THE INSTITUTE OF CANCER RESEARCH: ROYAL CANCER HOSPITAL

Patent Trials and Appeals Board

Jun 26, 2020

2019005963 (P.T.A.B. Jun. 26, 2020)

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.
14/898,284 12/14/2015 Richard Marais 0380-P06286US00 6952
110 7590 06/26/2020
DANN, DORFMAN, HERRELL & SKILLMAN
1601 MARKET STREET
SUITE 2400
PHILADELPHIA, PA 19103-2307
EXAMINER
NGUYEN, QUANG
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
06/26/2020 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):
docketclerk@ddhs.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte RICHARD MARAIS, CAROLINE SPRINGER, and
SERENA TOMMASINI1

Appeal 2019-005963
Application 14/898,284
Technology Center 1600
Before ERIC B. GRIMES, FRANCISCO C. PRATS, and
RACHEL H. TOWNSEND, 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 killing cancer cells, which have been rejected as obvious. We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

1 Appellant identifies the real party in interest as The Institute of Cancer
Research: Royal Cancer Hospital. Appeal Br. 3. 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
“Gene-directed enzyme prodrug therapy (GDEPT) . . . [is a] suicide-
gene therapy approach[] that aim[s] to increase the delivery of toxic
metabolites to solid tumours.” Spec. 1:9–13. “The GDEPT system
developed by the present inventors uses expression of the enzyme
carboxypeptidase G2 (CPG2) . . . [which] activates prodrugs . . . to release
L-glutamic acid and an active cytotoxic drug.” Id. at 1:25–30.
“Vaccinia virus . . . ha[s] a degree of natural affinity for tumour cells
due to the dysregulation of the cell cycle in tumour cells, and this selectivity
for tumour cells can be . . . increased by the inactivation of virulence genes,
e.g. the deletion of the viral thymidine kinase [vTK] gene.” Id. at 3:22–29.
“vTK may be inactivated by virtue of the insertion of a CPG2 expression
cassette.” Id. at 4:15–16. “The present inventors have developed a modified
vaccinia virus which expresses a prodrug-activating enzyme for use in a
GDEPT system for treating tumours.” Id. at 3:30–32.
Claims 32–37, 46, 47, 56, and 57 are on appeal. Claims 32 and 37,
reproduced below, are the independent claims:
32. A method of killing a neoplastic cell, the method
comprising treating the neoplastic cell with: a vaccinia virus
vector which expresses a glutamate carboxypeptidase within
said cell, and a prodrug which is converted into an active form
by said glutamate carboxypeptidase,
wherein the glutamate carboxypeptidase is a CPG2
enzyme of SEQ ID NO: 2, or a homologue thereof having an
amino acid sequence that is at least 80% identical to SEQ ID
NO: 2, said CPG2 enzyme being encoded by a nucleic acid
operably linked to a vaccinia virus promoter sequence inserted
into a virulence thymidine kinase (vTK) gene sequence, thereby
inactivating said thymidine kinase (vTK) gene, said vector also
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lacking a vaccinia growth factor (VGF) gene sequence, thereby
enhancing neoplastic cell selectivity and cell killing.

37. A method of treating a tumour in a patient in need of
treatment, the method comprising administering to the patient: a
vaccinia virus which expresses a glutamate carboxypeptidase in
a tumour cell; and, a prodrug which is converted into an active
form by the glutamate carboxypeptidase,
wherein the glutamate carboxypeptidase is a CPG2
enzyme of SEQ ID NO: 2, or a homologue thereof having an
amino acid sequence that is at least 80% identical to SEQ ID
NO: 2, said CPG2 enzyme being encoded by a nucleic acid
sequence operably linked to a p7.5 vaccinia virus promoter
sequence inserted into a virulence thymidine kinase (vTK) gene
sequence, thereby inactivating said thymidine kinase (vTK)
gene, said vector also lacking a vaccinia growth factor (VGF)
gene sequence, thereby enhancing tumour cell selectivity,
wherein the prodrug is N-(4-[bis(2-iodoethyl)amino]
phenoxycarbonyl)-L-glutamic acid or a salt thereof and
conversion of the prodrug produces a neoplastic cell killing
effect, thereby treating said tumour in said patient.

OPINION
Claims 32–37, 46, 47, 56, and 57 stand rejected under 35 U.S.C. § 103
as obvious based on McCart2 and Springer.3 Final Action4 5. The Examiner
finds that McCart discloses:
a vaccinia virus expression vector with a negative thymidine
kinase phenotype and a negative vaccinia virus growth factor
phenotype, wherein the vector comprises an expression cassette
containing an exogenous nucleotide sequence under the control

2 US 8,506,947 B2; Aug. 13, 2013.
3 US 6,004,550; Dec. 21, 1999.
4 Office Action mailed April. 5, 2018.
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of a vaccinia virus promoter (e.g., p7.5 promoter) . . . inserted
into the vaccinia virus genome . . . to inactivate or knockout the
vaccinia thymidine kinase and/or vaccinia growth factor genes.
Id. at 6 (emphasis omitted). The Examiner finds that “the vector has
enhanced safety by selectively replicating in tumor cells . . . but is
substantially incapable of replicating in non-dividing cells.” Id. (emphasis
omitted).
The Examiner also finds that McCart teaches that the exogenous gene
inserted into its vector can be a suicide gene such as CPG2, which can be
used with a prodrug such as 4-[(2-chloroethyl)(2-mesyloxyethyl)amino]
benzoyl-L-glutamic acid (CMDA) in a method of treating a tumor in a
patient. Id.
The Examiner finds that McCart does not teach CPG2 comprising an
amino acid sequence that is at least 80% identical to SEQ ID NO: 2, but
Springer teaches “a method of treating a tumor . . . in a patient comprising
administering to the patient an effective amount of a vector encoding a
carboxypeptidase and a prodrug capable of being converted by the enzyme
to an active drug.” Id. at 7 (emphasis omitted). The Examiner finds that
Springer teaches that “the enzyme is a bacterial carboxypeptidase CPG2
having SEQ ID NO: 1 that is 98.2% [identical] to SEQ ID NO: 2 of the
present application” and the prodrug can be CMDA or N-4-[N,N-bis(2-
idodoethyl)amino]phenoxycarbonyl-L-glutamic acid (aka ZD2767P5), as
recited in instant claim 37. Id. (emphasis omitted).
The Examiner concludes that it would have been obvious “to modify
McCart’s method by using the “CPG2 enzyme having SEQ ID NO:1 that is

5 See Spec. 12:21–22.
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98.2% identical to SEQ ID NO: 2 of the present application along with
nitrogen mustard prodrugs . . . as taught by Springer,” including ZD2767P,
to treat neoplastic cells or a tumor in a patient. Id. at 8. The Examiner finds
that a skilled artisan would have been motivated by Springer’s teaching of a
successful GDEPT method using its CPG2 enzyme and the disclosed
prodrugs. Id.
We agree with the Examiner that the cited references support a prima
facie case of obviousness. McCart discloses “mutant vaccinia virus
expression vectors . . . [that] show substantially no virus replication in non-
dividing cells and as such are superior to previous vaccinia virus expression
vectors.” McCart 1:20–24. McCart states that the “inability [to replicate in
non-dividing cells] arises from a combination of mutations in viral genes.”
Id. at 4:19–20. “[T]he combination of TK and VGF minus phenotypes
yield[s] a vaccinia virus with a diminished ability to replication in non-
dividing cells. . . . That is, it replicates selectively in dividing cells.” Id. at
4:30–33.
McCart states that “[t]o create a vaccinia virus with a TK- phenotype,
it is necessary to disrupt the nucleic acid sequence of the TK gene in such a
way that the TK gene no longer encodes an active and functional copy of the
TK gene. Disruption of the TK gene can be achieved through an insertion,
an amino acid sequence altering substitution . . . , or a deletion.” Id. at 4:37–
43. “[A] gene of interest can be placed under the control of a vaccinia virus
promoter and integrated into the genome of the mutant vaccinia virus.” Id. at
6:19–21. “Such nucleotide sequences can also be introduced to ‘knock out’
or inactivate the TK and/or VGF sequences.” Id. at 6:34–36.
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McCart states that one “class of genes for use with the vectors of [its]
invention are suicide genes. . . . Genes with this function include: . . .
carboxypeptidase G2.” Id. at 7:63 to 8:21. McCart states that “[t]hese genes,
inserted into target cells, provide an excellent method by which to sensitize
cells to certain chemotherapeutic agents. The double mutant vaccinia virus
expression vectors of the present invention are an excellent method for
introducing these genes into dividing target cells.” Id. at 8:22–27. McCart
discloses that carboxypeptidase G2 (CPG2) releases active agents from
prodrugs, including CMDA. Id. at 11:3–43. McCart states that “[v]arious
methods of tumor specific expression of CPG2 have been studied . . . ,
suggesting it would be a good enzyme for use in a suicide gene system.”
Id. at 11:34–38.
Thus, based on McCart’s teachings, it would have been obvious to
make a vaccinia virus expression vector having a CPG2 gene inserted into
the viral TK gene in order to inactivate it, and to also inactivate the vaccinia
growth factor (VGF) gene, because McCart states that the combination of
these mutations makes the viral vector selectively replicate in dividing cells,
such as cancer cells, and CPG2 acts on a prodrug such as CMDA to produce
an active chemotherapeutic agent.
Springer discloses “a two component system for gene-directed
enzyme prodrug therapy which comprises: (a) a vector which encodes a
carboxypeptidase which is expressed within a cell; and (b) a prodrug which
can be converted into an active drug by said carboxypeptidase.” Springer
1:46–50. Springer states that “[t]he enzyme is preferably a bacterial
carboxypeptidase, especially carboxypeptidase CPG2 (SEQ ID No. 1).” Id.
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at 1:50–52. The Examiner finds, and Appellant does not dispute, that
Springer’s SEQ ID No. 1 is 98.2% identical to the SEQ ID NO: 2 recited in
the instant claims. Final Action 7, Appeal Br. 5–12.
Springer discloses that its vector is useful in “a method of treating a
tumour in a patient in need of treatment which comprises administering to
said patient an effective amount of a vector encoding a carboxypeptidase and
a prodrug capable of being converted by said enzyme to an active drug.” Id.
at 1:59–63. Preferred prodrugs include CMDA and N-(4-[bis(2-
iodoethyl)amino]phenoxycarbonyl)-L-glutamic acid, as recited in instant
claim 37. Id. at 6:44–57.
Thus, based on the cited references, it would have been obvious to use
the CPG2 gene disclosed by Springer in McCart’s vaccinia virus vector,
because McCart expressly suggests using a CPG2 gene in its vector and
Springer discloses that its CPG2 gene is useful in making a vector to be
used, in combination with a prodrug, for treating tumors in patients.
Appellant argues that “the Examiner has . . . conclud[ed] that
motivation exists based on nothing beyond the mere presence of the
elements pulled from the separate references.” Appellant argues that
Springer et al. employ a different viral vector. . . . [T]he MLV
utilized by Springer et al. and the other ‘suitable viral vectors’
. . . are all retroviruses. Where Springer et al. discuss other
viral vectors . . . , adenovirus based vectors, not poxvirus
vectors of any kind are considered. Therefore, the types of viral
vectors envisaged by Springer et al. are all unrelated to the
vaccinia based vectors used by McCart.
Appeal Br. 7. Appellant argues that
McCart et al. describe no less than 18 different vaccinia vector
constructs in Table 1 . . . , 16 different enzyme/prodrug
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systems in Table 2 . . . , and thousands of genes for expression
in the vector . . . , while Springer et al. do not teach use of any
vaccinia vector for the expression of CPG2.
Id. at 9. Appellant argues that “the Office has failed to provide an objective
reason why one of skill in the art would have, not merely could have,
combined or modified the teachings of the cited art.” Id.
These arguments are not persuasive. McCart discloses that its vaccinia
virus vector has the benefit of replicating selectively in dividing cells, and
that it is useful in prodrug therapy when a suicide gene such as CPG2 is
cloned into it. Springer discloses that its specific CPG2 gene is useful in
combination with a prodrug for providing gene-directed enzyme prodrug
therapy. The combined teachings of the cited references thus would have
provided ample reason to combine Springer’s CPG2 gene with McCart’s
vaccinia virus vector.
With regard to the specific disclosures in McCart that Appellant
points to, we note that Table 1 is a list of vaccinia virus shuttle vectors
disclosed to be useful in making McCart’s expression vector (McCart 6:30–
37); Table 2 includes the carboxypeptidase G2/CMDA system as an
example of one that can be used with McCart’s vector (id. at 14:15–16); and
the “thousands of genes” that Appellant points to are disclosed as
“[e]xamples of genes expressable [sic] by the vaccinia virus expression
vector,” not as genes that are useful as suicide genes in combination with
prodrugs (id. at 14:64–65).
Appellant also argues that
[t]he Declaration of Dr. John Bell filed on 6/30/17, a renowned
expert in this field, makes clear that the presently claimed
methods employing a vaccinia vector system provided an
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unexpected increased efficacy in tumor cell killing when
compared to the viral system employed by Springer. . . . This
finding was wholly unexpected and cannot be gleaned from the
combined disclosures in McCart and Springer.
Appeal Br. 8.
We have considered the Bell Declaration but conclude that it does not
provide persuasive evidence of nonobviousness. “To be particularly
probative, evidence of unexpected results must establish that there is a
difference between the results obtained and those of the closest prior art, and
that the difference would not have been expected by one of ordinary skill in
the art at the time of the invention.” Bristol-Myers Squibb Co. v. Teva
Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014).
Appellant asserts that the Bell Declaration shows “an unexpected
increased efficacy in tumor cell killing when compared to the viral system
employed by Springer.” Appeal Br. 8. However, as Appellant acknowledges,
“Springer et al. teach that the system disclosed can be employed in several
different types of viral vectors. However, . . . all data presented relate to use
of an MLV vector system.” Id. at 6. “[T]he MLV utilized by Springer et al.
and the other ‘suitable viral vectors’ . . . are all retroviruses.” Id. at 7. Thus,
the closest prior art to the claimed combination of the CPG2 enzyme of SEQ
ID NO: 2 in a vaccinia virus vector is Springer’s exemplified retroviral
MLV-based vector comprising a CPG2 enzyme that is 98.2% identical to
SEQ ID NO: 2. See Springer 16:25–62, 18:21–34.
The Bell Declaration, however, compares a CPG2-expressing vaccinia
virus vector with a CPG2-expressing adenoviral vector. Bell Decl. ¶ 6.
Appellant has not persuasively explained why the adenoviral vector used in
the experiments of the Bell Declaration should be considered to be a better
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model for comparison to the claimed vector than the MLV-based vector
exemplified by Springer.
In addition, McCart discloses that its double mutant (TK-, VGF-)
vaccinia virus expression vector inhibits the growth of tumor cells even
when it is only expressing a reporter gene. Specifically, McCart discloses
that the construct “VVDDEGFP (TK- and VGF-deleted expressing green
fluorescent protein)” (McCart 41:10–11) was injected into mice that had
previously been inoculated with cancer cells. Id. at 42:35–42. McCart found
that
animals administered a double mutant vaccinia virus of the
disclosed invention experience[d] little or no tumor volume
increase, as opposed to animals that received medium alone.
These results show that administration of a double mutant
vaccinia virus of the disclosed invention to a tumor bearing-
host animal can significantly impact tumor growth in that host.
Id. at 42:48–54.
In view of this disclosure, the observation of “sustained reduction of
tumour volume that was achieved by the CPG2-expressing vaccinia, in
conjunction with prodrug” attested to by Dr. Bell, which Dr. Bell contends
“indicate[s] a strong synergy between the oncolytic effect of the vaccinia
vector and the CPG2-prodrug system” (Bell Decl. ¶ 6), would seem to have
been an expected tumor volume reduction, since both the vaccinia vector
itself and the active agent produced by CPG2 acting on a prodrug were
known to inhibit tumor cell growth. See Pfizer, Inc. v. Apotex, Inc., 480 F.3d
1348, 1371 (Fed. Cir. 2007) (“[B]y definition, any superior property must be
unexpected to be considered evidence of non-obviousness. Thus, in order to
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properly evaluate whether a superior property was unexpected, the [fact-
finder] should have considered what properties were expected.”).
With respect to claim 37, Appellant argues that “McCart et al. are
silent regarding use of ZD2767P as the prodrug.” Appeal Br. 5. Appellant
argues that
McCart et al. note that certain prodrug combinations can have
undesirable bystander cytotoxic effects on neighboring cells
(col. 13, L5–10). Appellants submit that the skilled person
would not be motivated to substitute the more potent mustard
precursor such as ZD2767P in the clinical setting of the type
disclosed by McCart et al. due to higher risk of undesirable
cellular toxicity on non target cells.
Id. at 10. Similarly, Appellant argues that
the skilled person would not be motivated to substitute the more
potent mustard precursors such as ZD2767P in the clinical
setting of the type disclosed by McCart et al. due to higher risk
of vaccinia virus inactivation and associated reduction in
therapeutic efficacy. The requisite expectation of success
cannot be found in this combination of references as the art
teaches that vaccinia viral replication is highly sensitive to
nitrogen mustard exposure.
Id.
These arguments are also unpersuasive. With regard to the “bystander
effect,” the passage cited by Appellant pertains to the enzyme/prodrug
combination of xanthine-guanine phosphoryltransferase (gpt) and 6-
thioxanthine (6-TX). See McCart 12:57 to 13:10. Appellant has not pointed
to any disclosure of a bystander effect caused by the action of CPG2 on a
prodrug. In any event, McCart implies that a bystander effect is an
advantage, rather than being undesirable. See id. at 10:28–35 (“These studies
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highlight several advantages of the PNP system. . . . Thirdly, 6-MP is freely
diffusible across cell membranes leading to a strong bystander effect.”)
With regard to the risk of inactivation of vaccinia virus by ZD2767P,
Appellant has not pointed to any evidence supporting the position that “the
art teaches that vaccinia viral replication is highly sensitive to nitrogen
mustard exposure.” Appeal Br. 10. The argument based on that assertion is
therefore unpersuasive.
For the reasons discussed above, we affirm the rejection of claims 32
and 37 under 35 U.S.C. § 103 based on McCart and Springer. Claims 33–36,
46, 47, 56, and 57 fall with claims 32 and 37 because they were not argued
separately. 37 C.F.R. § 41.37(c)(1)(iv).
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
32–37, 46,
47, 56, 57
103 McCart, Springer 32–37, 46,
47, 56, 57

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). See 37 C.F.R.
§ 1.136(a)(1)(iv).
AFFIRMED