethacrylamide-dilactacte) among others have this
property (see paragraph 71)” and that Soga13 “expounds upon this class of
polymers but does not introduce others beyond those with
poly(hydroxypropylmethacrylamide-lactacten) that exhibit this
functionality.” Id. at 3.
Therefore, the Examiner reasons, although the class of polymers
described in 71 of the Specification and in Soga “can exhibit this
functionality, there is no discussion of any other structures that correlate to
this function. As a result the identity of these ‘other’ polymers is not
known.” Id.
In particular, the Examiner reasons, the Specification does not provide
a “structure-function correlation” between the functionality required by
claim 22 and the structures of polymers having that functionality and,
therefore, “it would not have been clear to th[e skilled] artisan that the
applicant had possession of the scope of the invention as claimed at the time
of filing.” Id.
13 Osamu Soga, et al., Physicochemical Characterization of Degradable
Thermosensitive Polymeric Micelles, 20 Langmuir 9388-9395 (2004).
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Analysis
As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992):
[T]he examiner bears the initial burden ... of presenting a
prima facie case of unpatentability. . . .
After evidence or argument is submitted by the applicant
in response, patentability is determined on the totality of the
record, by a preponderance of evidence with due consideration
to persuasiveness of argument.
To meet the initial burden of establishing a prima facie case of
unpatentability based on a lack of written description, the Examiner must
“present[] evidence or reasons why persons skilled in the art would not
recognize in the disclosure a description of the invention defined by the
claims.” In re Alton, 76 F.3d 1168, 1175 (Fed. Cir. 1996).
We agree with Appellant that a preponderance of the evidence does
not support the Examiner’s finding that the claims lack adequate descriptive
support.
As our reviewing court has explained, “[f]or generic claims, we have
set forth a number of factors for evaluating the adequacy of the disclosure,
including ‘the existing knowledge in the particular field, the extent and
content of the prior art, the maturity of the science or technology, [and] the
predictability of the aspect at issue.’” Ariad Pharmaceuticals, Inc. v. Eli
Lilly and Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (quoting Capon v.
Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005).
Accordingly:
A claim will not be invalidated on section 112 grounds
simply because the embodiments of the specification do not
contain examples explicitly covering the full scope of the claim
language. That is because the patent specification is written for
a person of skill in the art, and such a person comes to the
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patent with the knowledge of what has come before. Placed in
that context, it is unnecessary to spell out every detail of the
invention in the specification; only enough must be included to
convince a person of skill in the art that the inventor possessed
the invention and to enable such a person to make and use the
invention without undue experimentation.
Falknerv. Inglis, 448 F.3d 1357, 1366 (Fed. Cir. 2006) (quoting LizardTech,
Inc. v. Earth Resource Mapping, PTY, Inc., 424 F.3d 1336, 1345 (Fed. Cir.
2005)); see also Capon v. Eshhar, 418 F.3d at 1359 (“It is not necessary that
every permutation within a generally operable invention be effective in order
for an inventor to obtain a generic claim, provided that the effect is
sufficiently demonstrated to characterize a generic invention.”).
In the present case, we acknowledge that claim 22 generically recites
“hydrogel particles having an ex vivo LCST that is below normal body
temperature and whose LCST increases in vivo after injection into a subject
from below normal body temperature to above body temperature.” Appeal
Br. 19 (claim 22).
In addition to the particularized disclosure in 71 of the Specification,
noted above, and also the teachings in Soga, the Examiner acknowledges
that the Hennink reference (discussed below in relation to the rejections
under § 103) includes at least three examples of polymers having the
properties required by claim 22. Ans. 3. The Examiner finds, nevertheless,
that Hennink’s examples “most[ly] are based upon the same lactate side
chain on an acrylate or acrylamide that is copolymerized with N-
isopropylacrylamide discussed in the example of the instant disclosure.” Id.
at 3—4. The Examiner contends, therefore, that “there is no delineated link
between the structure of the polymer and displaying an LCST that changes
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specifically from below normal body temperature to above normal body
temperature upon injection as required by the claims.” Id. at 4.
We are not persuaded, however, that the written description
requirement obliges an applicant to determine and disclose a relationship
between every functionally recited element and the structures capable of
performing those functions, such that a skilled artisan can envision every
potential embodiment having the required functionality. To the contrary, as
noted above, “it is unnecessary to spell out every detail of the invention in
the specification; only enough must be included to convince a person of skill
in the art that the inventor possessed the invention . . . .” Falkner v. Inglis,
448 F.3d at 1366. In the instant case, it is undisputed that the Specification
and prior art of record disclose the structure of polymers having the
functionality required by claim 22.
As noted above, moreover, to sustain a rejection on these grounds the
Examiner must “present[] evidence or reasons why persons skilled in the art
would not recognize in the disclosure a description of the invention defined
by the claims.” In re Alton, 76 at 1175.
In the present case, the Examiner does not direct us to clear or specific
evidence explaining why, despite the particularized disclosure in 71 of the
Specification noted above, and despite the disclosures in Soga and Hennink,
a skilled artisan would have failed to recognize that Appellant possessed the
composition as claimed. Absent such evidence, the alleged difference in
breadth between the claimed subject matter and the subject matter expressly
disclosed in the Specification, by itself, does not persuade us that the
Specification failed to describe the full scope of the claimed invention
sufficiently.
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In sum, as seen above, the Specification provides a detailed disclosure
of the feature in claim 22 at issue, and the prior art includes disclosures of
elements which undisputedly meet those functional requirements of claim
22. In contrast, the Examiner advances no specific evidence explaining
why, based on those disclosures, an ordinary artisan would have failed to
recognize that Appellant was in possession of the invention generically
recited in claim 22. Because the preponderance of the evidence, therefore,
does not support the Examiner’s finding that claim 22 lacks sufficient
descriptive support, we reverse the Examiner rejection of that claim, and its
dependents, under 35 U.S.C. § 112, first paragraph.
OBVIOUSNESS—CLAIM 21
The Examiner’s Prima Facie Case
In rejecting claim 21 for obviousness, the Examiner cites Escobar as
describing drug release from a hydrogel encompassed by the claim, and cites
Barker as evidence that Escobar’s hydrogel has an LCST above normal body
temperature, as required by claim 21. Final Act. 4-5.
The Examiner finds that that Escobar differs from claim 21 in that
Escobar does not “explicitly teach the drug (therapeutic agent) containing
hydrogels as particles.” Id. at 5.
To address that deficiency, the Examiner cites D’Emanuele as
disclosing a method of drug delivery in which the drug is released from
hydrogel microspheres having a particle size encompassed by claim 21. Id.
The Examiner cites Sawhney as evidence that it was known in the art
to use hydrogels that swell in response to temperature change for tissue
augmentation and embolization, as claim 21 also requires. Id.
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The Examiner cites Reb as teaching that swellable particles, similar to
the hydrogel described in in Sawhney, were known in the art to be useful for
both drug delivery and tissue embolization, and to be deliverable by
injection. Id.
Based on the references’ combined teachings, the Examiner reasons
that it would have been obvious to prepare Escobar’s drug-releasing
hydrogels in the form of particles, in view of D’Emanuele’s teaching that
such particles were useful as drug delivery vehicles. Id. at 5-6. The
Examiner reasons further:
Since 1) hydrogels with an LCST were envisioned for
use as occlusive therapies, 2) swellable particles were also
taught for embolization, and 3) hydrogels with an LCST above
body temperature swell in the body, it would have been obvious
to employ hydrogels that have an LCST above body
temperature as embolic materials by injecting them into a
subject. Given the desired function for embolic particles to
swell upon delivery and the property of an LCST polymer to
swell when transitioning from a temperature above the LCST to
a temperature below the LCST, it would have been obvious to
inject the crosslinked hydrogel particles of Escobar et al. in
view of D’Emanuele et al. at a temperature above the LCST to
have them swell after injection into a subject as desired by the
embolic procedure of Reb et al. After injection into the subject,
the particles would then also serve the drug delivery role that
Reb et al. also desires. Therefore claim 21 is obvious over
Escobar et al. in view of D’Emanuele et al. Sawhney et al., and
Reb et al. as evidenced by Barker et al.
Id. at 6.
Analysis
Appellant does not persuade us that a preponderance of the evidence
fails to support the Examiner’s prima facie case of obviousness. To the
contrary, with respect to this rejection, we adopt as our own the Examiner’s
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findings of fact as to the scope and content of the prior art, as well as the
Examiner’s conclusion of obviousness as to claim 21.
Turning to Appellant’s arguments, Appellant does not assert error in
the Examiner’s finding that an ordinary artisan had good reason to prepare
Escobar’s drug-delivering hydrogel in the form of the particles taught in
D’Emanuele, or that an ordinary artisan would have been motivated to
administer such particles in a tissue bulking/embolization treatment as
described in Sawhney and Reb. Rather, Appellant contends that “[tjhere is
no teaching or suggestion within the references to take temperature into
account during the injection process.” Appeal Br. 10.
In particular, Appellant contends that the Examiner erroneously relies
on 40 of Sawhney as suggesting injection of hydrogel particles above their
LCST, contending that Sawhney’s teaching at 40 “is remote from a
teaching or suggestion to introduce a hyd[r]ogel into a body of a subject at
elevated temperature.” Id. at 11
Therefore, Appellant contends, the cited references “do not teach or
suggest a method whereby hydrogel particles having a lower critical solution
temperature (LCST) that is above normal body temperature is introduced
into a subject at a temperature that is above the LCST of the hydrogel.” Id.
at 11; see also Reply Br. 10 (“[T]he Examiner provides no citation of a
method whereby a hydrogel in any form (much less a hydrogel particle)
having a lower critical solution temperature (LCST) that is above normal
body temperature is introduced into a subject at a temperature that is above
the LCST of the hydrogel.”).
As the Supreme Court has explained, however, “the [obviousness]
analysis need not seek out precise teachings directed to the specific subject
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matter of the challenged claim, for a court can take account of the inferences
and creative steps that a person of ordinary skill in the art would employ.”
KSR Inti v. Teleflex Inc., 550 U.S. 398, 418 (2007); see also id. at 421 (“A
person of ordinary skill is ... a person of ordinary creativity, not an
automaton.”).
In the instant case, we agree with the Examiner (Ans. 4-6) that an
ordinary artisan would have reasonably inferred that, when injecting a
drug-delivering swellable hydrogel with an LCST above normal body
temperature, such as the hydrogel taught by Escobar, it would have been
desirable to inject the hydrogel at a temperature above the LCST, thereby
allowing the hydrogel to swell after administration to the patient.
As explained in Sawhney, swellable hydrogels “may be
advantageously used to affect sealing, plugging, or augmentation of tissue,
defects in tissue and organs, and may optionally permit controlled release of
therapeutic agents at an implantation site.” Sawhney ^ 26.
Sawhney explains that the hydrogels should be administered in their
dehydrated or non-gelled state, and upon administration
[t]he hydrogel polymer preferably rehydrates rapidly, within a
few minutes of being placed in a moist tissue environment, so
as to anchor itself within tissue. During the hydration process,
the dried gel may expand volumetrically, e.g., in one, two or
three dimensions, to several times its original size, thereby
lodging the gel within the tissue and sealing against leakage of
fluids through the tissue.
Id. T| 28.
Sawhney discloses that, in addition to simply hydrating in the
presence of the moist environment in a patient’s tissue, “[hjydrogels also
may be formed to be responsive to changes in environmental factors, such as
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pH, temperature, ionic strength, charge, etc., by exhibiting a corresponding
change in physical size or shape, so-called ‘smart’ gels.” Id. 40 (emphasis
added).
As to such smart gels, Sawhney discloses, “[f]or example,
thermoreversible hydrogels, such as those formed of amorphous
N-substituted acrylamides in water, undergo reversible gelation when heated
or cooled about certain temperatures (lower critical solution temperature,
LCST).” Id.
As the Examiner points out, D’Emanuele discloses that N-substituted
acrylamides are in their gelled state below their LCST, whereas they are in a
lower volume collapsed state above the LCST. See D’Emanuele 238
(“When the temperature of the polymer is raised above the LCST a phase
separation occurs within the polymer accompanied by a dramatic shrinkage
in volume. It is this gel collapse phenomenon that has been utilised in the
development of thermoresponsive drug delivery systems.”). We note in
particular that Escobar’s drug-delivering N-substituted acrylamide hydrogel
is described as swelling at body temperature. See Escobar 3433 (Abstract;
describing study of swelling behavior of polymer at 37° C).
Thus, it might be true that Sawhney does not expressly describe
administering swellable hydrogels at a temperature above the LCST.
Sawhney, nonetheless, teaches that expandable hydrogels should be
administered in their contracted state and allowed to swell after
administration, and teaches, in addition, that the in vivo swelling may be
accomplished using hydrogels, such as N-substituted acrylamides, which
reversibly gel depending on their temperature in relation to their LCST.
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Those teachings from Sawhney, moreover, must be viewed in light of
D’Emanuele’s teaching that drug-delivering N-substituted acrylamide
particles are in their low volume contracted state above their LCST, and are
in their swollen gelled state below the LCST. Thus, viewing the combined
teachings of the references, we agree with the Examiner that an ordinary
artisan would have reasonably inferred that, when injecting drug-delivering
swellable hydrogel particles composed, for example, of the N-substituted
acrylamide hydrogel taught by Escobar, it would have been desirable to
inject the hydrogel at a temperature above the LCST in its contracted state,
to thereby allow the hydrogel to swell after administration to the patient, in
the manner desired by Sawhney.
Accordingly, because Appellant’s arguments do not persuade us, for
the reasons discussed, that the Examiner erred in concluding that the process
recited in claim 21 would have been obvious to an ordinary artisan, we
affirm the Examiner’s rejection of that claim under § 103.
OBVIOUSNESS-
CLAIMS 22-26, 33, 36, and 38
The Examiner’s Prima Facie Case
In rejecting claims 22-26, 33, 36, and 38 for obviousness, the
Examiner cites Hennink as disclosing an injectable composition composed
of a polymer-based hydrogel with an ex vivo LCST that is below normal
body temperature, and whose LCST increases to above body temperature in
vivo after injection into a subject, as required by claim 22. Final Act. 7. The
Examiner concedes, however, that Hennink’s composition differs from the
composition of the rejected claims in that Hennink does not “explicitly teach
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the preparation of hydrogel particles from these polymers or that they are
crosslinked,” as recited in independent claim 22. Id.
To address those deficiencies, the Examiner cites D’Emanuele as
disclosing drug-delivering hydrogel-based particles having the size required
by claim 22, composed of crosslinked poly(N-isopropylacrylamide). Id.
The Examiner highlights D’Emanuele’s polymers in particular because
“when crosslinked and subjected to a temperature above the LCST, the
particles shrink (see page 238 first column first full paragraph). This
temperature responsiveness makes such polymers desirable for controlled
drug delivery.” Id. at 7-8.
The Examiner cites Nagaoka as disclosing a crosslinked poly(N-
isopropylacrylamide) hydrogel that swells and expands below its LCST, but
which collapses above the LCST. Id. at 8.
The Examiner cites Hirt as disclosing temperature-sensitive drug­
delivering hydrogels that shrink and expand to allow drug delivery. Id.
Based on the references’ combined teachings, the Examiner reasons
that, based on their temperature responsiveness, an ordinary artisan would
have reasoned that Hennink’s polymers “would be useful as drug delivery
vehicles when treated in the same way. Specifically, crosslinking of such
polymers yields a shrinking or swelling due to exposure to a temperature
above or below the LCST, respectively.” Id.
Therefore, the Examiner concludes, an ordinary artisan would have
considered it obvious
to provide a hydrogel form of the polymer of Hennink et al. that
is crosslinked, so that it would be able to provide active
controlled release as its LCST migrates due to hydrolysis.
Sizing these hydrogels as taught by D’Emanuele et al. to
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dimensions known to effectively exploit this temperature
responsiveness also would have been obvious.
Id. at 9.
Analysis
In KSR, although the Supreme Court emphasized “an expansive and
flexible approach” to the obviousness question, 550 U.S. at 415, it also
reaffirmed the importance of determining “whether there was an apparent
reason to combine the known elements in the fashion claimed by the patent
at issue.” Id. at 418 (emphasis added).
Thus, “[ojbviousness requires more than a mere showing that the prior
art includes separate references covering each separate limitation in a claim
under examination.” Unigene Laboratories, Inc. v. Apotex, Inc., 655 F.3d
1352, 1360 (Fed. Cir. 2011).
Instead, “[i]n determining whether obviousness is established by
combining the teachings of the prior art, the test is what the combined
teachings of the references would have suggested to those of ordinary skill
in the art.” In re GPACInc., 57 F.3d 1573, 1581 (Fed. Cir. 1995) (internal
quotations omitted).
In the present case, Appellant persuades us that a preponderance of
the evidence does not support the Examiner’s prima facie case of
obviousness as to independent claim 22. In particular, as Appellant argues
(Appeal Br. 12-16), given the disparate nature of the teachings in the cited
references, we are not persuaded that the Examiner has explained adequately
why the cited references would have suggested modifying Hennink’s drug
delivery polymers to be crosslinked, as required by claim 22.
As the Examiner finds, Hennink describes a drug delivery
composition that includes polymers with an ex vivo LCST that is below
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normal body temperature, and whose LCST increases to above body
temperature in vivo after injection into a subject, as required by claim 22.
Hennink 6:32-35 (disclosing polymers in which “more preferably the value
of LCST crosses the normal human body temperature (which is typically
37°C) upon incubation so that the LCST before incubation is below 37°C,
preferably below 35°C, and LCST after incubation is above 37°C, preferably
above 38°C”).
Hennink explains that the change in the solubility properties of its
polymers results from “hydrolysis of a group present on at least one of the
monomers that form the polymer. Such a group is preferably chosen from
ester, amide, carbonate, carbamate, and anhydride groups. Even more
preferably such a group comprises a lactate unit. . . .” Id. 6:4-7.
In the context of an embodiment employing an AB block copolymer,
cited in the Examiner’s rejection, Hennink describes the mechanism of
action of drug delivery as follows: “In aqueous solution such polymers form
a micellar structure when the temperature rises above its LCST. These
micelles destabilize when the hydrolysis results in a[n] A block with an
increased LCST (above the temperature at which the micelles are applied,
preferably at body temperature).” Id. at 8:34-9:2.
In the context of an embodiment employing an ABA block
copolymer, cited in the Examiner’s rejection, Hennink describes the
mechanism of action of drug delivery as follows:
The ABA block copolymers formed by this route will be
soluble in water below the LCST. When the temperature is
risen above the LCST of block A, a phase separated system will
be formed, wherein as a result of the choice of block copolymer
architecture, a hydrogel will be obtained. This hydrogel will
dissolve gradually when the LCST of block A increases to
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above 37°C, due to the hydrolysis of the groups present on the
monomers of this block.
Id. at 9:13-19
As noted above, the Examiner’s rationale for modifying Hennink’s
drug-delivering polymers to be crosslinked is “so that [they] would be able
to provide active controlled release as its LCST migrates due to hydrolysis.”
Final Action 9; see also Ans. 7 (“[Cjrosslinking LCST polymers in
hydrogels is a beneficial alteration to make for drug delivery and that both
swelling and shrinking of drug delivery particles are known and viable
active mechanisms for drug delivery.”).
In that regard, we acknowledge the following disclosure in
D’Emanuele regarding drug delivery from crosslinked polymers having an
LCST:
Certain hydrogels, such as crosslinked poly(/V,/V'-alkyl
substituted acrylamides), possess a lower critical solution
temperature (LCST) when placed in solution. When the
temperature of the polymer is raised above the LCST a phase
separation occurs within the polymer accompanied by a
dramatic shrinkage in volume. It is this gel collapse
phenomenon that has been utilised in the development of
thermoresponsive drug delivery systems.
D’Emanuele 238.
We acknowledge also Nagaoka’s disclosure regarding drug delivery
of such polymers:
Pol y(/V-isopropyl acrylamide) [poly(NIP AAm)] shows a
typical thermal reversibility of phase transition in aqueous
solutions. That is, it precipitates from solution above a critical
temperature called the lower critical solution temperature
(LCST) and dissolves below this temperature. When it is cross­
linked, the obtained hydrogel collapses above LCST, while it
swells and expands below LCST. This hydrogel has . . . been
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proposed for various applications ranging from controlled drug
delivery to solute separation.
Nagaoka 7386 (emphasis added; citations omitted).
Although we thus acknowledge that it was known in the art that
crosslinked polymers having an LCST could provide controlled drug release,
Hennink’s polymers already provide a controlled release of drug, due to the
hydrolysis of the ester groups on the polymers, noted above. We are not
persuaded, therefore, that the Examiner has adequately explained why an
ordinary artisan would have used crosslinking to modify Hennink’s
polymers to have a property they already possess. Indeed, given Hennink’s
disclosure that, in one embodiment, its polymer should form a hydrogel
above the LCST (Hennink 9:14-16), in contrast to the teachings in
D’Emanuele and Nagaoka that the hydrogel formed using crosslinked
polymers collapses above the LCST (D’Emanuele 238; Nagaoka 7386), we
are not persuaded that an ordinary artisan would have been motivated to
modify Hennink’s polymers to have the properties described in D’Emanuele
and Nagaoka.
In sum, we have carefully considered the positions of both Appellant
and the Examiner. For the reasons discussed, we are not persuaded that the
Examiner has adequately explained why an ordinary artisan would have
considered it obvious to modify Hennink’s polymers to be crosslinked, as
required by independent claim 22. We, therefore, reverse the Examiner’s
rejection of that claim, and its dependent claims 23-26, 33, 36, and 38 for
obviousness over Hennink, D’Emanuele, Nagaoka, and Hirt.
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REMAINING OBVIOUSNESS REJECTIONS
Each of the remaining obviousness rejections is directed to claims that
depend directly or ultimately from independent claim 22, discussed above.
Final Act. 9-15. In each of those rejections, the Examiner relies on the base
combination of Hennink, D’Emanuele, Nagaoka, and Hirt, discussed above,
further combined with additional references cited to show the obviousness of
the additional elements recited in the dependent claims. See id. Because
none of the additional references cited by the Examiner remedies the
deficiency, discussed above, of Hennink, D’Emanuele, Nagaoka, and Hirt as
to claim 22, we reverse those rejections as well.
SUMMARY
For the reasons discussed, we affirm the Examiner’s rejection of claim
21, under 35 U.S.C. § 103(a), as being unpatentable over Escobar,
D’Emanuele, Reb, Sawhney, and Barker.
For the reasons discussed, however, we reverse the Examiner’s
rejections of:
(1) Claims 22, 23, 26-29, and 33^10, under 35 U.S.C. § 112, first
paragraph, as failing to comply with the written description requirement.
(2) Claims 22-26, 33, 36, and 38, under 35 U.S.C. § 103(a) as being
unpatentable over Hennink, D’Emanuele, Nagaoka, and Hirt;
(3) Claims 27, 35, and 39, under 35 U.S.C. § 103(a) as being
unpatentable over Hennink, D’Emanuele, Nagaoka, and Hirt, and Soga B;
(4) Claims 28, 29, and 40, under 35 U.S.C. § 103(a) as being
unpatentable over Hennink, D’Emanuele, Nagaoka, Hirt, Soga B, Sawhney,
and Reb;
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(5) Claim 37, under 35 U.S.C. § 103(a) as being unpatentable over
Hennink, D’Emanuele, Nagaoka, Hirt, Soga B, Sawhney, Reb, and Warren;
and
(6) Claim 34, under 35 U.S.C. § 103(a) as being unpatentable over
Hennink, D’Emanuele, Nagaoka, Hirt, Soga B, and Ramstack.
TIME PERIOD
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
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