Ex Parte Gu et al

Patent Trial and Appeal Board

Feb 15, 2019

13995063 (P.T.A.B. Feb. 15, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/995,063 01/27/2014
21968 7590 02/15/2019
NEKT AR THERAPEUTICS
455 Mission Bay Blvd., South, Suite 100
San Francisco, CA 94158
FIRST NAMED INVENTOR
XuyuanGu
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. CONFIRMATION NO.
SHE0347.00 2577
EXAMINER
KOSACK, JOSEPH R
ART UNIT PAPER NUMBER
1626
MAIL DATE DELIVERY MODE
02/15/2019 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte XUYUAN GU, JENNIFER RIGGS-SAUTHIER,
MICHAEL D. BENTLEY, and TACEY X. VIEGAS 1
Appeal 2018-001585
Application 13/995,063
Technology Center 1600
Before RICHARD M. LEBOVITZ, GEORGIANNA W. BRADEN, and
ELIZABETH A. LA VIER, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves claims directed to a water-soluble polymer
conjugate oftopotecan. The Examiner rejected the claims as obvious under
35 U.S.C. § 103. Pursuant to 35 U.S.C. § 134, Appellants appeal the
Examiner's determination that the claims are unpatentable. We have
jurisdiction under 35 U.S.C. § 6(b ). The Examiner's decision is affirmed.
1 The Appeal Brief ("Br."; entered Aug. 16, 2017) lists Nektar Therapeutics
as the real party in interest. Br. 1.
Appeal 2018-001585
Application 13/995,063
STATEMENT OF THE CASE
Claims 14, 15, and 39 stand finally rejected by the Examiner under
pre-AIA 35 U.S.C. § 103(a) as obvious in view of Greenwald et al. (U.S.
Pat. No. 6,011,042, issued Jan. 4, 2000) ("Greenwald") and Zhao et al. (WO
2005/028539 A2, published Mar. 31, 2005) ("Zhao"). Ans. 3; Final Act. 5.
Claim 14, the only independent claim on appeal, is reproduced below:
14. A water-soluble polymer conjugate oftopotecan having the
structure:
\/
N
HO
o"(
NH
HO
and pharmaceutically acceptable salts thereof, wherein the
value of n ranges from about 10 to 1500.
REJECTION
The topotecan conjugate of claim 14 is reproduced below with
annotations added herein:
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Application 13/995,063
\/
N
(' tc,;:,otc:,:, :c
co~~"'-/
:::- t) ,c~ -
0 ~~.
0
~n J~1::10 .::"~:::~t~i:;:,;·;• 4cn1~ . N w.,;~ \,
·:;,;~·-·· ·"'' e;-{
HO - 0
' ,.,:,,.-~,tc~<•,
,1
I '-.
The claimed topotecan conjugate, reproduced above, shows two
topotecan molecules linked together at the 20-hydroxyl group of the E-ring
via an amino acid and a polyethylene glycol polymer.
The Examiner found that Example 3 of Greenwald shows a 10-
poly( ethylene glycol) ester oftopotecan. Final Act. 5. The structure (with
annotations added) is reproduced below:
Example 3 of Greenwald, shown above, shows a polyethylene glycol
polymer covalently bonded to two topotecan via the hydroxyl group of the
A-ring of each molecule (Greenwald cols. 15-16).
The Examiner found that Greenwald differs from the topotecan
conjugate of claim 14 in the following ways: 1) not having the polyethylene
glycol linked to the topotecan molecules via an amino acid and 2) in the
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Appeal 2018-001585
Application 13/995,063
topotecan being linked to the A-ring and not position 20 of the E-ring as in
the claimed topotecan conjugate. Final Act. 5.
To meet the deficiencies of Greenwald, the Examiner further cited
Zhao. The Examiner found that Zhao describes attaching irinotecan, an
analog of topotecan, to a multi-armed polyethylene glycol dendrimer. Final
Act. 5. The Examiner found that Zhao teaches that linkage to the
polyethylene glycol dendrimer can be through a glycine, or other amino acid
residue, via the 20-hydroxyl group of the E-group of the camptothecin class
of compounds, of which topotecan is a member. Id. This is the same
linkage in the topotecan conjugate of rejected claim 14.
The reaction scheme of Zhao is reproduced below (Zhao 53: 20-22):
IXX:, J>M.Al'
-- ............... ~
The reaction scheme from Zhao (above) shows irinotecan, having the
same base ring structure as topotecan, reacted with a glycine residue (the
amino acid) to form a linkage with the E-ring at position-20 of irinotecan,
the same linkage in the claimed topotecan conjugate. This linkage is
different from Greenwald, which shows the polyethylene glycol polymer
conjugated to the A-ring.
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Application 13/995,063
The Examiner determined it would have been obvious to one of
ordinary skill in the art to conjugate the two topotecan molecules together
via the 20-position of the E-ring (as required by rejected claim 14), rather
than the A-ring as in Greenwald, and use an amino acid as a spacer (as also
required by claim 14) to protect the 20-position and esterify the sterically
hindered 20-hydroxy group as described by Zhao (citing Zhao 46:22--48:6).
Final Act. 3, 5-6.
The Examiner explained:
Zhao et al. also teach that the E-ring lactone (where the 20-
hydroxyl group is located) undergoes an undesirable hydrolysis
reaction when in the free state. See page 3, lines 16-23.
Therefore, the person of ordinary skill in the art would look to
the teaching of Zhao et al. as a method of reducing the
hydrolysis of the E-ring lactone that is present in topotecan by
easily binding the polymer backbone to the 20-hydroxyl group
and providing steric bulk.
Final Act. 3.
DISCUSSION
Appellants state that "an essential feature of the prodrugs of
Greenwald is the attachment to a carrier molecule such as a polyethylene
glycol via an aromatic hydroxyl group of the aromatic molecule." Br. 7.
Appellants contend that the modification of Greenwald to attach the
polyethylene carrier to another position as described by Zhao "goes against
an essential feature of the prodrugs of Greenwald." Id. We disagree and
address this argument below.
In Greenwald's discussion of prodrugs, it is stated that the "only
limitations on the types of aromatic molecules suitable for inclusion herein is
that there is available at least one aromatic OH-containing position which
can react with a carrier portion and that there is not substantial loss of
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Application 13/995,063
bioactivity after the prodrug releases and regenerates the parent compound,
i.e. Ar-OH." Greenwald 9:52-57. The aromatic ring in topotecan is the A-
ring. The linkage of the polyethylene dendrimer in Zhao and in rejected
claim 14 is via the E-ring, which is not an aromatic ring.
However, as explained above, the Examiner provided a fact-based
reason as to why one of ordinary skill in the art would have linked topotecan
via the E-ring at position 20 using an amino acid spacer. Specifically, the
Examiner found that Zhao teaches undesirable lysis at position-20 of the E-
rmg:
The clinical effectiveness of many small molecule
therapeutics, and oncolytics in particular, is limited by several
factors. For instance, irinotecan and other camptothecin
derivatives undergo an undesirable hydrolysis of the E-ring
lactone under alkaline conditions.
Zhao 3:16-20.
The Examiner also found that Zhao specifically mentioned Greenwald
as prior art in stating the need to improve methods of drug delivery of
camptothecins, identifying hydrolysis at the 20-position of the E-ring as
limiting the effectiveness of camptothecins. Final Act. 3; Zhao 3: 5-19.
Based on these teachings, the Examiner determined that one of
ordinary skill in the art would have found it obvious to utilize Zhao' s
method to reduce hydrolysis at the 20-position of the E-ring by conjugating
a polymer to that location, instead of the A-ring as in Greenwald.
Furthermore, the Examiner found it obvious to use the amino acid as a
spacer to overcome steric hindrance, as specifically disclosed by Zhao:
In turning now to one of the preferred classes of active
agents, the camptothecins, since the 20-hydroxyl group of the
camptothecin compound [ of which topotecan is a member] is
sterically hindered, a single step conjugation reaction is difficult
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Application 13/995,063
to accomplish in significant yields. As a result, a preferred
method is to react the 20-hydroxyl group with a short linker or
spacer moiety carrying a functional group suitable for reaction
with a multi-arm polymer. Such an approach is applicable to
many small molecules, particularly those having a site of
covalent attachment that is inaccessible to an incoming reactive
polymer. Preferred linkers include t-BOC-glycine or other
amino acids having a protected amino group and an available
carboxylic acid group.
Zhao 46: 22-33.
The Examiner's reasoning to conjugate the polymer to the E-ring,
rather than the A-ring as in Greenwald, is therefore supported by a
preponderance of the evidence. Appellants did not identify a defect in this
reasomng.
Appellants then attempt to distinguish Zhao on the basis that it
discloses "water-soluble polymer having three or more arms, at least three
of which are covalently attached to an active agent, e.g., a small molecule
(page 4, lines 7-10)," and not a linear conjugate of any molecule as claimed
and disclosed in Greenwald. Br. 12.
This argument is not persuasive. The Examiner cited Greenwald as
the reason to make a linear molecule as claimed. Ans. 4. As explained by
the Examiner, Zhao teaches how to attach compounds through the 20-
hydroxyl group and the reason for doing so. Ans. 4--5. While Zhao may
teach multi-armed polymers, Appellants did not identify a reason as to why
such disclosure would have dissuaded one of ordinary skill in the art from
applying Zhao's teaching to a linear molecule such as the one depicted in
Example 3 of Greenwald.
Appellants argued that Greenwald does not provide a suggestion or
guidance for arriving at the claimed structure (Br. 8), but the Examiner did
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Application 13/995,063
not rely on Greenwald for a reason to have modified the topotecan structure
of Example 3.
Appellants also argue that Example 3 of Greenwald, relied upon by
the Examiner is prophetic and that "there is nothing in Greenwald to direct
one of skill in the art to tum with any degree of particularity to Example 3 in
the first place." Br. 8. Appellants further argue that there is no data or
"detailed description is provided regarding synthesis of the title compound,
or whether it could actually be synthesized in the first place, its
characterization, its structure, its purity, or any indication of whether such
compound would actually have any degree of efficacy." Id.
This argument is not persuasive. First, even if Example 3 is
prophetic, it is still an explicit example in Greenwald that would have
commanded the attention of one of ordinary skill in the art. The fact that it
is prophetic does not make it any less of a teaching of the disclosed
conjugate. "[ A ]11 disclosures of the prior art, including unpreferred
embodiments, must be considered." Merck & Co v. Biocraft Laboratories,
874 F.2d 804, 807 (Fed. Cir. 1989). Second, Appellants have not provided
evidence that the compound could not be synthesized utilizing Greenwald' s
method nor any reason to doubt that such compound would be active. See
Ans. 4. "[A] prior art printed publication cited by an examiner 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).
Thus, we find Appellants' arguments regarding the selection of the
compound in Example 3 of Greenwald to be unavailing.
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Appellants also argue that Example 3 of Greenwald would not have
been selected as a lead compound because of its "inadequate description."
Br. 11.
Under the lead compound analysis rubric, we must first "determine[]
whether a chemist of ordinary skill would have selected the asserted prior art
compounds as lead compounds, or starting points, for further development
efforts." Otsuka Pharm. Co. v. Sandoz, Inc., 678 F.3d 1280, 1291 (Fed. Cir.
2012). Because the compound is explicitly disclosed in Greenwald, the
Examiner had a reasonable basis to identify it as lead compound. Appellants
identify reasons that might have dissuaded one of ordinary skill in from
choosing it, such as its alleged lack of efficacy and inability to synthesize it.
Br. 11. However, Appellants do not provide evidence of these deficiencies,
but rather rely entirely on attorney argument. An argument made by counsel
in a brief does not substitute for evidence lacking in the record. Estee
Lauder, Inc. v. L 'Orea!, S.A., 129 F.3d 588, 595 (Fed. Cir. 1997). Thus,
Appellants do not establish by evidence that the description of the compound
of Example 3 is inadequate. See also Ans. 4 for the Examiner's well-
reasoned explanation as to why Appellants' arguments are not persuasive.
SUMMARY
For the foregoing reasons, the rejection of claim 14 as obvious in view
of Greenwald and Zhao is affirmed. Dependent claims 15 and 39 were not
argued separately and therefore fall with claim 14. 37 C.F.R.
§ 4I.37(c)(iv)(l).
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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)(l )(iv).
AFFIRMED
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