Ex Parte LIU et al

Patent Trial and Appeal Board

Apr 22, 2016

12762768 (P.T.A.B. Apr. 22, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
121762,768 04/19/2010 LILI LIU
68705 7590 04/26/2016
TAROLLI, SUNDHEIM, COVELL & TUMMINO, LLP
1300 EAST NINTH STREET
SUITE 1700
CLEVELAND, OH 44114
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.
CWR-018698US ORD 4216
EXAMINER
OLSON, ERIC
ART UNIT PAPER NUMBER
1673
NOTIFICATION DATE DELIVERY MODE
04/26/2016 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):
rkline@tarolli.com
docketing@tarolli.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte LILI LIU and ST ANTON GERSON1
Appeal2013-009721
Application 12/762,768
Technology Center 1600
Before DEMETRA J. MILLS, ERIC B. GRIMES, and ULRIKE W. JENKS,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 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.
STATEMENT OF THE CASE
"Injury to DNA is minimized by enzymes that recognize errors,
remove them, and replace the damaged DNA with corrected nucleotides."
(Spec. i-f 43.) "Base excision repair (BER) is initiated by a DNA glycosylase
1 Appellants identify the Real Party in Interest as Case W estem Reserve
University. (Appeal Br. 2.)
Appeal2013-009721
Application 12/762,768
that ... generat[es] an abasic site (e.g., an apurinic or apyrimidinic (AP)
site). An apurinic or apyrimidinic (AP) site results from the loss of a purine
or pyrimidine residue, respectively, from DNA." (Id. at i-f 44.) "The AP site
is further processed by a 5'-3' endonuclease (AP endonuclease (APE)) that
incises the phosphodiester bond on both sides of the damaged purine or
pyrimidine base." (Id. at i-f 45.)
The Specification discloses "methods useful in the treatment of
certain cancers ... [in which] an inhibitor of the base excision pathway,
such as an AP endonuclease inhibitor (e.g., methoxyamine ), is combined
with an antimetabolite antineoplastic agent." (Id. at i-f 7.) More specifically,
"[t]he inhibition of the BER pathway with an AP endonuclease inhibitor
(e.g., methoxyamine (mx)) can potentiate the cytotoxic effects of [a]
nucleoside analog administered to cancer cells." (Id. at i-f 50.) Decitabine
(5-aza-2'-deoxycytidine) is a nucleoside analog (Spec. i-f 53).
Claims 1-3, 6-12, 15-20, and 22-26 are on appeal. Claim 1 is
illustrative and reads as follows:
Claim 1: A method of treating cancer in a subject comprising:
administering to the subject a therapeutically effective amount
of 5-aza-2'-deoxycytidine that induces formation of AP sites in cancer cells
of the subjects and an amount AP endonuclease inhibitor effective to
potentiate the cytotoxicity of the 5-aza-2'-deoxycytidine to the cancer cells,
the AP endonuclease inhibitor being a small molecule with a primary amine
group that forms a covalent linkage with an aldehyde group of an AP site
induced by 5-aza-2'-deoxycytidine.
2
Appeal2013-009721
Application 12/762,768
All of the claims on appeal stand rejected under 35 U.S.C. § 103(a)
based on either (a) Zarling,2 Redkar, 3 and Palii4 (Ans. 3--4) or (b) Kelley, 5
Fortini,6 and Ruiz7 (Ans. 9).
I
The Examiner has rejected all of the claims on appeal as obvious
based on Zarling, Redkar, and Palii. The Examiner finds that Zarling
discloses a method of treating cancer "comprising administering to the
individual a composition comprising a BER inhibitor, e.g. an Ape 1 inhibitor
such as methoxyamine, a DSBR [double-strand break repair] inhibitor, e.g.,
a Rad5 l inhibitor, and a sensitizing agent, e.g., either a radio sensitizing
agent and/or a chemotherapeutic agent." (Ans. 4.) The Examiner finds that
Zarling also discloses that its method can include providing a DNA-
damaging agent after administration of the above composition, and that
preferred DNA-damaging agents include nucleoside analogues. (Id.) The
2 Zarling et al., US 2003/0229004 Al, published Dec. 11, 2003.
3 Redkar et al., US 2006/0074046 Al, published Apr. 6, 2006.
4 Palii et al., DNA Methylation Inhibitor 5-Aza-2 '-Deoxycytidine Induces
Reversible Genome-Wide DNA Damage That Is Distinctly Influenced by
DNA Methyltransferases 1 and 3B, 28 Molecular and Cellular Biology 752-
771 (2008).
5 Kelley et al., US 5,919,643, issued July 6, 1999.
6 Fortini et al., Mutagenic Processing of Ethylation Damage in Mammalian
Cells: The Use of Methoxyamine to Study Apurinic/Apyrimidinic Site-
induced Mutagenesis, 53 Cancer Research 1149-1155 (1993).
7 Veronique W.T. Ruiz van Haperen and Godefridus J. Peters, New targets
for pyrimidine antimetabolites for the treatment of solid tumours, 16
Pharmacy World & Science 104--112 (1994).
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Application 12/762,768
Examiner also finds that Zarling discloses that BER inhibitors and DSBR
inhibitors increase sensitivity to DNA-damaging agents. (Id.)
The Examiner notes that Zarling does not disclose using decitabine
(5-aza-2'-deoxycytidine) as the chemotherapeutic agent or the DNA-
damaging agent in its method. (Id. at 5.) The Examiner finds, however, that
Redkar discloses using decitabine to treat cancers, among other diseases.
(Id. at 6.) The Examiner also finds that Palii discloses that decitabine
treatment led to formation of double-strand breaks in DNA and therefore a
skilled artisan would recognize it as a DNA-damaging agent. (Id.)
The Examiner concludes that it would have been obvious to use
Redkar's decitabine as the DNA-damaging agent in Zarling's method (id. at
7) because decitabine was a known nucleoside analogue and DNA damaging
agent. (Id. at 8.) The Examiner finds that a skilled artisan would reasonably
have expected the combination to potentiate the cytotoxicity of decitabine
because Zarling teaches that the combination increases sensitivity of cancer
cells to DNA-damaging agents. (Id.)
We agree with the Examiner's fact-finding and conclusion. Zarling
discloses "methods ... to inhibit cell proliferation, comprising
administration of both BER pathway and DSBR pathway inhibitors,
combined with DNA chemo-[ or ]radio-sensitizing drugs." (Zarling i-f 5.)
Zarling states that its methods are particularly useful for treatment of cancers
of various types and tissues. (Id. at i-f 55.) Zarling states that
"[ m ]ethoxyamine (MX) is an alkoxyamine derivative able to block the
single nucleotide BER pathway." (Id. at i-f 11.) Methoxyamine is a small
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Application 12/762,768
molecule having the function recited in Appellants' claim 1. (See, e.g.,
dependent claim 2.)
Zarling discloses that its methods "can further include the step of
providing radiation or DNA damaging agents after administration of [its]
composition." (Zarling i-f 28.) "Preferred DNA damaging agents may
include, but are not limited to, nucleoside analogues, alkylating agents," etc.
(Id. at i-f 61.) Zarling states that "the BER and DSBR inhibitors herein
induce sensitivity to DNA damaging agents." (Id. at i-f 60.)
Redkar discloses that decitabine is an analogue of the natural
nucleoside 2'-deoxycytidine (Redkar i-f 3) and that it is used to treat cancer
(id. at i-f 188.) Palii discloses that treatment of tumor cells with decitabine
(which Palii refers to as 5-azadC) led to formation of DNA double-stand
breaks. (Palii, abstract.)
We agree with the Examiner that the method of claim 1 would have
been obvious to a person of ordinary skill in the art based on the teachings of
Zarling, Redkar, and Palii. Specifically, it would have been obvious to
include decitabine as the DNA-damaging agent in Zarling's method because
Zarling suggests using nucleoside analogs as DNA-damaging agents, and
decitabine is an analog of the nucleoside 2'-cytidine. In addition, Zarling
teaches that its composition comprises BER and DSBR inhibitors, which
induce sensitivity to DNA-damaging agents, and Palii teaches that
decitabine treatment leads to double-strand breaks in DNA. Thus, a skilled
artisan would reasonably expect that Zarling's composition would induce
sensitivity to decitabine.
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Application 12/762,768
Appellants argue that "the fact that IPDR, IUDR and 5-aza-2'-
deoxycytidine are each nucleoside analogues does not mean that IPDR,
IUDR and 5-aza-2'-deoxycytidine each would be expected to form AP sites
and induce the BER pathway in cancer cells." (Appeal Br. 15.) Appellants
argue that "an ordinary artisan at the time of the invention could not
reasonably predict that the administration of an AP endonuclease inhibitor of
claim 1 could potentiate the cytotoxicity of 5-aza-2'-deoxycytidine and thus
[be] utilized in an effective method of treating cancer" and therefore the
rejection is based on hindsight. (Id. at 16.)
This argument is unpersuasive. The cited references provide a reason
to treat cancer by administering both decitabine and an AP endonuclease
inhibitor such as methoxyamine, because Palii teaches that decitabine
treatment leads to double-strand breaks in DNA, and Zarling teaches that its
composition-which contains both a BER inhibitor such as methoxyamine
and a DSBR inhibitor-induces sensitivity to DNA damaging agents, like
decitabine, in target cells.
We agree with the Examiner that the claim language stating that
decitabine induces formation of AP sites in cancer cells simply reflects the
mechanism of action of the administered decitabine. It does not result in any
manipulative difference in the claimed method. Thus, the method defined
by claim 1 would have been prima facie obvious to a person of ordinary skill
in the art based on the teachings of Zarling, Redkar, and Palii.
Appellants argue, however, that they have provided evidence of
unexpected results. (Appeal Br. 17.) Specifically, Appellants argue that
"methoxyamine synergistically enhances decitabine induced apoptosis in
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Application 12/762,768
melanoma cells." (Id. at 18.) Appellants point to the disclosure in the
Specification's i-f 1378 as evidence supporting their position (id.), and argue
that their results would not have been expected because decitabine was not
known to activate the base excision repair (BER) pathway (id. at 19-20).
We have considered the evidence cited by Appellants but do not agree
that it shows that the claimed method would have been nonobvious. The
Specification describes an experiment in which cells were treated with
decitabine (5-aza-dC) or methoxyamine (MX) alone, or a combination of the
two. (Spec. i-f 137.) The Specification states that, after treatment with either
agent alone, 97% of the cells remained viable, but when they were treated
with a combination of the two agents, "5-fold more cells were killed by
forcing target cells to go into apoptosis." (Id.) The Specification concludes
that "[t]hus, the combined treatments as compared with single treatment
result in more effective apoptotic response in cells." (Id.)
We do not find the proffered data adequate to show that the claimed
method would have been nonobvious, for two reasons. First, Appellants
have not pointed to any evidentiary basis for concluding that the cited results
would have been unexpected, or even to an unsupported statement to that
effect in the Specification. Although Appellants characterize the results as
unexpected in the Appeal Brief, "[a]ttomey's argument in a brief cannot take
the place of evidence." In re Pearson, 494 F.2d 1399, 1405 (CCPA 1974).
Second, "when unexpected results are used as evidence of
nonobviousness, the results must be shown to be unexpected compared with
8 Appellants actually cite the Specification's i-f 150, but the quoted language
appears in i-f 137 in the Specification as originally filed.
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the closest prior art." In re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed.
Cir. 1991 ). Here, Zarling presents a working example showing that
methoxyamine sensitizes ovarian and colon cancer cells to the nucleoside
analogue iododeoxyuridine (IUDR). (Zarling i-fi-f 14, 77-79.) Zarling also
presents a working example showing that methoxyamine (MX) increases the
sensitivity of Chinese hamster ovary (CHO) cells to the nucleoside analogue
fludarabine. (Id. at i-fi-f 14, 80-81.)
Appellants have not presented data showing a comparison of the
claimed method of treating cancer cells with decitabine and an AP
endonuclease inhibitor such as methoxyamine with the methods shown in
Zarling's examples. Appellants therefore have not shown that the claimed
method produces results that are superior, let alone unexpectedly superior,
compared to the closest prior art.
For the reasons discussed above, we affirm the rejection of claim 1
under 35 U.S.C. § 103(a) based on Zarling, Redkar, and Palii. Claims 2, 3,
6-8, 10-12, 15-20, and 22-25 have not been argued separately and therefore
fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
With respect to claims 9, 17, and 23, Appellants argue that it would
not have been predictable to a person of ordinary skill in the art that the
claimed method could be practiced to treat cancer without causing undue
sensitization of normal cells, as recited in those claims. (Appeal Br. 21.)
The Examiner did not address the specific limitation of claims 9, 17,
and 23 in the statement of the rejection (Ans. 3-9) and, as Appellants
pointed out (Reply Br. 10-11 ), did not respond to Appellants' argument on
this point. Because the Examiner has the initial burden of showing
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Application 12/762,768
unpatentability, and did not do so with respect to claims 9, 17, and 23, we
reverse the rejection of those claims.
With respect to claim 26, Appellants argue that it would not have been
reasonably predictable that the claimed method could be practiced to treat
melanoma, as recited in that claim. (Appeal Br. 10-11.)
We agree with the Examiner, however, that a skilled artisan would
have reasonably expected the method made obvious by the cited references,
and encompassed by claim 26, to be useful in treating melanoma. As the
Examiner has pointed out (Ans. 4, 6-7), both Zarling and Redkar disclose
that their methods can be used to treat melanoma. (Zarling i-f 55; Redkar
i-f 191.) Thus, a skilled artisan would have reasonably expected that the
combination of the active agents disclosed by each of Zarling and Redkar
would also be useful in treating melanoma.
II
The Examiner has rejected all of the claims on appeal as obvious
based on Kelley, Fortini, and Ruiz. The Examiner finds that Kelley teaches
that inhibiting AP endonuclease (APE) function enhances sensitivity of a
tumor cell to chemotherapy, and teaches that chemotherapeutic agents
include nucleoside analogues (Ans. 9-10), but does not teach either
methoxyamine or decitabine (id. at 11-12). The Examiner finds that Fortini
discloses that methoxyamine inhibits DNA repair via AP endonuclease
cleavage, and Ruiz discloses that decitabine can be used to treat tumors. (Id.
at 12.) The Examiner concludes that it would have been obvious to use
methoxyamine as an AP endonuclease inhibitor and decitabine as a chemo-
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therapeutic agent in Kelley's method based on the teachings of the cited
references. (Id.)
Appellants contend that this rejection is improper because "without
the discoveries described in the present specification, one of ordinary skill in
the art could not reasonably predict the outcome of a method of claim 1
without the benefit of improper hindsight." (Appeal Br. 28.)
We agree with Appellants that the Examiner has not shown that a
person of ordinary skill in the art would have had adequate reason to
combine the teachings of Kelley, Fortini, and Ruiz.
Kelley discloses "a method for enhancing the sensitivity of a tumor
cell to a chemotherapy ... comprising reducing the amount of APE activity
in the cell .... [T]he reducing may comprise inhibiting APE function."
(Kelley 6: 12-18.) Fortini discloses that, "after reaction with MX, AP sites
become resistant to cleavage by human and hamster AP endonucleases"
(Fortini 1150, right col.) and MX forms a "substituted derivative of the AP
site ... which is relatively stable and inhibits DNA repair via AP-
endonuclease cleavage" (id. at 1153, left col.). Ruiz teaches that
"[ d]ecitabine ... has shown considerable activity in ... human acute
myelogenous leukaemia." (Ruiz 107, left col.)
However, Ruiz also states that the
mechanism of action at the DNA level is not to disturb the
structure of the newly synthesized DNA. Because of its
molecular structure, decitabine is easily incorporated into DNA.
Once incorporated, decitabine inhibits the action of DNA
methyltransferase, by forming covalent adducts with the enzyme.
In this way, DNA becomes hypomethylated, which has major
consequences for cell differentiation.
(Id. at 107, bridging paragraph (citations omitted).)
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Thus, Ruiz discloses that decitabine' s activity is due to its inhibition
of DNA methyltransferase, and the resulting differentiation of the cancer
cells. Ruiz does not suggest that decitabine has an effect on DNA that
would be subject to repair via AP-endonuclease cleavage, which is the
activity that is disclosed by Fortini to be inhibited by methoxyamine.
Similarly, Kelley states that the sensitivity of a tumor cell is enhanced
by inhibiting AP-endonuclease function. However, because none of the
cited references disclose that decitabine' s activity is associated with the
activity of AP-endonuclease, the evidence does not support the Examiner's
conclusion that a person of ordinary skill in the art would have considered it
obvious to combine the teachings of Kelley, Fortini, and Ruiz in the manner
recited in the claims on appeal.
SUMMARY
We affirm the rejection of claims 1-3, 6-8, 10-12, 15, 16, 18-20, 22,
and 24--26 under 35 U.S.C. § 103(a) based on Zarling, Redkar, and Palii.
We reverse the rejection of claims 9, 17, and 23 under 35 U.S.C.
§ 103(a) based on Zarling, Redkar, and Palii.
We reverse the rejection of claims 1-3, 6-12, 15-20, and 22-26 under
35 U.S.C. § 103(a) based on Kelley, Fortini, and Ruiz.
TIME PERIOD FOR RESPONSE
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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