Parry Guilford et al.

Patent Trials and Appeals Board

Dec 29, 2020

2020005169 (P.T.A.B. Dec. 29, 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.
11/658,220 03/30/2009 Parry John Guilford PEBL-01012US2 3985
66936 7590 12/29/2020
BORSON LAW GROUP, PC
1078 CAROL LANE, #200
LAFAYETTE, CA 94549
EXAMINER
DENT, ALANA HARRIS
ART UNIT PAPER NUMBER
1643
MAIL DATE DELIVERY MODE
12/29/2020 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 PARRY JOHN GUILFORD,
NATALIE JANE KERR, and ROBERT CRAIG POLLOCK
Appeal 2020-005169
Application 11/658,220
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, 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 39, 40, and 50–52. We have
jurisdiction under 35 U.S.C. § 6(b).
We REVERSE and enter new grounds of rejection as to claims 50 and
52.

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 Pacific
Edge Limited. Appeal Br. 3.
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Application 11/658,220

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STATEMENT OF THE CASE
“[D]evelopments that lead to early diagnosis of bladder cancer can
lead to an improved prognosis for . . . patients.” Spec. 1:26–27. The
Specification states that, “[a]t present, the most reliable method for detecting
bladder cancer is cystoscopy accompanied by histology of biopsied lesions,”
but “this technique is time consuming, invasive, and . . . sensitivity [of] only
approximately 90%.” Id. 2:7–10. The Specification states that, “urine
cytology, which detects exfoliated malignant cells microscopically,” is the
current preferred non-invasive method for detecting bladder cancer but “has
poor sensitivity (9–25%) for low-grade lesions, is extremely dependent on
sample quality and suffers from high inter-observer variability.” Id. at 2:10–
14. The Specification states that more recently microarray analysis has been
used to identify “a number of putative markers for bladder cancer.
However, array technology is relatively non-quantitative and is highly
variable.” Id. at 2:16–21.
According to the Specification, “[t]he detection of blood or urine
markers that indicate the presence of bladder cancer provides one potential
method for the improved detection of this disease,” but “little progress has
been made developing blood markers for bladder cancer.” Spec. 2:22–24.
Further according to the Specification, while “several urine protein markers
are available[, t]ests for these markers . . . tend to suffer from sub-optimal
specificity because elevated levels of these markers are also commonly
observed in patients with non-malignant diseases.” Id. at 2:25–29. Finally,
the Specification states that, while RT-PCR amplification of gene transcripts
in urine samples “offer[s] the potential of high sensitivity, . . . the specificity
of existing RT-PCR markers remain unclear.” Id. at 2:32–3:2.
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The Specification states that “[t]here is a need for further tools for the
early detection and diagnosis of cancer” and states that the invention “relates
to use of oligonucleotide, protein, and/or antibody markers in the urine for
detection, typing and staging of bladder cancer.” Id. at 1:18–19.

CLAIMED SUBJECT MATTER
The claims are directed to a polymerase chain reaction (PCR) based
kit for detecting bladder cancer. Claim 39 is illustrative:
39. A polymerase chain reaction (PCR) based kit for
detecting bladder cancer, consisting of a forward primer, a
reverse primer, and a labeled probe for each of the markers,
sperm associated antigen 5 (SPAG5), topoisomerase (DNA) II
alpha 170kDa (TOP2A), cell division cycle 2, G1 to S and G2
to M (CDC2), endoglin (Osler-Rendu-Weber syndrome 1)
(ENG), insulin-like growth factor binding protein 5 (IGFBP5),
nephroblastoma overexpressed gene (NOV), neuropilin 1
(NRP1), sema domain, immunoglobulin domain (Ig), short
basic domain, secreted, (semaphorin) 3F (SEMA3F), EGF-like-
domain, multiple 6 (EGFL6), matrix Gla protein (MGP),
semaphorin (SEM2), chromogranin A (parathyroid secretory
protein 1) (CHGA), Thy-1 cell surface antigen (THY1),
ubiquitin-conjugating enzyme E2C (USE2G), homeo box A13
(HOXA13), midkine (neurite growth-promoting factor 2)
(MDK), baculoviral IAP repeat-containing 5 (survivin)
(BIRC5), and SMC4 structural maintenance of chromosomes 4-
like 1 (yeast) (SMC4L1); and
solutions for mixing reagents; and
reaction chambers for carrying out PCR amplification of
each marker.
Appeal Br. 14 (Claims App.).

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EXAMINER’S REJECTION
Claims 39, 40, and 50–52 are rejected under pre-AIA 35 U.S.C.
§ 103(a) as being unpatentable over Orntoft,2 Clarke,3 Nakamura,4 Keifer,5
and Randazzo.6

OPINION
A. Obviousness rejection over Orntoft, Clarke, Nakamura, Keifer and
Randazzo (claims 39, 40, and 50–52)
1. Issue
The Examiner finds that
Orntoft teaches a multitude of urinary bladder tumor
markers (UBTM) including ubiquitin-conjugating enzyme
(USE2G); human chromogranin A; human DNA topoisomerase
II (TOP2A); human insulin-like growth factor binding protein 5
(IGFBP5); human Thy-1 glycoprotein (THY1); homeobox A13
(HOXA13); human cdc2-related protein kinase (CDC2); human
semaphorin III family homolog or sema domain,
immunoglobulin domain (Ig), short basic domain, secreted
(SEMA3F); matrix Gla protein (MGP); endoglin (Osler-Rendu-
Weber syndrome I) (ENG); nephroblastoma overexpressed
gene (NOV), and their assessment on oligonucleotide arrays.
Ans. 3 (citations omitted).

2 Orntoft, US 2004/0038207 A1, published Feb. 26, 2004.
3 Clarke et al., US 2006/0019256 A1, published Jan. 26, 2006.
4 Nakamura et al., US 2009/0175844 A1, published July 9, 2009.
5 Keifer, WO 92/12243, published July 23, 1992.
6 Randazzo et al., WO 2005/000087 A2, published Jan. 6, 2005.
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The Examiner finds that Orntoft does not teach the following markers
in a PCR kit with specific primers for the markers: “sperm associated
antigen 5 (SPAG5); neuropilin 1 (NRP 1); EGF-like-domain, multiple 6
(EGFL6); midkine (neurite growth-promoting factor 2) (MDK); baculoviral
IAP repeat-containing 5 (survivin) (BIRC5); and SMC4 structural
maintenance of chromosomes 4-like 1 (yeast) (SMC4L1) within a
polymerase chain reaction (PCR) kit comprising specific primers for said
candidate bladder cancer markers.” Ans. 3. However, the Examiner finds
that “Clarke teaches additional cancer biomarkers that can be assessed using
PCR,” including EGFL6, THY1, NRP1, SMC4L1, BIRC5, and SPAG5. Id.
at 4. The Examiner finds that “Nakamura also teaches additional bladder
cancer biomarkers assessed using PCR within a kit,” including “#1 BIRC5;
#21 MDK; and #225 sema domain, immunoglobulin domain (Ig), short basic
domain, secreted, (semaphorin) 3F.” Id. (citations omitted).
Finally, the Examiner cites to Kiefer as teaching “PCR reactions
performed with a kit including instructions for using PCR primers,” as well
as “agents required to detect biomarkers.” Ans. 4. The Examiner further
cites to Kiefer and Randazzo as teaching specific PCR primer and probe
sequences recited in one or more of the dependent claims on appeal. Id.
The Examiner concludes that
[i]t would have been prima facie obvious to one of ordinary
skill in the art at the time the claimed invention was made to
combine the teachings of the references that read on all of the
components of the claimed kit. One of ordinary skill in the art
would have been motivated to implement the teachings of all
the references to generate gene expression profiles with
microarrays, tailor primers to specific sizes and include
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necessary reagents in a kit to assess candidate bladder cancer
biomarkers.
Ans. 4–5.
Appellant contends that, while Orntoft, Clarke, and Nakamura each
discloses long lists of genetic markers for, e.g., bladder cancer, none of the
references “disclose any of the combinations of markers claimed to detect
bladder cancer” or “provide any specific guidance that would lead a person
of skill to select the claimed combinations.” Appeal Br. 6–7. Accordingly,
Appellant contends that the Examiner failed to articulate a reason a skilled
artisan would have selected the claimed combination of markers based on
the cited references. Id. at 8–12. Appellant further contends that the
rejection is based on “impermissible hindsight reconstruction.” Id. at 12.
The issue with respect to this rejection is whether a skilled artisan
would have had a reason to combine the cited references to arrive at a kit
consisting of, among other things, a labeled probe for each of the markers
recited in the claims.
2. Analysis
On balance, we agree with Appellant that the Examiner has not
established a prima facie case of obviousness with respect to claim 39.
The Examiner cites to Orntoft for teaching urinary bladder tumor
markers including, among others, endoglin (Osler-Rendu-Weber syndrome
1) (ENG), insulin-like growth factor binding protein 5 (IGFBP5), and homeo
box A13 (HOXA13). We are not persuaded, however, that the Examiner has
shown that Orntoft teaches that these genes are in fact expressed in and/or
useful for detecting bladder cancer.
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In particular, the Examiner cites to Table 87 of Orntoft (pp. 211, 100,
and 119 respectively) for disclosing these markers. Ans. 3. Orntoft
describes Table 8 as showing “gene expression in bladder cancer from
different stages of the disease” and further states that “[g]enes identified as
being up and/or down regulated at least two fold during the change from
normal urothelium via superficial disease to invasive cancer can be used for
staging, grading, prognosis, prescription” and that “[a]n intensity value of 21
or greater indicates expression of the gene.” Orntoft ¶ 48.
As shown on pages 211 and 119 of Orntoft, however, the genes the
Examiner cites to as ENG and HOXA138 appear to have expression
intensities of 20 in all tissues for which values are reported (i.e.,
suburothelial connective tissue, normal urothelium, and transitional cell
carcinoma stages Ta-GrI, Ta-GrII, T2-GrIII, and T2-GrIV). Based on
Orntoft’s teaching cited above, therefore, it would appear that ENG and
HOXA13 are not expressed in either normal urothelium or in bladder cancer
cells. The Examiner does not explain why, given their apparent lack of

7 The table set forth on pages 57–230 of Orntoft is not labeled. However, we
understand this table to be Table 8, both because the table appears as the
eighth table in Orntoft (between a table labeled as Table 6 and a table
labeled as Table 10,) and because it appears to match the description of
Table 8 in paragraph 48 of Orntoff.
8 The Examiner cites to page 119 of Orntoft as disclosing HOXA 13. The
only homeobox (HOX) gene referenced on this page is “Homo sapiens
homeobox protein (HOX-1 3) ‘gene,’ complete cds.” Orntoft 119. Thus,
although there are other homeobox genes listed in Table 8, including those
with up regulated expression in cancer cells, see, e.g., Orntoft 95 (Homo
sapiens homeobox protein (HOX) ‘gene,’ 3’ end), we understand the
Examiner to be relying on the HOX-1 3 disclosed on Orntoft pg. 119 for the
disclosure of the HOXA 13 marker recited in claim 39.
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expression in (as well as lack of change in expression between) normal
urothelium and bladder cancer cells, a skilled artisan would have included
labeled probes for these two markers in a kit.
Similarly, page 100 of Orntoft reports the intensity value for IGFBP5
expression to be 20, 35, 65, 20, 20, and 20 in, respectively, suburothelial
connective tissue, normal urothelium, and transitional cell carcinoma stages
Ta-GrI, Ta-GrII, T2-GrIII, and T2-GrIV. While IGFBP5 expression does
appear to be up regulated in cancer stage Ta-GrI and down regulated in
cancer stages Ta-GrII, T2-GrIII, and T2-GrIV as compared to IGFBP5
expression in normal urothelium, the expression does not appear to be “up
and/or down regulated at least two fold.” The Examiner does not explain
why a skilled artisan would include labeled probe for IGFBP5 given that
Orntoft teaches that genes that can be used for “staging, grading, prognosis,
and prescription” are those that are “up and/or down regulated at least two
fold during the change from normal urothelium via superficial disease to
invasive cancer.”9 Orntoft ¶ 48

9 While we do not rely on the below in reversing the rejection, we note that
the Examiner cited pages 214 and 219 of Orntoft as disclosing NOV as a
marker. Ans. 3. Page 214 of Orntoft teaches H. sapiens nov gene 1 /gb =
X80923 as having expression intensities of 48, 32, 52, 41, 54, and 69 in,
respectively, suburothelial connective tissue, normal urothelium, and
transitional cell carcinoma stages Ta-GrI, Ta-GrII, T2-GrIII, and T2-GrIV.
Orntoft 214. Thus, on this page at least, Orntoft does appear to teach the
nov gene as up-regulated at least two fold in cancer stage T2-GrIV as
compared to normal urothelium and thus useful for bladder cancer “staging,
grading, prognosis, and prescription.” Orntoft ¶ 48. However, page 219 of
Orntoft, also cited by the Examiner, suggests that the expression intensity for
“H. sapiens mRNA for NOV protein” was 20 (i.e., not expressed) in all
tissues tested. Orntoft 219. The Examiner does not explain how the latter
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Accordingly, for the reasons stated above, we reverse the Examiner’s
rejection of claim 39 as obvious over Orntoft, Clarke, Nakamura, Kiefer, and
Randazzo.10 Because each of claims 40 and 50–52 also appear to recite a
labeled probe for at least HOXA13, discussed above, we also reverse the
obviousness rejection of these claims for the same reasons.
B. New grounds of rejection
Under the provisions of 37 C.F.R. § 41.50(b), we enter the following
new grounds of rejection:
We reject claims 50 and 52 under 35 U.S.C. § 112, fourth paragraph
as being of improper dependent form.
We reject claims 50 and 52 under 35 U.S.C. § 112, second paragraph
as indefinite.
1. Improper dependency
The fourth paragraph of 35 U.S.C. § 112 (pre-AIA) states that “a
claim in dependent form shall contain a reference to a claim previously set
forth and then specify a further limitation of the subject matter claimed,” and

teaching would lead a skilled artisan to include the NOV marker in the
claimed kit.
10 The Examiner cites to Kiefer (relating to IGFBP6) and Randazzo as
disclosing, respectively, SEQ ID NO: 31 and SEQ ID NO: 36, which
according to the Specification are probes. Spec. 13:21–33. However, the
Examiner does not assert that these sequences are probes for specific
markers such as ENG, HOXA13, or IGFBP5. Thus, we understand the
Examiner to rely only on Orntoft for the disclosures of these markers. As
discussed above, we do not find Orntoft’s disclosures sufficient to establish
a prima facie case that a skilled artisan would have found it obvious to
include these markers in a kit as claimed.
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“shall be construed to incorporate by reference all the limitations of the
claim to which it refers.” 35 U.S.C. § 112 (pre-AIA), fourth paragraph.
Claim 39, which is set forth above and the only independent claim on
appeal, recites a kit consisting of 18 markers.
Dependent claims 50 claims “[t]he kit of Claim 39, said markers
consisting of CDC2, IGFBP5, HOXA13, and MDK.” Appeal Br. 15
(Claims App.). CDC2, IGFBP5, HOXA13, and MDK is a subset of the
markers recited in claim 39. Claim 50 thus appears to exclude markers
recited in claim 39, a claim from which it depends. Because a dependent
claim must incorporate all the limitations of the claim to which it refers and
then specify a further limitation of the subject matter claimed, claim 50 is in
improper dependent form.
Likewise, dependent claim 52 depends from claim 51, which depends
from claim 40, which in turn depends from claim 39. Both claims 40 and 51
are thus construed to incorporate all the limitations of claim 39, including a
labeled probe for each of the 18 markers enumerated in claim 39.11
Claim 52, however, recites “[t]he kit of claim 51, further consisting
of a forward primer, a reverse primer, and a labeled probe specific for each

11 Claim 40 recites the kit of claim 39, wherein “at least two . . .
combinations of oligonucleotides . . . are selected from the group consisting
of” an enumerated set of three-oligonucleotide combinations. Appeal Br.
14–15 (Claims App.). Claim 51 depends from claim 40 and further recites
that “said combinations of three oligonucleotides are selected from the group
consisting of” two sets of three oligonucleotides. Id. at 15. Although claim
39 does not recite the phrase “oligonucleotides,” we understand based on the
Specification that the sets of three-oligonucleotide combinations recited in
claims 40 and 51 are sets including, respectively, a forward primer, a reverse
primer and a probe. Spec. 13:21–33.
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of the markers HOXA13 and MDK.” Appeal Br. 15–16 (Claims App.). As
discussed above, HOXA13 and MDK is only a subset of the markers recited
in claim 39. Thus, as with claim 50, claim 52 appears to exclude markers
recited in claim 39 and incorporated by reference in claim 51 (i.e., the claims
from which it depends). Because a dependent claim must incorporate all the
limitations of the claim to which it refers and then specify a further
limitation of the subject matter claimed, claim 52 is in improper dependent
form.
2. Indefiniteness
As discussed above, dependent claims are construed to incorporate all
of the limitations of the claim to which they refer. Thus, both claims 50 and
52 are construed to require a labeled probe for each of the 18 markers recited
in claim 39. However, claims 50 and 52 both recite a kit “consisting of,”
among other things, a labeled probe for a smaller set of markers. The
requirement that claims 50 and 52 incorporate all limitations of claim 39, on
the one hand, and the use of the closed transitional phrase “consisting of” in
dependent claims 50 and 52 in connection with only a subset of the 18
markers recited in claim 39, on the other hand, results in an ambiguity as to
what labeled probes may be included in the kits of these dependent claims.
Accordingly, we also set forth a new ground of rejection under pre-AIA 35
U.S.C. § 112, second paragraph, for dependent claims 50 and 52, as being of
indefinite scope.

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CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/
Basis
Affirmed Reversed New
Ground
39, 40,
50–52
103(a) Orntoft,
Clarke,
Nakamura,
Keifer,
Randazzo
39, 40,
50–52

50, 52 112 Indefiniteness 50, 52
50, 52 112 Improper
dependency
50, 52
Overall
Outcome
39, 40,
50–52
50, 52

TIME PERIOD FOR RESPONSE
This decision contains new grounds of rejection pursuant to 37 C.F.R.
§ 41.50(b). Section 41.50(b) provides “[a] new ground of rejection pursuant
to this paragraph shall not be considered final for judicial review.” Section
41.50(b) also provides:
When the Board enters such a non-final decision, the appellant,
within two months from the date of the decision, must exercise
one of the following two options with respect to the new ground
of rejection to avoid termination of the appeal as to the rejected
claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating
to the claims so rejected, or both, and have the matter
reconsidered by the examiner, in which event the prosecution
will be remanded to the examiner. The new ground of rejection
is binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the
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opinion of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the
claims, appellant may again appeal to the Board pursuant to this
subpart.
(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure § 1214.01.

REVERSED; 37 C.F.R. § 41.50(b)