Lin Cheng et al.

Patent Trials and Appeals Board

Dec 27, 2019

13995415 - (D) (P.T.A.B. Dec. 27, 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.
13/995,415 09/06/2013 Lin Cheng SHE0361.00 3386
21968 7590 12/27/2019
NEKTAR THERAPEUTICS
455 Mission Bay Blvd., South, Suite 100
San Francisco, CA 94158
EXAMINER
DECK, JASON A
ART UNIT PAPER NUMBER
1627
MAIL DATE DELIVERY MODE
12/27/2019 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 LIN CHENG and JENNIFER RIGGS-SAUTHIER
Appeal 2018-000608
Application 13/995,415
Technology Center 1600
Before RICHARD M. LEBOVITZ, ULRIKE W. JENKS, and TAWEN
CHANG, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1, 10, and 16. We have jurisdiction
under 35 U.S.C. § 6(b).
We REVERSE.

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 Nektar
Therapeutics. Appeal Br. 3.
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BACKGROUND
Pemetrexed, an antifolate drug, has been used to treat cancer patients
and has the following chemical structure:

Spec. ¶ 5; Ans. 13. The Specification states that it would be desirable to
modify pemetrexed in order to “(i) reduce peak-to-trough variation (with the
potential to reduce dose-limiting toxicities), (ii) accumulate in tumor tissues
while still retaining efficacy, and (iii) extend the effective half-life to thereby
provide less frequent dosing.” Id. ¶ 8. The invention “seeks to address these
and/or other needs” by providing certain pemetrexed conjugates. Id. ¶ 9.
CLAIMED SUBJECT MATTER
The claims are directed to a conjugate of pemetrexed according to a
recited formula. Claim 1 is illustrative:
1. A conjugate according to Formula I:

wherein:
R is a residue of pentaerythritol;
R1 is H;
R2 is H;
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R3 is amino;
Q is -O-;
POLY1 is a poly(alkylene glycol);
X is -C(O)-NHCH2CH2(OCH2CH2)2NH-C(O)-, -CH2-C(O)-
NHCH2CH2OCH2CH2O-C(O)-, or -CH2-C(O)-NH-CH2-CH(R4)-O-
C(O)-;
R4 is H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, or –
CH(CH3)CH2CH3; and
q is 4;
and pharmaceutically acceptable salts and solvates thereof.
Appeal Br. 12 (Claims App.).
In response to the Examiner’s September 28, 2015 Requirement for
Restriction/Election, Appellant elected without traverse compound 20d,
which has the structure set forth below:
,
wherein n is defined to provide a 4-arm-PEG 40k. Reply to Restriction
Requirement (Nov. 24, 2015). We limit our consideration on the merits to
the elected species. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BPAI
1987).
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REJECTION(S)
A. Claims 1, 10, and 162 are rejected under pre-AIA 35 U.S.C. § 103(a)
as being unpatentable over Ootsu,3 Harris,4 and Zhao.5

OPINION
A. Issue
The Examiner finds that Ootsu teaches “oligoglutamate conjugates of
folates (i.e. oligomeric conjugates . . .) including pemetrexed derivatives like
the amide-linked one shown below”:

Ans. 3. The Examiner finds that Ootsu further discloses that “oligo-
conjugates are excellent anti-tumor compounds with highly specific
toxicities for cancers, and have excellent water solubility.” Id. at 4.
The Examiner finds that Ootsu “does not specifically disclose the . . .
claimed polymer scaffold.” Id. However, the Examiner finds that Harris
teaches “improved drug-polymer multifunctional conjugates based on, for
example, pegylated pentaerythritol . . . that are useful with drugs such as

2 Claims 4–7 and 15 have been withdrawn. Appeal Br. 4.
3 Akimoto et al., EP 0 492 316 A1, published July 1, 1992. Although
Akimoto is listed as the first inventor, both the Examiner and Appellant
refers to the reference as Ootsu. Thus, to avoid confusion, we also refer to
the reference as Ootsu in our opinion.
4 Harris et al., US 2006/0275252 A1, published Dec. 7, 2006.
5 Zhao et al., US 2009/0074704 A1, published Mar. 19, 2009.
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pemetrexed” and that Zhao teaches “multi-arm polymeric prodrugs . . .
based on the pentaerythritol-scaffold shown below”:

Id. The Examiner finds that Zhao exemplifies this class of drugs with
different anti-cancer compounds, thus demonstrating that “the polymer-
conjugates can be beneficially used with different anti-cancer drugs with
unrelated structural motifs.” Id. The Examiner also finds that Zhao teaches
that “X in Q-POLY1X-D can preferably be - (CRxRy)a-K-(CRxRy)b-
(OCH2CH2)c-Z where R[x] and R[y] can be H, a can be 0, K can be –
C(O)NH-, c can be 2, and Z can be a variety of carbonyl functionalities . . . ;
i.e. X can preferably be -C(O)NH-(CH2)2-(OCH2CH2)[2]-carbonyl linker.”
Id. at 5. In short, the Examiner cites Harris for suggesting conjugating
pemetrexed with a multi-arm PEG polymer, as claimed, and cites Zhao for
suggesting a multi-arm PEG polymer conjugate with the specific claimed
spacer between the PEG polymer and active ingredient.
The Examiner finds that a skilled artisan “would have been motivated
to make and use pemetrexed conjugated via an amide to a multi-arm
polymer,” with a reasonable expectation of success, because “the prior art
demonstrates that pemetrexed can be beneficially modified via conjugation,
discloses an appropriate site on pemetrexed for attachment, discloses the
attachment via an amide linkage, and teaches that pemetrexed can be
beneficially conjugated to a multi-arm PEG-based polymer.” Id. at 5. The
Examiner further finds that a skilled artisan “would have been motivated to
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make and use pemetrexed conjugated with the claimed species of polymer,”
with a reasonable expectation of success, because “the prior art demonstrates
that the claimed class of polymer-conjugates are useful for the treatment of
cancers, demonstrates that different cancer compounds can be successfully
appended to the class of polymer conjugates, and teaches which portions of
the conjugate can, and should, be modified and in what fashion.” Id. at 5–6.
The Examiner notes that “compounds differing by the successive addition of
the same chemical group, e.g., by -CH2- groups or PEG groups, are
generally of sufficiently close structural similarity that there is a presumed
expectation that such compounds possess similar properties,” and, “[a]bsent
any criticality, the simple addition or deletion of repeat groups would be
prima facie obvious.” Id.
Appellant contends that the combination of prior art would not result
in a conjugate within the scope of claim 1. Appeal Br. 9–10.
Appellant further contends that “a finding of obviousness based on
chemical similarity requires . . . (i) the selection of a lead compound, (ii)
identification of a reason to modify the lead compound, and (iii) the
predictability of the result of the modification to the lead compound.” Id. at
7–8. Appellant contends the Examiner has not explained why a skilled
artisan would have selected any particular compound in Ootsu as a lead
compound for modification or why a skilled artisan would have modified
such a compound to arrive at the claimed invention. Id. at 8. Appellant
contends that, in fact, a skilled artisan “looking to optimize the conjugates of
Ootsu would have retained the oligoglutamate moiety of these compounds,
since it is these moieties which are asserted in Ootsu to provide beneficial
properties.” Id. Appellant further contends that a skilled artisan “would
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[not] have had a reasonable expectation of success or predictable results in
making and testing a hypothetical pemetrexed conjugate” because Zhao
“show[s] significantly different efficacy for conjugates of anti-cancer drugs
with unrelated structural motifs.” Id. at 8–9.
Finally, Appellant contends that the claimed subject matter exhibits
unexpected results. Id. at 7.
The issue with respect to this rejection is whether a skilled artisan
would have had reason to combine the teachings of the cited prior art to
arrive at the elected compound, with a reasonable expectation of success.
B. Analysis
To facilitate our discussion, the elected species is reproduced below
with annotations:

On balance, we find Appellant to have the better argument. In
particular, the Examiner has not persuasively explained why a skilled
artisan, in view of Ootsu, Harris, and Zhao, would have had reason to
conjugate pemetrexed to the multi-arm polymer suggested by Zhao
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(corresponding to the claimed pentaerythritol, PEG, spacer) via an amide
linkage, as required by the elected species of the claims.
The Examiner asserts that Ootsu teaches that the amide-linked
pemetrexed derivative shown below is an excellent anti-tumor compound
that also has excellent water solubility:

Ans. 3–4 (annotations added). The Examiner asserts the prior art suggests
anti-cancer drugs including pemetrexed can be beneficially conjugated to the
claimed multi-arm PEG-based polymer, while this disclosure in Ootsu
teaches both “an appropriate site on pemetrexed for attachment” as well as
“attachment via an amide linkage.” Id. at 5. The Examiner asserts that,
given the combination of these disclosures, a skilled artisan would have had
reason to “attach pemetrexed with an amide linker to a multi-arm PEG-based
polymer during the routine optimization of pemetrexed derivatives,” with a
reasonable expectation of success. Id. at 5–6.
We are not persuaded. Ootsu teaches that certain condensed
heterocyclic oligoglutamate derivatives, including the glutamate derivative
of pemetrexed, are useful as water-soluble antitumor agents. Ootsu Title,
Abstract, 2:3–4, 4:4–11, 9:17–18, claim 29. The Examiner essentially
suggests that it would be obvious to a skilled artisan to replace the glutamate
moiety of the compound taught in Ootsu with the multi-arm polymer
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conjugate taught by Zhao, while retaining the amide linkage of Ootsu’s
compound.6
As an initial matter, the Examiner does not persuasively explain why a
skilled artisan would replace the glutamate moiety of Ootsu’s compound,
given that Ootsu teaches that glutamate moieties provide beneficial
properties to the compound.
In response to that argument by the Appellant, the Examiner states
that, while “[t]he disclosure of Ootsu . . . generally teaches that
oligoglutamate compounds have beneficial properties with respect to the
parent, non-oligomer conjugated, compounds,” it is “silent as to the benefit,
or lack thereof, of alternate oligomer-conjugation,” and such “silence is not
sufficient to be a teaching-away from the use of alternate oligomers for
conjugation.” Ans. 11.
We agree that Ootsu does not teach away from the use of other
pemetrexed conjugates. Nevertheless, a lack of teaching away is not the
same as a reason to combine, and the Examiner’s response does not explain
why a skilled artisan would replace the glutamate moiety from Ootsu’s
compound with Zhao’s multi-arm polymer while retaining an amide linkage
between pemetrexed and a different conjugate.7 For instance, the Examiner

6 The amide linkage in the pemetrexed derivate taught by Ootsu results from
the reaction between the terminal carboxylic acid group of the pemetrexed
and the amine moiety of the glutamate. That is, the nitrogen in the amide
linkage is contributed by the glutamate, not pemetrexed.
7 In this regard, we note that the Examiner does not suggest that Zhao itself
discloses a 4-arm moiety that, when conjugated to pemetrexed, would result
in a linkage via an amide bond. The Examiner does not describe how such
linkage would be made, e.g., by identifying an amino group in Zhao’s
polymer through which the conjugation to pemetrexed would be made.
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has cited no evidence that it is the amide linkage, rather than the glutamate
moiety, that provides the beneficial properties to the pemetrexed derivative
taught in Ootsu. Neither has the Examiner provided evidence that the
glutamate moiety in Ootsu is functionally equivalent to the multi-arm
polymer conjugate of Zhao.
Indeed, we note that Zhao teaches that its polymer conjugate should
be attached to the active agent (e.g., pemetrexed) via a hydrolyzable linkage.
Zhao ¶ 17. Zhao further teaches that a “hydrolyzable” bond is a bond, such
as a carboxylate ester, that “reacts with water (i.e., is hydrolyzed) under
physiological conditions,” while amides are examples of a hydrolytically
stable bond that “does not undergo hydrolysis under physiological
conditions to any appreciable extent over an extended period of time.” Id.
¶¶ 118, 120. If anything, therefore, Zhao would appear to teach away from
using an amide linkage with its polymer conjugate unless it forms a linkage
that is hydrolytically degradable when taken together with the spacer or a
portion of the spacer. Id. ¶ 118 (explaining that Z, the linkage to the active
agent itself, need not be hydrolytically degradable, if it forms a
hydrolytically degradable linkage when taken together with a covalently
attached spacer fragment or a portion thereof).
Neither are we persuaded by the Examiner’s assertion that a skilled
artisan would have “made and used the instantly claimed polymer conjugate
of pemetrexed during the routine optimization of the polymer conjugated
pemetrexed.” Ans. 6. It is true that, “where the general conditions of a
claim are disclosed in the prior art, it is not inventive to discover the
optimum or workable ranges by routine experimentation.” In re Aller, 220
F.2d 454, 456 (CCPA 1955). In this case, however, the Examiner has not
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established that the general conditions of the claims are disclosed in the prior
art.
Finally, the Examiner argues that
compounds differing by the successive addition of the same
chemical group, e.g., by -CH2- groups or PEG groups, are
generally of sufficiently close structural similarity that there is a
presumed expectation that such compounds possess similar
properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA
1977). Absent any criticality, the simple addition or deletion of
repeat groups would be prima facie obvious.
Ans. 6. We are not persuaded. The Examiner does not explain how the
doctrine elucidated in In re Wilder applies in this case. “[R]ejections on
obviousness grounds cannot be sustained by mere conclusory statements;
instead, there must be some articulated reasoning with some rational
underpinning to support the legal conclusion of obviousness.” KSR Int’l Co.
v. Teleflex Inc., 550 U.S. 398, 418 (2007) (quoting In re Kahn, 441 F.3d
977, 988 (Fed. Cir. 2006)).
Accordingly, for the reasons explained above, we reverse the
Examiner’s rejection of claims 1, 10, and 16 as obvious over Ootsu, Harris,
and Zhao.
CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 10, 16 103(a) Ootsu, Harris,
Zhao
1, 10, 16

REVERSED