City of Hope

Patent Trials and Appeals Board

Mar 18, 2021

2021002450 (P.T.A.B. Mar. 18, 2021)

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.
14/978,590 12/22/2015 Don J. Diamond 048440-532N01US 7205
64046 7590 03/18/2021
Mintz Levin/San Diego Office
One Financial Center
Boston, MA 02111
EXAMINER
PAPCIAK, SHARON M
ART UNIT PAPER NUMBER
1651
NOTIFICATION DATE DELIVERY MODE
03/18/2021 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):
IPDocketingBOS@mintz.com
IPFileroombos@mintz.com
mintzdocketing@cpaglobal.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DON J. DIAMOND and EDWIN MANUEL1
Appeal 2021-002450
Application 14/978,590
Technology Center 1600
Before ERIC B. GRIMES, ROBERT A. POLLOCK, and TAWEN CHANG,
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 or stimulating the immune system in a subject,
which have been rejected as obvious. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 Appellant identifies the real party in interest as City of Hope. Appeal Br. 2.
We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R.
§ 1.42.
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Application 14/978,590

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STATEMENT OF THE CASE
The Specification states that “[o]verexpression of indoleamine 2,3-
dioxygenase (IDO) in PDAC [pancreatic ductal adenocarcinoma] plays a
major role in accelerating disease progression by suppressing antitumor
immunity.” Spec. ¶ 2. The Specification also states that “[s]hIDO-ST is a
Salmonella typhimurium (ST) cell that expresses a small hairpin (sh)RNA to
specifically silence indoleamine-pyrrole 2,3-dioxygenase (IDO) with
decreased toxicity.” Id. ¶ 55.
The Specification states that “the term ‘tumor penetrating agent’
refers to an agent that is capable of penetrating a tumor and/or a tumor
cell. . . . By way of example, a tumor penetrating agent penetrates a tumor
by breaking down or degrading the extracellular matrix surrounding tumor
cells.” Id. ¶ 25. Hyaluronidase polypeptides are an example of tumor
penetrating agents. Id.
The Specification states that “the combination of pegylated
recombinant human hyaluronidase PH20 . . . and shIDO-ST resulted in
effective control of and, in some cases, complete elimination of established
pancreatic tumors in autochthonous and orthotopic models.” Id. ¶ 55.
Claims 1–5, 8, 9, 11, 12, 14, 15, 18, 42, and 43 are on appeal.
Claims 1 and 3, the independent claims, are illustrative and are reproduced
below:
1. A method of treating cancer in a subject
comprising administering to the subject a combined effective
amount of a bacterial cell and a tumor penetrating agent,
wherein administration treats the cancer in the subject, wherein
the tumor penetrating agent is a hyaluronidase polypeptide,
wherein the combined effective amount is effective to increase
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tumor penetration by the bacterial cell relative to absence of the
tumor penetrating agent, and wherein said tumor penetrating
agent is not expressed by said bacterial cell, wherein the tumor
penetrating agent is formulated in combination with a
pharmaceutically acceptable carrier.
3. A method of stimulating an immune system in a
subject comprising administering to the subject a combined
effective amount of a bacterial cell and a tumor penetrating
agent, wherein administration of the bacterial cell and the tumor
penetrating agent stimulates the immune system of the subject,
wherein the tumor penetrating agent is a hyaluronidase
polypeptide, and wherein the combined effective amount is
effective to increase tumor penetration by the bacterial cell
relative to absence of the tumor penetrating agent, wherein said
tumor penetrating agent is not expressed by said bacterial cell,
wherein the tumor penetrating agent is formulated in
combination with a pharmaceutically acceptable carrier.

Appeal Br. 15 (Claims Appendix).
OPINION
Claims 1–5, 8, 9, 11, 12, 14, 15, 18, 42, and 43 stand rejected under
35 U.S.C. § 103 as obvious based on Xu,2 Frost,3 and Bookbinder.4 Ans. 5.5
The Examiner finds that Xu discloses a method “for inhibiting growth or
reducing the volume of a solid tumor cancer comprising administering an
effective amount of an attenuated Salmonella sp. . . . expressing a short

2 Xu et al. (US 2009/0208534 A1, published August 20, 2009).
3 Frost et al. (WO 2009/128917 A2, published October 22, 2009).
4 Bookbinder et al. (US 2009/0123367 A1, published May 14, 2009).
5 The Examiner also cites evidence provided by a BLAST sequence
alignment, but this evidence is only relevant to the SEQ ID Nos recited in
claim 18. Ans. 5, 7.
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hairpin (sh) RNA [that] is capable of inhibiting the growth or reducing the
volume of the solid tumor cancer (shRNA-Stat3).” Id.
The Examiner acknowledges that Xu does not disclose hyaluronidase
as a tumor penetrating agent or increased anti-cancer or immune-stimulation
activity by the combination of a bacterial cell and hyaluronidase. Id. at 7–8.
However, the Examiner finds that Frost discloses that “the introduction of
soluble hyaluronidases to tumor interstitia would enhance delivery of locally
and systemically delivered anti-cancer agents which can more readily
penetrate the tumor.” Id. at 8. The Examiner also finds that Frost discloses
that “[t]he co-administration of pegylated rHuPH20 [hyaluronidase PH20]
with a chemotherapeutic agent can increase the anti-tumor activity of the
therapeutic agent compared to when the therapeutic agent is administered
alone.” Id. at 9.
The Examiner finds that Bookbinder teaches “soluble enzymes that
are members of the hyaluronidase glycoprotein family (sHASEGPs).” Id.
The Examiner finds that Bookbinder teaches that sHASEGPs “would
enhance delivery of anti-cancer agents which can more readily penetrate the
tumor when . . . diffusion and/or convective transport [is] increased.” Id.
“[T]he effects of diffusion were greatest with particles less than about
500nm in diameter.” Id. at 10. The Examiner finds, however, that
Bookbinder also teaches that when “larger pores or channels are desired,
sHASEGP . . . can be combined with relatively pure forms of other matrix-
degrading enzymes to facilitate further spreading of larger size
macromolecular complexes or cells.” Id.
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The Examiner concludes that it would have been obvious to modify
Xu’s method of treating cancer “by administering to the subject an effective
amount of the bacterial cell Salmonella expressing an antisense nucleic acid
. . . by adding a tumor penetrating agent such as hyaluronidase . . . as shown
by Frost.” Id. The Examiner reasons that Frost shows that hyaluronidase
“increas[es] tissue permeability,” and therefore “contacting tumor tissue
with exogenous hyaluronidase and an anti-tumor agent . . . would increase
the permeability of the ECM [extracellular matrix] to said anti-tumor agent.”
Id. at 11.
The Examiner also notes that Bookbinder “shows a method for
reducing and/or treating tumors using hyaluronidase polypeptides and a
variety of other anti-cancer agents.” Id. The Examiner finds that
“Bookbinder et al. teaches that there is an expectation that particles which
are greater than 500nm in diameter, such as (bacterial) cells, could readily
penetrate tumor tissue if other (EC)matrix-degrading enzymes were
combined with the specific form of hyaluronidase (i.e., sHASEGP) shown in
Bookbinder et al.” Id.
Appellant argues that Xu does not teach any tumor penetrating agents,
while Frost only teaches combining hyaluronidase with small molecule
drugs, and “fails to provide a reasonable expectation that any enhancement
would be achieved for much larger agents, such as a bacterial cell.” Reply
Br. 4–5.6

6 In the Answer, the Examiner withdrew the pending rejections and entered a
new ground of rejection. Ans. 3–4. Appellant responded to the new ground
of rejection in the Reply Brief.
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Appellant also argues that “Bookbinder repeatedly emphasizes what
was believed to be an ‘upper limit’ to the size of molecules whose diffusion
could be enhanced by hyaluronidase, and repeatedly refers to 500 nm as that
upper limit. Bookbinder also expressly states that the ‘pores’ opened by
hyaluronidase are not large enough to promote movement of cells.” Id. at
6. Appellant argues that, “[a]s such, a person of ordinary skill in the art
would have had no reason to combine a hyaluronidase polypeptide with a
bacterial cell in general, or the Salmonella cells of Xu et al. in particular.
Moreover, one of ordinary skill in the art would have had no reasonable
expectation of success.” Id.
Finally, Appellant cites the Diamond Declaration7 as evidence
showing skepticism by an expert regarding the claimed invention. Reply Br.
9–10. “Specifically, an expert reviewing a grant application proposing
experiments to test the effect of a hyaluronidase polypeptide (PEGPH20) on
anti-cancer activity of a Salmonella typhimurium (ST) bacteria expressly
doubted whether hyaluronidase would have any beneficial effect on delivery
due to the size of bacteria.” Id. at 10.
We agree with Appellant that a preponderance of the evidence of
record does not show that a skilled artisan would have reasonably expected
administration of Xu’s bacterial cell together with a hyaluronidase to result
in “the combined effective amount [being] effective to increase tumor
penetration by the bacterial cell relative to absence of the” hyaluronidase, as
required by the claims.

7 Declaration under 37 C.F.R. § 1.132 of Don J. Diamond, filed March 7,
2019.
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Xu discloses “a method of inhibiting the growth . . . of a solid tumor
cancer comprising administering an effective amount of an attenuated
Salmonella sp. to a patient . . . , wherein said attenuated Salmonella sp. is a
tumor targeting attenuated Salmonella sp. expressing a short hairpin (sh)
RNA.” Xu ¶ 5. Although, as the Examiner points out (Ans. 6), Xu discloses
that “Salmonella specifically home to the tumor” (Xu ¶ 34), Xu does not
disclose any tumor penetration agents for use with its therapeutic bacterial
cell.
Frost discloses “methods for treating hyaluronan-associated diseases
or conditions . . . [by] administering a hyaluronan degrading enzyme, such
as a hyaluronidase.” Frost 2:20–22. Hyaluronan-associated diseases include
hyaluronan-rich cancers such as solid tumors. Id. at 133:7–15. Frost suggests
“administration of the hyaluronan degrading enzyme in combination with
. . . a chemotherapeutic or other anti-cancer agent or treatment.” Id. at
147:30 to 148:1. Frost suggests numerous anti-cancer agents that can be
administered with a hyaluronan degrading enzyme, see id. at 148:16 to
152:28, but the Examiner has not identified any therapeutic cells in the list
of suggested agents.
Bookbinder discloses “members of the soluble neutral-active
Hyaluronidase Glycoprotein family (also referred to [t]herein as
sHASEGPs) . . . , particularly the human soluble PH-20 Hyaluronidase
Glycoproteins (also referred to [t]herein as rHuPH20s).” Bookbinder ¶ 20.
Bookbinder states that
sHASEGPs open channels in the interstitial space through
degradation of glycosaminoglycans that generally permit the
diffusion of molecules less than about 500 nm in size. . . . Such
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channels can be used to facilitate the diffusion of exogenously
added molecules such as fluids, small molecules, proteins,
nucleic acids and gene therapy vectors and other molecules less
than about 500 nm in size.
Id. ¶ 51. “The introduction of sHASEGPs to tumor interstitia would thus
tend to enhance the delivery of . . . anti-cancer agents which can more
readily penetrate the tumor when interstitial oncotic pressure is reduced and
diffusion and/or convective transport increased.” Id. ¶ 78.
In summary, Xu does not disclose any tumor penetrating agents that
would be suitable for use with its Salmonella bacteria and Frost suggests
combining a hyaluronidase with any of a variety of anti-cancer agents, but
does not suggest combining it with a therapeutic bacterial cell.
Bookbinder expressly suggests using a hyaluronidase (“sHASEGPs”)
to enhance delivery of anti-cancer agents to tumors. See Bookbinder ¶ 78.
As Appellant has pointed out (Reply Br. 5–6), however, Bookbinder
consistently emphasizes that hyaluronidase’s effect of enhancing delivery of
anti-cancer agents to tumors is limited to agents less than 500 nm in size. See
Bookbinder ¶ 51 (“molecules less than about 500 nm in size”), ¶ 533
(“These pores generally do not enhance the diffusion of substances greater
than about 200–500 nm in diameter.”); and ¶ 576 (“molecules and
macromolecular complexes ranging from less than about 10 nm to around
500 nm in diameter”).
With regard to therapeutic bacterial cells, Bookbinder states that
“sHASEGPs generally act to open channels that are substantially large
enough to permit the movement of most therapeutic and other
pharmacological agents of interest . . . and yet are generally not so large as
to promote the dislocation and movement of cells.” Bookbinder ¶ 533.
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Bookbinder teaches that a hyaluronidase “can be combined with . . . other
matrix-degrading enzymes such as collagenases to facilitate further
spreading of larger size macromolecular complexes or cells.” Id. ¶ 578.
However, as Appellant has pointed out (Reply Br. 8), both of the
independent claims require a combined amount of hyaluronidase and
bacterial cell that is “effective to increase tumor penetration by the bacterial
cell relative to absence of the tumor penetrating agent [hyaluronidase].” The
claim language therefore requires an amount of hyaluronidase, not some
other matrix-degrading enzyme, that is effective to increase tumor
penetration of the bacterial cell.
In short, none of the references cited by the Examiner would have
provided a skilled artisan with a reasonable expectation that administering a
combination of Xu’s bacterial cell and a hyaluronidase would provide
increased tumor penetration of the bacterial cell, relative to administration of
the bacterial cell by itself. Thus, the cited references do not provide a
reasonable expectation of success in practicing the claimed methods.
As further evidence that those of skill in the art would not have had a
reasonable expectation of success, Appellant cites the Diamond Declaration.
Dr. Diamond states that he applied for a grant from the National Institutes of
Health, “propos[ing] experiments including testing the effect of a
hyaluronidase polypeptide (PEGPH20) on anti-cancer activity of Salmonella
typhimurium (ST) bacteria.” Diamond Decl. ¶ 3. Dr. Diamond states that the
“Summary Statement released . . . [by] a review panel of over 20 experts”
included a critique from a member of the panel expressing “concern [that]
the effect of PEGPH20 on a large particle like ST is not well elucidated” and
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“stat[ing] that ‘it is questionable if PEGPH20 enhances the delivery of ST.’”
Id. ¶¶ 4–5; see also Decl., Exh. A.
The evidence provided by the Diamond Declaration supports the
disclosure in Bookbinder that hyaluronidase, by itself, would not have
reasonably been expected to increase tumor penetration of a Salmonella
bacterial cell. While the Declaration does not identify the individual who
provided the quoted critique, that person was asked to evaluate an NIH grant
application and therefore it is reasonable to conclude that this person’s
opinion is at least probative of the level of ordinary skill in the art. And the
critique expresses doubt regarding whether a hyaluronidase (“PEGPH20”)
would enhance delivery of therapeutic Salmonella bacteria (although the
reviewer noted that it might not matter, “since shIDO-ST is working in
prelim data without PH20”).
In summary, a preponderance of the evidence of record does not
support a reasonable expectation of successfully combining Xu’s Salmonella
bacteria with a hyaluronidase, and producing a “combined effective amount
[that] is effective to increase tumor penetration by the bacterial cell relative
to absence of the tumor penetrating agent [hyaluronidase],” as required by
the claims.
The Examiner reasoned that, because
Bookbinder et al. teaches that there is an expectation that
particles which are greater than 500nm in diameter, such as
(bacterial) cells, could readily penetrate tumor tissue if other
(EC)matrix-degrading enzymes were combined with the
specific form of hyaluronidase (i.e., sHASEGP) shown in
Bookbinder et al. . . . one of ordinary skill in the art of enzyme
biochemistry would understand that by increasing the
concentration of the hyaluronidase enzyme or by increasing the
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stability of the hyaluronidase enzyme there is a reasonable
expectation of success that pores could be introduced into the
tumor matrix that would allow the penetration of bacteria-sized
cells, in view of the teachings of Bookbinder et al.
Ans. 11–12 (emphasis added).
As Appellant has pointed out (Reply Br. 8), however, the Examiner
has not cited evidence supporting the position that a skilled artisan would
have expected that increasing the concentration or stability of hyaluronidase
in Bookbinder’s method would increase tumor penetration by Xu’s bacterial
cells. As the Examiner herself noted, Bookbinder expressly suggests
combining another matrix-degrading enzyme with hyaluronidase, not
increasing the hyaluronidase’s concentration or stability, in applications
where larger pores are desired. Ans. 11; Bookbinder ¶ 578. Because the
above-quoted rationale is unsupported by evidence, it does not show that
those skilled in the art would have had a reasonable expectation of
successfully practicing the claimed methods based on the cited references.
DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
1–5, 8, 9,
11, 12, 14,
15, 18, 42,
43
Xu, Frost, Bookbinder 1–5, 8, 9,
11, 12, 14,
15, 18, 42,
43

REVERSED