Chih-Peng Liu et al.

Patent Trials and Appeals Board

Nov 26, 2019

15142170 - (D) (P.T.A.B. Nov. 26, 2019)

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.
15/142,170 04/29/2016 Chih-Peng LIU 2668-0131PUS1 1032
2292 7590 11/26/2019
BIRCH STEWART KOLASCH & BIRCH, LLP
8110 Gatehouse Road
Suite 100 East
Falls Church, VA 22042-1248
EXAMINER
KATAKAM, SUDHAKAR
ART UNIT PAPER NUMBER
1658
NOTIFICATION DATE DELIVERY MODE
11/26/2019 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
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PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte CHIH-PENG LIU, YA-CHIN LO, MING-CHENG WEI,
MAGGIE LU, SHUEN-HSIANG CHOU, SHIH-TA CHEN, and
HSIANG-WEN TSENG1
Appeal 2018-002755
Application 15/142,170
Technology Center 1600
Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and RYAN H. FLAX,
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
method of treating cancer, which have been rejected as obvious. We have
jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM-IN-PART, but designate the affirmance a new ground of
rejection.

1 Appellant identifies the real party in interest as INDUSTRIAL
TECHNOLOGY RESEARCH INSTITUTE. Appeal Br. 1. We use the word
Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a).
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STATEMENT OF THE CASE
“Hyaluronic acid (HA) is a natural polysaccharide . . . that is
distributed into the lymphatic system and is a ligand for the CD44 receptor,
which is overexpressed in lymphatic tumors.” Spec. ¶ 6. The Specification
discloses “a method of treating lymphatic cancer using hyaluronan
nanoparticles. The hyaluronan nanoparticles may comprise a hyaluronic acid
derivative and a platinum compound. The hyaluronic acid derivative itself
may comprise: a hyaluronic acid; a modified histidine [and] optionally a
polymer or C4-C20 alkyl.” Id. ¶ 7.
Claims 1–25 are on appeal. Claim 1, reproduced below, is illustrative:
1. A method of treating a tumor in a lymphatic system of
a subject, comprising:
administering a hyaluronan nanoparticle comprising a
hyaluronic acid derivative and a platinum compound to the
subject with tumors in the lymphatic system, wherein the
hyaluronic acid derivative comprises:
hyaluronic acid,
modified histidine, and
optionally at least one of a polymer or a C4–C20 alkyl,
wherein the modified histidine and the optional at least
one of polymer or C4–C20 alkyl are grafted at least to primary
hydroxyl groups of the hyaluronic acid, and
wherein a graft ratio of the modified histidine is within
20–100%, and a graft ratio of the optional at least one of
polymer or C4–C20 alkyl is within 0–40% based upon the total
number of hydroxyl groups on the hyaluronic acid.
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OPINION
Obviousness
Claims 1–25 stand rejected under 35 U.S.C. § 103 as obvious based
on Forrest,2 Wu,3 Shih,4 and either Pitarresi5 or Lo.6 Ans. 4. The Examiner
finds that “Forrest et al teach methods of administering the
chemotherapeutic agents using HA based nano-carriers to target tumors in
the lymphatic system.” Id. at 7. The Examiner also finds that
Wu et al or Shih et al teach histidine-hyaluronic acid conjugate
nanoparticles as carriers, Pitarresi et al teach synthesis of
novel graft copolymers of hyaluronan, polyethyleneglycol and
polylactic acid, and Lo et al teach hyaluronic acid grafted with
a modified histidine and a polymer or C4–C20 alkane. This
suggests technology of grafting side chains on HA, can be
charged or neutral, is well known in the art.
Id.
The Examiner concludes that the claimed method would have been
obvious to those skilled in the art because “one is motivated to use known
structurally similar HA based nano-carriers in targeting lymphatic system in
a subject.” Id.
We agree with the Examiner’s conclusion but, in our view, the
rejection is not based on the most pertinent disclosures in the cited

2 Forrest et al., US 2012/0100218 A1, published Apr. 26, 2012.
3 Wu et al., et al., Preparation and characterization of nanoparticles based on
histidine-hyaluronic acid conjugates as doxorubicin carriers, Journal of
Materials Science: Materials in Medicine, 23(8):1921–29 (2012).
4 Shih et al., US 2014/0186415 A1, published July 3, 2014.
5 Pitarresi et al., Synthesis of novel graft copolymers of hyaluronan,
polyethyleneglycol and polylactic acid, MMAIJ, 3(2):53–56 (2007).
6 Lo et al., US 2015/0118322 A1, published Apr. 30, 2015.
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references. Specifically, Lo discloses a composition that meets all of the
structural limitations of claim 1, and therefore constitutes the closest prior
art for purposes of analyzing obviousness.
Lo discloses
a biomedical composition, comprising: a hyaluronic acid; a
modified histidine; and a polymer or C4–C20 alkane, wherein
the modified histidine and the polymer or C4–C20 alkane are
grafted to at least one primary hydroxyl group of the hyaluronic
acid to allow the hyaluronic acid to form a hyaluronic acid
derivative, wherein a graft ratio of the modified histidine is
about 1–100%, and a graft ratio of the polymer or C4–C20
alkane is about 0–40%.
Lo ¶ 8. Thus, Lo discloses a hyaluronic acid derivative comprising
hyaluronic acid (HA), modified histidine (His), a polymer or C4–C20 alkyl
group, with the modified His and polymer/alkyl group grafted to at least one
primary hydroxyl group of HA, with graft ratios that are the same as or
encompass those recited in claim 1.
Lo discloses that “the biomedical composition . . . may further
comprise an active ingredient with a positive charge in water.” Id. ¶ 43. “The
. . . active ingredient with a positive charge in water may comprise a drug
(such as antibiotics, platinum-based antineoplastic drugs).” Id. ¶ 45. Thus,
Lo expressly suggests including a platinum compound in its composition.
Lo states that
the active ingredient with a positive charge in water and a
carboxyl group of the hyaluronic acid derivative repulse each
other due to different charge, and furthermore, by a
hydrophobic effect produced from the modified histidine
grafted on the hyaluronic acid and used to modify the
hyaluronic acid, the active ingredient can be agglomerated, and
make the active ingredient with a positive charge in water
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mentioned above be packaged in the preceding hyaluronic acid
derivative.
Id. ¶ 43. Thus, Lo states that the HA derivative and platinum compound
agglomerate, and therefore Lo’s composition reasonably appears to meet the
limitation of a “hyaluronan nanoparticle,” as recited in claim 1.
Based on the above disclosures, Lo would have made obvious a
composition meeting all of the structural limitations recited in claim 1. In
view of Lo’s suggestion to include “platinum-based antineoplastic drugs”
(id. ¶ 45, emphasis added), such as cisplatin (id. ¶ 47), a skilled artisan
would have considered it obvious to administer the composition to a patient
having a tumor, because antineoplastic drugs such as cisplatin are used to
treat cancer.
Lo teaches that its composition can be administered in several ways,
including parenterally; e.g., subcutaneously or intracutaneously. Id. ¶ 53. Lo
also teaches that its composition addresses the need in the art for a “drug
delivery system that has high bio-compatibility, and that can be designed to
release a drug only in an appropriate environment.” Id. ¶ 7. More
specifically, “as compared with a level of pH 7.4, hyaluronic acid
derivative/doxorubicin complex nano-carriers . . . have higher cumulative
drug release rates at pH 5.0 (greater than 2.5 fold).” Id. ¶ 133.
Lo thus makes obvious all of the limitations of claim 1 except that it
does not suggest treating a subject with a tumor specifically in the lymphatic
system. Forrest, however, discloses a composition comprising “a
nanoconjugate comprising: a nanocarrier configured for preferential
intralymphatic accumulation after percutaneous or interstitial administration;
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and a plurality of chemotherapeutic agents coupled to the nanocarrier.”
Forrest ¶ 11.
Forrest discloses that its composition “includes a nanocarrier that is
optimized in size and composition to preferentially be translocated into the
lymphatic system rather than spread and concentrate systemically. It has
been found that hyaluronan polymeric carriers and some dendritic carriers,
such as those described herein, have such a[] selective translocation
characteristic into the lymphatic system.” Id. ¶ 55.
“The chemotherapeutic agents are preferably selected from the group
consisting of cisplatin, doxorubicin, and docetaxel.” Id. ¶ 12. “Cisplatin is
one of the most widely used chemotherapy agents for solid tumors; however,
its toxicity and resistance severely limits its dose and use in many patients.”
Id. ¶ 56. Forrest states that its “invention can include a nanoconjugate of the
polysaccharide hyaluronan (‘HA’) with a chemotherapeutic drug (e.g.,
cisplatin or other platinum).” Id. ¶ 60. “The HA nanoconjugate is formulated
with a molecular weight/size of HA that is effective in concentrating
cisplatin to the breast lymphatics, and reduce peak plasma concentrations
that are toxic.” Id.
Based on Forrest’s disclosure, it would have been obvious to a person
of ordinary skill in the art to administer Lo’s composition to a patient having
a tumor in their lymphatic system, because Lo’s composition comprises
nanoconjugates of a platinum-based antineoplastic compound (e.g.,
cisplatin) and a hyaluronic acid derivative, and Forrest teaches that
nanoconjugates of hyaluronic acid with a chemotherapeutic drug (e.g.,
cisplatin) are preferentially translocated to the lymphatic system.
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Forrest teaches that the cisplatin is concentrated to the breast
lymphatics by the HA conjugate, thus reducing toxicity. A skilled artisan
therefore would have expected that administering Lo’s composition to a
patient with a tumor in the lymphatic system would result in reduced
cisplatin toxicity.
The teachings of Wu, Shih, and Pitarresi are not necessary for a prima
facie case of obviousness with respect to claim 1.
Appellant argues that “one of ordinary skill in the art would not have
a reasonable expectation of success in intralymphatic delivery of a platinum
compound to treat a tumor in a lymphatic system of a subject based on such
a combination.” Appeal Br. 6. Appellant argues that Forrest’s disclosure
shows that “that knowledge of intralymphatic delivery of hyaluronic acid by
subcutaneous administration as of the filing of Forrest is limited to the
experiments conducted in Forrest.” Id. at 7. Appellant also argues that the
“relationship between chemical structures and pharmacology has long been
known to be an unpredictable art.” Id. at 8.
These arguments are unpersuasive. Forrest discloses that its
nanoconjugates of HA and a chemotherapeutic drug accumulate in
cancerous cells in the lymphatic system. Forrest ¶¶ 59–60. Forrest discloses
that the molecular weight of the HA affects the lymphatic drug
concentration, and states that the optimal molecular weight is between 10 kD
and 200 kD. Id. ¶¶ 67–68. Forrest also discloses that the size of the
nanoconjugates affects their translocation to the lymphatic system, and states
that sizes between about 10 nm and 80 nm are appropriate. Id. ¶ 70. Thus,
Forrest provides a reasonable amount of guidance regarding which
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parameters are important for intralymphatic delivery, and what values of
those parameters are suitable. Appellant has not pointed to persuasive
evidence showing that undue experimentation would have been required to
modify Lo’s composition in such a way as to achieve the lymphatic
accumulation disclosed by Forrest.
Appellant argues that Wu, Shih, and Pitarresi do not cure the alleged
deficiencies of Forrest. Appeal Br. 10–11. Similarly, Appellant argues that
Wu, Shih, Lo, and Pitarresi disclose different structural modifications of
hyaluronic acid, and therefore conflict with each other. Id. at 11.
These arguments are unpersuasive because, as discussed above, Lo
and Forrest support a prima facie case of obviousness. Wu, Shih, and
Pitarresi are cumulative and unnecessary to the prima facie case.
With regard to Lo, Appellant argues
Lo discloses a modified hyaluronic acid for controlled drug
release. This function in Lo has no disclosed effect in the prior
art on intralymphatic delivery. . . . There is no motivation for
one of ordinary skill in the art to use the hyaluronic acid
modifications in Lo to the hyaluronan nanoparticle in Forrest,
because there is no reasonable expectation of success that
intralymphatic delivery can occur with the modifications in Lo.
Id.
This argument is also unpersuasive. Even though Lo does not disclose
that its compounds accumulate in the lymphatic system, it discloses that the
hyaluronic acid derivative and active agent in its composition agglomerate.
Lo ¶ 43. Thus, a skilled artisan would recognize that they are structurally
similar to Forrest’s “nanoconjugate[s] of the polysaccharide hyaluronan
(‘HA’) with a chemotherapeutic drug (e.g., cisplatin or other platinum).”
Forrest ¶ 60. And, as previously discussed, Appellant has not shown that any
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modifications of Lo’s agglomerates necessary for intralymphatic delivery
would have required undue experimentation.
Appellant lists each of the dependent claims under its own
subheading. Appeal Br. 11–17. However, with regard to claims 2–5, 12–15,
17, and 19, Appellant’s only argument is that “there is no motivation to
combine the primary reference of Forrest with the secondary references as
presented under claim 1.” Id. at 11. That argument is unpersuasive for the
reasons discussed above.
Appellant separately argues claims 6–11. Appeal Br. 12–14.
Appellant acknowledges that Lo discloses the Boc-histidine and graft ratio
recited in dependent claims 6 and 7, as well as the polyethylene glycol and
graft ratio recited in dependent claims 8 and 9, and the combined Boc-
histidine and polyethylene glycol modifications recited in dependent claims
10 and 11. Id. Appellant argues, however, that “Wu teaches different
modifications of hyaluronic acid by histidine than Lo, and Pitarresi teaches
different modifications of hyaluronic acid by polyethylene glycol than Lo.”
Id. at 14.
Similarly, Appellant acknowledges that “Lo discloses polyethylene
glycol and DACHPt,” as recited in claim 16, and “Lo discloses linking
groups for a polymer (Formula (IV)),” as recited in claim 18. Id. at 15.
Appellant argues, however, that “Pitarresi discloses a different substitution
of hyaluronic acid polymer than Lo.” Id.
The arguments presented with respect to claims 6–11, 16, and 18 are
unpersuasive because the disclosures of Wu and Pitarresi are not required to
show that these claims would have been obvious to a skilled artisan—as
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Appellant concedes, Lo by itself discloses the limitations added to claim 1
by each of claims 6–11, 16, and 18. The additional limitations therefore
would have been obvious to a skilled artisan based on Lo and Forrest.
Claims 20–23 add limitations regarding the route of administration:
claims 20–22 recite parenteral, including subcutaneous, administration; and
claim 23 is limited to intravenous injection. With respect to claims 20–22,
Appellant argues that the types of administration, including “subcutaneous
administration[,] in Lo is not applied to intralymphatic delivery. There is no
reasonable expectation of success in applying the subcutaneous
administration in Forrest to a hyaluronan nanoparticle modified according to
the secondary references.” Appeal Br. 16.
This argument is not persuasive. Lo discloses that its composition can
be administered parenterally, including subcutaneous or intracutaneous
administration. Lo ¶ 53. Forrest states that its “nanoconjugates can be
subcutaneously administered for accumulation in intralymphatic tissue.”
Forrest ¶ 59. Forrest’s nanoconjugates, like those of Lo, “include a
nanoconjugate of the polysaccharide hyaluronan (‘HA’) with a
chemotherapeutic drug (e.g., cisplatin or other platinum.” Id. ¶ 60. Although
Lo’s nanoconjugates also include a modified histidine and a polymer grafted
to the HA moiety, Appellant has not provided evidence or sound technical
reasoning to show that those differences would have led a skilled artisan to
expect Lo’s HA/cisplatin nanoconjugates to behave differently from
Forrest’s HA/cisplatin nanoconjugates.
With regard to claim 23, Appellant argues that “Lo discloses
intravenous administration ([0053]). However, the intravenous
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administration in Lo is not applied to intralymphatic delivery.” Appeal Br.
17.
We agree with Appellant that the cited references would not have
provided a reasonable expectation of success in administering the
nanoconjugates disclosed by Lo intravenously to treat a patient having a
tumor in the lymphatic system. Lo discloses that its nanoconjugates can be
administered intravenously. Lo ¶ 53. However, Lo does not expressly
suggest treating tumors in the lymphatic system. Forrest does teach
administering its compounds to treat lymphatic system tumors. Forrest ¶ 53.
However, Forrest expressly states that its composition “is not systemically
administered. That is, the formulation is not administered via intravenous
administration.” Id. Thus, the combined teachings of Lo and Forrest would
not have provided a skilled artisan with a reasonable expectation of success
in treating a lymphatic system tumor by administering Lo’s composition
intravenously. The Examiner has not pointed to any disclosure in Wu, Shih,
or Pitarresi that makes up for this deficiency in Lo and Forrest. We therefore
reverse the rejection of claim 23.
With regard to claims 24 and 25, Appellant argues that “Forrest
discloses metastatic tumors. However, there is no motivation or reasonable
expectation of success in using the hyaluronan nanoparticle of Forrest
modified by the secondary references.” Appeal Br. 17.
This argument is unpersuasive. Forrest states that “[t]he subcutaneous
administration of a nanoconjugate that can accumulate in intralymphatic
tissues is beneficial for treating many cancers, such as breast cancers,” as
recited in claim 25. See Forrest ¶ 59. Forrest also states that its
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“nanoconjugates . . . accumulate in the cancerous cells that are present in the
lymphatic system and/or intralymphatic tissues and thereby act on lymphatic
metastases without undesirable systemic toxicities.” Id. (emphasis added).
Appellant has not provided evidence or sound technical reasoning to show
that a skilled artisan would not have expected Lo’s similar nanoconjugates to
also accumulate in the lymphatic system, and thus also be effective in
treating metastatic tumors, including breast cancer.
CONCLUSION
We affirm the rejection of claims 1–22, 24, and 25 under 35 U.S.C.
§ 103 based on Forrest, Wu, Shih, and either Pitarresi or Lo. Because our
fact-finding and reasoning differ substantially from that of the Examiner,
however, we designate the affirmance a new ground of rejection in order to
give Appellant a fair opportunity to respond. See In re Kronig, 539 F.2d
1300, 1302–03 (CCPA 1976).
We reverse the rejection of claim 23 under 35 U.S.C. § 103 based on
Forrest, Wu, Shih, and either Pitarresi or Lo.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/
Basis
Affirmed Reversed New
Ground
1–25 103 Forrest, Wu,
Shih,
Pitarresi, Lo
1–22, 24,
25
23 1–22,
24, 25

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TIME PERIOD FOR RESPONSE
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review.”
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating to
the claims so rejected, or both, and have the matter reconsidered
by the examiner, in which event the prosecution will be
remanded to the examiner. The new ground of rejection is
binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the opinion
of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the claims,
appellant may again appeal to the Board pursuant to this subpart.
(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.

Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure § 1214.01.
AFFIRMED IN PART; 37 C.F.R. § 41.50(b)