Ex Parte HELLER et al

Patent Trial and Appeal Board

Nov 6, 2018

14689683 (P.T.A.B. Nov. 6, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
14/689,683 04/17/2015 Daniel A. HELLER
48329 7590 11/08/2018
FOLEY & LARDNER LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
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
ATTORNEY DOCKET NO.
2003080-0840
SK2013-082-0
CONFIRMATION NO.
3929
EXAMINER
DICKINSON,PAUL W
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
11/08/2018 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):
ipdocketing@foley.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Exparte DANIEL A. HELLER and YOSEF SHAMAY 1
Appeal2017-006528
Application 14/689,683
Technology Center 1600
Before ULRIKE W. JENKS, KRISTI L. R. SA WERT, and
DAVID COTTA, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant appeals from Examiner's
decision to reject claims directed to a polymeric nanogel with affinity to P-
selectin as obvious. We have jurisdiction under 35 U.S.C. § 6(b ).
We AFFIRM.
1 Appellant is the Applicant, Memorial Sloan Kettering Cancer Center,
which according to the brief is the real party in interest. Appeal Br. 2.
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Application 14/689,683
STATEMENT OF THE CASE
According to the Specification,
[f]ucoidans are a class of sulfated, fucose-rich polymers that can
be found, for example, in brown macroalgae. Fucoidans have
been reported to have anticoagulant, antiviral, anti-
inflammatory, and anticancer activities, as well as high affinity
to P-selectin. P-selectin is an inflammatory cell adhesion
molecule responsible for leukocyte recruitment and platelet
binding.
Spec. ,r 5. The Specification states that "P-selectin is the new target for drug
delivery in various cancers." Id. ,r 12. "Nanogels -- porous nanoscale
hydro gel networks -- are a class of nanomaterials with tunable chemical
properties that facilitate targeting and delivery to specific tissues. They are
intrinsically porous and can be loaded with small drugs or macromolecules
by physical entrapment, covalent conjugation or controlled self-assembly."
Id. ,I 4.
Claims 1-5, 7-15, and 30-32 are on appeal, and can be found in the
Claims Appendix of the Appeal Brief. Claim 1 is representative of the
claims on appeal, and reads as follows:
1. A polymeric nanogel with affinity to P-selectin, the nanogel
compnsmg:
(i) a sulfated polymer species comprising free hydroxyl
moieties and sulfate moieties capable of targeting P-selectin;
(ii) a drug; and
(iii) polyethylene glycol (PEG), wherein the drug is
conjugated to the polyethylene glycol via hydrozone linkages.
Appeal Br. 19 (Claims Appendix).
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Appellant requests review of the following grounds of rejection made
by Examiner:
I. Claims 1-5, 7-13, and 30-32 under 35 U.S.C. § I03(a) as
unpatentable over Sezer2 in view of Ruan. 3
II. Claims 1-5, 7-13, 15, and 30-32 under 35 U.S.C. § I03(a) as
unpatentable over Sezer in view of Ruan in further view Chung. 4
III. Claims 1-5, 7-14, and 30-32 under 35 U.S.C. § I03(a) as
unpatentable over Sezer in view of Ruan in further view Zhang. 5
Obviousness over Sezer and Huan
Examiner's position is that Sezer and Ruan in combination disclose
nanogel particles comprising fucoidan and a drug. Ans. 2. "The particles
[of Sezer] are made of chitosan-fucoidan (a hydrogel)." Id. Sezer further
discloses that fucoidan can be found on the surface of the particle. Id.
Examiner acknowledges that Sezer fails to teach a drug that is conjugated to
PEG (e.g., "a DOX-PEG-DOX construct"). Id. Examiner looks to Ruan for
teaching this drug. Id.
2 Ali Demir Sezer, WO 2006/091180 A2, published Aug. 31, 2006
("Sezer").
3 Menglei Ruan et al., In Vitro and In Vivo Antitumor Activity of a Novel pH
Activated Polymeric Drug Delivery System for Doxorubicin, 7 PLOS ONE 1-
11 (2012) ("Ruan").
4 Leland W.K. Chung et al., US 2011/0085974 Al, published Apr. 14, 2011
("Chung").
5 Zhongyuan Zhang et al., Fucoidan Extract Enhances the Anti-Cancer
Activity of Chemotherapeutic Agents in MDA-MB-231 and MCF-7 Breast
Cancer Cells, 11 MAR. DRUGS 81-98 (2013) ("Zhang").
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Examiner concludes that it would have been obvious to one of
ordinary skill in the art at the time of the invention to substitute one active
agent for another. Specifically, it would have been obvious to incorporate
DOX-PEG-DOX into the particles of Sezer because the DOX-PEG-DOX
compound was demonstrated to have higher cytotoxicity against cancer than
doxorubicin alone. Ans. 3. The Examiner states: "The rationale for this is
that Sezer teaches methods of treatment of diseases using its formulation.
By incorporating DOX-PEG-DOX into the formulation of Sezer, the
formulation of Sezer may be used to treat cancer." Final Act. 3. 6
The issue is: Does the evidence of record support Examiner's
conclusion that the combination of Sezer and Ruan teach a nano gel
comprising a sulfated polymer, a drug, and PEG as claimed?
Findings of Fact
FF 1. Sezer teaches using fucoidan multiparticulate systems as a drug
carrier. Sezer 3 :7. "[F]ucoidan, a polysaccharide; which is obtained
from algae and due to the sulfates in its structure shows an anionic
character." Id. at 3: 15-1 7. To form the multi particulate structure,
fucoidan is mixed with chitosan, another polysaccharide with cationic
properties. Id. at 3: 17-19. "The mixture ratio of chitosan and
fucoidan solutions is 0.5: 2.0." Sezer 4:5. Fucoidan microspheres
range in size from 300-500 nm. Id. at 5:31.
FF2. Sezer teaches incorporating ofloxacin, a flouroquinolone group
antibiotic, into one of the multi-particulate structures. Id. at 5:5.
6 Final Office Action mailed May 17, 2016 ("Final Act.").
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FF3. Examiner finds that ofloxacin is a cationic drug (i.e. having positive
charge). Ans. 2.
FF4. Ruan teaches "[a] pH stimuli-sensitive conjugate based on
polyethylene glycol (PEG) with covalently attachment doxorubicin
[DOX] via hydrazone bond (PEG-hyd-DOX)." Ruan, Abstract. The
PEG-hyd-DOX conjugate can target tumor tissues, inhibit tumor
growth, as well as prolong the life of tumor-bearing mice when
compared to using free DOX. Id. at 2.
Principle of Law
"If the claim extends to what is obvious, it is invalid under§ 103."
KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,419 (2007). "[W]hen a patent
claims a structure already known in the prior art that is altered by the mere
substitution of one element for another known in the field, the combination
must do more than yield a predictable result." Id. at 416, citing United
States v. Adams, 383 U.S. 39, 50-51 (1966).
Analysis
Appellant contends that Sezer's nanoparticles are structurally different
than the nanogels presently claimed. Appeal Br. 8. Specifically, Appellant
contends that the hydroxyl moieties of the nanoparticles of Sezer are "not
free." Id. at 9; see Reply Br. 5. Appellant also contends that the sulfate
moieties are bound and thereby not free. Appeal Br. 9; see Reply Br. 6.
Thus, Appellant contends that Sezer's nanoparticles do not have free
hydroxyl or sulfate moieties. Appeal Br. 8 ("[ A ]mphiphilic nanoparticles
( e.g., having both hydrophobic and hydrophilic properties) do not have free
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hydroxyl groups, and thus are not able to target cancer"). Specifically,
Appellant contends that Sezer's chitosan-fucoidan hydroxyl or sulfate
moieties are not free because the oppositely charged molecules are bound in
the formation of the multiparticulate. See id. at 9 ("[T]he sulfate moieties of
the nanoparticles of Sezer are bound (i.e. not free) to the positively charged
moieties of the chitosan to form chitosan-fucoidan multiparticulates").
First, we observe that Appellant's argument-that the interaction
between fucoidan and chitosan in forming multiparticulate structures results
in an amphiphilic product having no charge - is a conclusory argument
without supporting evidence, and is thereby unpersuasive. "Attorney's
argument in a brief cannot take the place of evidence." In re Pearson, 494
F.2d 1399, 1405 (CCPA 1974). Second, we find that the Examiner made a
prima facie case that the overall charge of the nanoparticle structure of Sezer
is not neutral based on the evidence of record and sound reasoning, which
Appellant failed to rebut. As the Examiner explained, "the presence of
anionic and cationic groups does not mean that hydroxyl groups of fucoidan
are not free." Ans. 5. We agree with Examiner that the evidence of record
establishes that the overall charge of the nanoparticle structure of Sezer is
not neutral. Sezer teaches that the nanoparticles contain a "mixture ratio of
chitosan and fucoidan solutions is 0.5:2.0." FPL The nanoparticles of Sezer
therefore contain more fucoidan than chitosan. FF 1. This supports
Examiner's position that fucoidan is present in an amount sufficient to
maintain the negative charge of the structure, including the presence of
negatively charged hydroxyl groups.
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Next, Appellant contends that Sezer does not demonstrate the efficacy
of the fucoidan-chitosan particles nor is there evidence that the particles in
combination with a drug demonstrated efficacy. See Appeal Br. 10.
We are not persuaded by the Appellant's efficacy argument. There is
no requirement in the claim that the product is efficacious, all that is
required is that it be "capable" of fulfilling the function. Claiming the
product to have particular functionality shifts the burden to Appellant to
show that the prior-art product could not satisfy that functionality. "A patent
applicant is free to recite features of an apparatus [ or product] either
structurally or functionally. See In re Swinehart, 439 F.2d 210, 210 (CCPA
1971) ("There is nothing intrinsically wrong with [ defining something by
what it does rather than what it is] in drafting patent claims."). Yet choosing
to define an element functionally, i.e., by what it does, carries with it a risk.
As our predecessor court stated in Swinehart:
where the Patent Office has reason to believe that a functional
limitation asserted to be critical for establishing novelty in the
claimed subject matter may, in fact, be an inherent
characteristic of the prior art, it possesses the authority to
require the applicant to prove that the subject matter shown to
be in the prior art does not possess the characteristic relied on.
439 F.2d at 213; see also, In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir.
1997).
Here, Examiner explained that even though fucoidan-chitosan have
opposite charges and therefore would be attracted to each other to form the
particular nano structure, the evidence and Examiner's reasoning on this
record suggests that not all available negative charges are occupied. See
Ans. 5---6. Specifically, Examiner explains:
Although Sezer teaches incorporating two polymers of which
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one is anionic and the other is cationic ( claim 1 ), the presence of
anionic and cationic groups does not mean that hydroxyl groups
[ or sulfate moieties] of fucoidan are not free. There is no
teaching in Sezer that the hydroxyl groups of fucoidan are not
free. In the embodiment where fucoidan is paired with chitosan,
although a fraction of the hydroxyl groups [ as well as sulfate
moieties] on fucoidan interact with the positively charged groups
on chitosan, the hydroxyl groups are still free because the
interaction with chitosan is ionic, which is a weak interaction that
still leaves the hydroxyl groups available for further chemical
interaction. As the hydroxyl groups are available for further
chemical interaction, they are free.
Ans. 5---6. The same reasoning also applies to the sulfate groups. Examiner
has provided a sound explanation, that Appellant did not rebut, as to why the
fucoidan component of Sezer's particulate mixture would contain free
hydroxyls as well as free sulfate groups and therefore there is sufficient
reason to believe that the amount of free hydroxyls group is sufficient to
bind P-selectin. Compare In re Spada, 911 F.2d 705 (Fed. Cir. 1990), with
In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
Appellant contends that their composition shows unexpected results.
See Appeal Br. 10-12, see id. at 13-14; Reply Br. 12-13.
We agree with Examiner that Appellant's unexpected results
argument with respect to the fucoidan-chitosan particles of Sezer is not
persuasive. "The results [ relied on by Appellant] show that fucoidan-DOX
... show higher efficacy against B 16F 10 melanoma cells compared to the
equivalent dosage of fucoidan, DOX, and DOX-PEG-DOX." Ans. 7. As
explained by Examiner, "Sezer teaches that fucoidan particles provide
sustained release of drugs encapsulated therein." Ans. 8.
The results with which the actual difference was seen have been
related with the controlled release of ofloxacin from the system.
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The release time was extended up to 6 days for fucoidan
microspheres prepared at two different rpm rates, and while the
effect of high amount drug release within the first hours called
burst effect was decreased to 20%, this effect was decreased to
42% at most for the crosslinked chitosans, however it was seen
that whole drug, was released within the first 8 hours in the non-
crosslinked chitosan formulations. In addition, while it was seen
that drug release for fucoidan microspheres complied with the 0
degree kinetic after the first 8 hours, for chitosan micro particles,
such a release kinetic was not seen, on the contrary, for the
crosslinked chitosan microspheres, a triphasic release profile was
seen.
Sezer 5: 17-27. As Examiner explains, the evidence provided in the
Specification shows that, individually, DOX, fucoidan, and DOX-PEG-DOX
are not as effective as the combination of fucoidan nanogel and DOX-PEG-
DOX. Examiner finds that this is not unexpected because the combination
of the fucoidan nano gel with the drug allows greater loading of the particle
that is then released over time. "One would expect mice administered
fucoidan-DOX to have a longer survival rate compared to mice administered
DOX-PEG-DOX alone because fucoidan provides the feature of release of
DOX over time, and DOX-PEG-DOX alone does not have this feature."
Ans. 8. In other words, Examiner's position is that increased survival is an
expected result of the sustained release formulation. See Ans. 8. We agree
with Examiner's position that formulating a drug into a sustained release
composition would result in the expected effect of providing the drug to the
target over time. Accordingly, we agree with Examiner that the results
provided in the Specification are expected results and thereby not sufficient
to overcome the prima facie case of obviousness.
Appellant contends that Examiner's rejections are based on hindsight.
See Appeal Br. 6; see Reply Br. 6.
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We are not persuaded. Appellant has not directed us to what
knowledge could only have been gleaned from the Specification and that
was not available in the art relied on by Examiner in formulating the
rejection.
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level of
ordinary skill at the time the claimed invention was made and
does not include knowledge gleaned only from applicant's
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971).
In summary, we find the preponderance of evidence of record
sufficient to support Examiner's conclusion that the composition as
suggested by the combination of Sezer and Ruan would be capable of
targeting P-selectin. Appellant's secondary considerations of unexpected
results were considered by Examiner but found to be unpersuasive. We have
reviewed the same evidence and agree with Examiner that the evidence is
insufficient to support of finding of unexpected results.
Accordingly, we affirm the obviousness rejection of claim 1.
Appellant does not separately argue dependent claims 2-5, 7-13, and 30-32.
Therefore, these claims fall with claim 1. 37 C.F.R. § 4I.37(c)(l)(iv).
Obviousness over Sezer, Huan, and Chung
Claim 15 is dependent on claim 1 and further recites a fluorophore
infra-red dye IR783. See Appeal Br. 21 (Claims Appendix). Appellant
contends that Chung "fails to cure any deficiency of Sezer, alone or in
combination." Appeal Br. 13.
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Having found no error in the combination of Sezer and Ruan, we are
not persuaded by Appellant's intimation that Chung fails to make up for an
alleged deficiency in the combination of Sezer and Ruan. Accordingly, we
affirm the rejection for the reasons set out by Examiner in the Final Office
Action and Answer.
Obviousness over Sezer, Huan, and Zhang
Claim 14 is dependent on claim 1 and further recites a fluorophore.
See Appeal Br. 21 (Claims Appendix). Appellant contends that in Zhang
"the drugs are not conjugated to the [ fucoidan extract] FE ..... Appellant
submits that co-administering two free compositions will not result in the
formation of a nanogel." Appeal Br. 14.
Zhang teaches "that fucoidan inhibits angiogenesis of melanoma" and
other tumors. Zhang 82. "Since fucoidan has anti-tumor properties both in
vitro and in vivo, a combination of fucoidan with chemotherapeutic drugs
might be an intriguing option in the therapy of cancer patients." Id.
Fucoidan extract from seaweed (Cladosiphon navae-caledoniae) consists of
"mostly fucose (73%), xylose (12%) and mannose (7%). The ratio of
sulfation was 14.5%." Id. at 92. Zhang discloses using a fluorescent
component to monitor "generation of intracellular ROS, ... [by measuring]
cellular fluorescence intensity" over time. Id. at 94.
We are not persuaded by Appellant's contention that Zhang fails to
teach a nanogel, because Examiner is not relying on Zhang for teaching
fucoidan based nano gels. Examiner relies on the teachings of Sezer for
disclosing nanogels/nanoparticles and teaching the incorporation of drugs
for achieving extended release profile. See Ans. 7. Finding no error with
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the Examiner's combination, we affirm the rejection for the reasons set out
by Examiner in the Final Office Action and Answer.
SUMMARY
We affirm the rejection of claims 1-5, 7-13, and 30-32 under
35 U.S.C. § 103(a) over Sezer and Ruan.
We affirm the rejection of claims 1-5, 7-13, 15, and 30-32 under
35 U.S.C. § 103(a) over Sezer, Ruan, and Chung.
We affirm the rejection of claims 1-5, 7-14, and 30-32 under
35 U.S.C. § 103(a) over Sezer, Ruan, and Zhang.
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
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