SANOFI

Patent Trials and Appeals Board

Dec 28, 2020

2020003259 (P.T.A.B. Dec. 28, 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.
15/414,722 01/25/2017 Jennifer DREYMANN 601667: SA9-238 3142
17387 7590 12/28/2020
Lathrop GPM LLP | Sanofi-Aventis
28 State Street
Boston, MA 02109
EXAMINER
ALLEN, MICHAEL D
ART UNIT PAPER NUMBER
1642
NOTIFICATION DATE DELIVERY MODE
12/28/2020 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):
bostonpatent@lathropgage.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JENNIFER DREYMANN,
CAROLINE PACCARD, and MARIELLE CHIRON-BLONDEL

Appeal 2020-003259
Application 15/414,722
Technology Center 1600
____________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
FRANCISCO C. PRATS, Administrative Patent Judges.

LEBOVITZ, Administrative Patent Judge.

DECISION ON APPEAL
The Examiner rejected claims 4, 7, 8, and 15 under 35 U.S.C. § 103 as
obvious and under non-statutory obviousness-type double patenting.
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s
decision to reject the claims. We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

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 Sanofi.
Appeal Br. 3.
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STATEMENT OF THE CASE
The claims stand rejected by the Examiner as follows:
Claims 4, 7, 8, and 15 under 35 U.S.C. § 103 as obvious in view of
Liu et al. (Cancer Medicine, 2013, 2(2): 234–242) (“Liu”), Castan (US
2014/0051642 A1, published Feb. 20, 2014) (“Castan”), and Compton et al.
(US 6,500,633 B1, published Dec. 31, 2002) (“Compton”). Ans. 3.
Claims 4, 7, 8, and 15 on the ground of non-statutory obviousness-
type double patenting as obvious in view of claims 1–10 and 12–21 of co-
pending Application No. 14/113,757 and Liu, Castan, and Compton. Ans. 7.
Claims 4, 7, 8, and 15 on the ground of non-statutory obviousness-
type double patenting as obvious in view of claims 1–16 of co-pending
Application No. 15/408,827 and Liu, Castan, and Compton. Ans. 7–8.
Application 15/408,827 has now issued as U.S. Patent 10,501,523.
Claim 4, the only independent claim on appeal, is reproduced below:
4. A method for treating a patient, wherein the patient has
colon cancer, a colorectal cancer or a rectal cancer, comprising
administering a therapeutically effective amount of ziv-
aflibercept to the patient, wherein a level of expression of a first
protein consisting of the amino acid sequence, SEQ ID NO: 1,
detected in a biological sample obtained from the patient is
lower than a reference level of expression of the first protein,
and wherein the biological sample is selected from the group
consisting of blood, serum, and plasma.
An oral hearing was held December 3, 2020. A transcript of the
hearing will be entered into the record in due course.

§ 103 REJECTION
The Examiner found that Liu describes measuring plasma levels of
VCAM-1 in patients having colorectal cancer who are treated with
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bevacizumab. Non-Final Act. 23.2 VCAM-1 is the same protein of SEQ ID
NO: 1 recited in claim 4 which is detected in a biological sample.
Bevacizumab “is a monoclonal antibody that specifically binds the
angiogenic factor VEGF-A, thereby inhibiting downstream signaling.” Liu
234. Liu also teaches that bevacizumab is used to treat colorectal cancer in
patients (“CRC”) (Liu 234), which is one of the diseases listed in claim 4.
The Examiner also found that Liu teaches that patients with VCAM-1
levels below a median value of 1000 ng/ml were classified as a low-risk
group and had longer overall survival (“OS”) than patients with levels above
this amount who were classified as a high-risk group and had a shorter
overall survival. Non-Final Act. 23. The Examiner found that Liu teaches
that patients with a “lower than a reference level of expression of the first
protein [SEQ ID NO: 1; VCAM-1]”, as recited in claim 4, had a better
outcome when treated with bevacizumab than patients with CRC treated
with bevacizumab who had VACM-1 levels above the reference level (the
“median” value in Liu).
The Examiner found that Liu does not teach treating CRC patients
with ziv-aflibercept (also referred to as “aflibercept”), the claimed protein
administered to cancer patients. Non-Final Act. 24. Aflibercept is a fusion
protein which binds to VEGF-A, VEGF-B, and PlGF. Spec. ¶ 22. To meet
this deficiency, the Examiner cited Castan for its teaching of treating
patients having CRC with aflibercept. Non-Final Act. 24. The Examiner

2 Non-Final Office Action, August 3, 2018. We cite the Non-Final Office
Action because the Examiner did not repeat the basis of the rejection in the
Final Office Action of March 3, 2019. In the Answer, the Examiner
substantially repeated the rejection that had maintained in the Final Office
Action.
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found that “aflibercept is an anti-VEGF therapy which binds VEGF
molecules (VEGF trap). Thus, it shares a mechanism of action with
bevacizumab” because they both bind VEGF. Id. Based on this finding, the
Examiner concluded it would have been obvious to one of ordinary skill in
the art before the filing of the application to use Liu to determine patients
who are “likely anti-VEGF therapy responders” by measuring VCAM-1 and
then to treat them with aflibercept because it has same mechanism of action
as bevacizumab “for the advantage of improving patient survival.” Id.
Appellant argues that one of ordinary skill in the art would not have
reasonably expected that patients with CRC could be treated with aflibercept
as claimed because “Liu does not teach if bevacizumab is effective in
treating patients with low VCAM-1 expression.” Appeal Br. 5. Specifically,
Appellant argues that “Liu does not contain data regarding placebo, so the
effectiveness of bevacizumab cannot be deduced from the teachings of Liu.”
Id. To support this argument, Appellant cites the following disclosure from
Liu:
Although many of our results were highly statistically
significant, they should nevertheless be considered exploratory
and hypothesis generating. While treatment related changes use
each patient as their own control, it is not yet clear whether
these changes are driven primarily by bevacizumab, by the
capecitabine/oxaliplatin chemotherapy, or by the tumor’s or
host’s response to these agents.
Liu 241.
Appellant’s argument does not persuade us the Examiner erred.
Liu measured various biomarkers in the blood of colorectal cancer
patients receiving a combination of receiving capecitabine, oxaliplatin, and
bevacizumab. Liu 234 (Abstract). One of the biomarkers was VCAM-1, the
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same protein which is claimed. Liu 236 (Table 2). A baseline level for each
biomarker was measured and a median level was determined. Liu 236 (Table
2), 237 (col. 2). Liu correlated baseline levels with progression free survival
(“PFS”) and overall survival (“OS”). Liu 237 (“Univariate correlation of
biomarkers with patient outcome”). Liu found:
The high-risk group (Ang-2, IGFBP-3, VCAM-1 > median
value; IL-6 < median value) and low-risk group (Ang-2,
IGFBP-3, VCAM-1 < median value; IL-6 > median value) had
median survival of 18.1 and 33.9 months, respectively (P =
0.016).
Liu 239 (emphasis added).
Liu therefore teaches that CRC patients with VCAM-1 levels below a
median value had a higher median survival time when treated with the
combination of capecitabine, oxaliplatin, and bevacizumab as compared to
patients with a VCAM-1 level above the median value. The “median value”
in Liu is the same as the claimed “reference level.”
It is correct that Liu describes treating patients have CRC with a
combination of capecitabine, oxaliplatin, and bevacizumab. Liu 234
(Abstract). However, the claim recites “comprising administering a
therapeutically effective amount of ziv-aflibercept to the patient” which is
open-ended because of the recitation of “comprising,” and therefore does not
exclude the administration of additional agents to the cancer patient. In other
words, Liu provides a reasonable expectation of success that treating a
patient having a level of VCAM-1 which is lower than a “reference level”
would have a better outcome, namely survival time, as compared to patients
with a VCAM-1 level higher than the reference level when treated with
bevacizumab and the two other cancer agents. Because bevacizumab is an
anti-VEGF drug, the Examiner found that this expectation would extend to
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other anti-VEGF drugs, including the claimed aflibercept. The claim does
not require that only the anti-VEGF drug is administered.
Appellant attempts to distinguish the claims by saying that Liu did not
compare the results to a placebo. Appeal Br. 5, 6, 7, 8, 9, 11, 12, 13. A
placebo is generally used to determine whether a drug is effective by
comparing a group of patients who are administered the drug to a group who
do not receive the drug. When the group taking the drug shows a benefit as
compared to patients who did not take the drug, it is concluded that the drug
is responsible for the benefit. In Liu, the combination of capecitabine,
oxaliplatin, and bevacizumab administered to the lower-than-median level
VCAM-1 group was shown to improve overall survival time as compared to
the higher-than-medium level VCAM-1 group. The benefit of the
combination was demonstrated in the lower-than-median level VCAM-1
group. A placebo was not needed because the comparison was made to the
higher-than-medium level VCAM-1 group of patients who received the
same drug combination. Final Act. 11.
We agree with Appellant that Liu did not show that its VCAM-1
results were applicable to the bevacizumab, alone. However, it does not have
to be shown that the anti-VEGF drug alone was responsible for the
correlation between VCAM-1 levels and overall survival because the claims
do not require that the anti-VEGF drug aflibercept alone is administered to
the patient population. Therefore, while the claims “are limited to treating
patients with lower VCAM-1 expression,” we do not agree that there “is no
motivation to treat this patient population in the teachings of Liu, since Liu
does not show if bevacizumab, let alone aflibercept, if effective in treating
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this patient population” (Appeal Br. 10) because the claim does not require
administration of only aflibercept.
Appellant further states that bevacizumab is an anti-VEGF-A
antibody, which also binds to VEGF-B and placental growth factor. Appeal
Br. 9. Appellant argues that “[b]ecause of the differing structures and
functions of bevacizumab and aflibercept, . . . one of ordinary skill in the art
would not expect that if VCAM-1 were diagnostic for the efficacy of one,
that it would be diagnostic for the efficacy of the other.” Id. Appellant
contends that “the Examiner has not explained why it would have been
obvious to substitute bevacizumab with aflibercept when they have differing
structures and functions.” Id.
This argument does not identify reversible error in the Examiner’s
rejection. The Examiner expressly explained that because bevacizumab and
aflibercept “both neutralize VEGFA as a mechanism of action,” there would
have been reason to use aflibercept in Liu’s method. Non-Final Act. 24.
Appellant does not explain why the additional activity of aflibercept would
have led one of ordinary skill in the art to not use it in Liu’s method and to
expect that it would not work. Indeed, Liu characterizes its results as
consistent with results from other anti-VEGF agents:
[T]he treatment-related changes seen in the current study are
consistent with multiple reports with various anti-VEGF agents
and appear to describe an anti-VEGF class effect on PlGF,
Ang-2, and sVEGF-R2.
Liu 241.
Appellant also argues that one of ordinary skill in the art “would have
been surprised to be shown that patients with high VCAM-1 level showed
no statistically significant improvement” as shown in Figure 2 of the
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Specification. Appeal Br. 8. Appellant states that the “effectiveness of
aflibercept in high VCAM-1 patients is not just somewhat inferior, it is
ineffective,” and thus Liu, Castan and Compton “teach away” from claimed
subject matter. Id.
The claims cover the treatment of patients having CRC with
aflibercept who have levels of VCAM-1 which are lower than a reference
level. Ans. 25. The issue is therefore whether one of ordinary skill in the art
would have had reason to treat this class of patients. The Examiner
established a reason to do so based on the expectation that other anti-VEGF
agents would act similarly to bevacizumab, a finding supported by Liu’s
own statements (Liu 241 reproduced above). The “teaching away” described
by Appellant has to do with whether one of ordinary skill in the art would
expect patients with levels of VCAM-1 higher than the reference level to
benefit from the treatment. But, as indicated by the Examiner, this class of
patients is not covered by the claims and therefore the argument is not
persuasive. Appellant responds that the claims “exclude treatment of the
high VCAM-1 patients because treatment would be ineffective.” Reply Br.
6. However, Appellant did not address the fact that the class of patients
actually covered by the claim is the class which Liu suggests would benefit
from anti-VEGF therapy.
Appellant makes the same unpersuasive arguments for dependent
claim 15.

“Evidence of Unexpected Properties”
Appellant contends that the Examiner’s prima facie case, even if it
had been established, has been “rebutted . . . with evidence of unexpected
properties.” Appeal Br. 10. Appellant points to the description on pages 17-
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18 of the Specification of “subjects with low VCAM-1” who “had a better
response rate with aflibercept that without aflibercept.” Appeal Br. 10. With
respect to the data in the Specification, as shown in Table 1 and Figures 1
and 2, Appellant argues that there is “a statistically significant improvement
in the overall survival (OS) (Figure 2) and progression free survival (PFS)
(Figure 1) in patients for whom the VCAM-1 level is lower than 6.32 (p-
values < 0.01).” Appeal Br. 11. Appellant states “[s]urprisingly, there is no
statistically significant improvement in the OS or PFS in patients for whom
the VCAM-1 level is greater than 6.32 (comparing patients with high
VCAM-1 who received placebo compared to high VCAM-1 patients who
received aflibercept).” Appeal Br. 12. Appellant further states that “[e]ven
more surprisingly, the global p-value in Figure 2 is only 0.11, suggesting
that treatment with aflibercept does not improve OS over placebo unless one
selects and treats low VCAM-1 patients.” Id. Appellant also asserts that
“unexpectedly, Applicant found that measuring VCAM-1 provides a way of
showing prognosis for aflibercept treatment in CRC patients. This is clearly
surprising, especially in light of the art cited by the Examiner.” Id. at 13.
To begin, Appellant has not met the standard set forth in In re Soni, 54
F.3d 746 (Fed. Cir. 1995) to establish unexpected results. According to Soni,
54 F.3d at 750–51, prima facie obviousness can be rebutted with
a showing of “unexpected results,” i.e., to show that the
claimed invention exhibits some superior property or advantage
that a person of ordinary skill in the relevant art would have
found surprising or unexpected. The basic principle behind this
rule is straightforward - that which would have been surprising
to a person of ordinary skill in a particular art would not have
been obvious.
. . . .
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[W]hen an applicant demonstrates substantially improved
results, as Soni did here, and states that the results were
unexpected, this should suffice to establish unexpected results
in the absence of evidence to the contrary.
Here, Appellant has not provided evidence “that a person of ordinary
skill in the relevant art would have found” the results described in the
Specification “surprising or unexpected.” Such statements are made by
counsel in the Appeal Brief, but we have not been directed to a statement by
“a person of ordinary skill” in the “particular art” that such results are
unexpected, surprising, and not obvious, as required by In re Soni. For
example, we have not been pointed to such a statement in the Specification.
The crux of Appellant’s argument is that it would not have been
expected, based on Liu, Castan, and Compton, that aflibercept would have
no benefit for patients with high VCAM-1 levels, and a benefit in
progression free survival for patients with VCAM-1 levels lower than the
reference amount. Appeal Br. 13. With respect to treating patients with high
VCAM-1 levels, we have already explained that this group is outside the
scope of the claim. We therefore only address the argument that aflibercept
unexpectedly increased PFS in colorectal cancer patients – in contrast to
Liu’s failure to extend PFS in patients treated with bevacizumab.3 We
address this argument only to be inclusive; as indicated above, Appellant did
not establish that the PFS result would have been “unexpected” by one of
ordinary skill in the art because Soni was not satisfied.

3 Liu 239 (“The best model for PFS using baseline analyte values that could
be developed was a seven-marker signature consisting of HGF, VEGF-R1,
MMP-9, Ang-2, TF, VEGF-A, and VEGF-C, although this model was not
statistically significant (P = 0.37, and data not shown).” VCAM-1 was not
mentioned as marker for PFS, although it was measured by Liu.
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We do not find this argument persuasive of Examiner error. Castan
teaches that aflibercept is effective in treating patients with colorectal
cancer. Castan ¶¶ 16, 19–23; Non-Final Act. 24; Appeal Br. 5 (“Castan
teaches treatment of metastatic colorectal cancer with aflibercept.”). It is
reasonable to expect4 (based on Liu) that the aflibercept in Castan was
inherently treating patients with amounts of VCAM-1 lower than a reference
level because they are members of the larger class of CRC patients treated
by Castan. As explained In re Baxter Travenol Labs, 952 F.2d 388, 392
(Fed. Cir. 1991), “[m]ere recognition of latent properties in the prior art does
not render nonobvious an otherwise known invention. In re Prindle, 297
F.2d 251, 254, 132 USPQ 282, 283–84 (CCPA 1962).” (“Since the prior art
bags plasticized with DEHP were inherently suppressing hemolysis, albeit
unknown at the time of the Becker document, this hemolysis-suppressing
function is not a basis for rebutting a prima facie finding of obviousness.”).
Thus, the observation that aflibercept benefits progression free survival in
CRC patients with levels of CRC below a reference amount is not a basis to
rebut a prima facie finding of obviousness. Specifically, aflibercept had been
used in Castan to treat CRC patients and therefore the result of the treatment
had already been experienced by patients although an increase in
progression free survival may have been unrecognized at the time.

4 “Whether the rejection is based on ‘inherency’ under 35 U.S.C. § 102, on
‘prima facie obviousness’ under 35 U.S.C. § 103, jointly or alternatively, the
burden of proof is the same, and its fairness is evidenced by the PTO’s
inability to manufacture products or to obtain and compare prior art
products.” In re Best, 562 F.2d 1252, 1255 (CCPA 1977).
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Claims 7, 8
Claim 7 depends from claim 4 and further recites “wherein the
reference level of expression of the first protein is between 406 and 577
ng/mL.” Claim 8 depends from claim 4 and further recites “wherein the
reference level of expression of the first protein is 553 ng/mL.”
The Examiner found that the “cutoff values” recited in the claims are
“readily determined by one of ordinary skill in this art and, since they
establish disease prognoses, they are result effective variables.” Non-Final
Act. 25. The Examiner further cited Compton as teaching that one of
ordinary skill in the art “would know to first establish a positive indicator
threshold level for a particular sample technique such as serum by
comparing samples from normal patients with those having particular
cancers” to establish a diagnostic threshold. Id.
Appellant argues the recited cutoff values recited in claim 7 and 8 are
not disclosed in ether Liu or Castan. Appeal Br. 14. In addition to repeating
the same unpersuasive arguments regarding Liu and Castan, Appellant
argues that Compton does “not teach or suggest that one of ordinary skill in
the art would know to first establish a positive indicator threshold level for a
particular sample technique such as serum by comparing samples from
normal patients with those having particular cancers.” Id. at 15.
This argument is not persuasive. Liu discloses a reference “cutoff”
value for VCAM-1. We agree with the Examiner that it would be routine to
determine the cutoff value for aflibercept in view of Liu’s teaching of the
existence of a cut-off value for another anti-VEGF agent, bevacizumab. As
found by the Examiner, Liu established VCAM-1 is a result-effective
variable. Non-Final Act. 25. Appellant did not dispute this finding. The
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“discovery of an optimum value of a result effective variable in a known
process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272,
276 (CCPA 1980). Compton is just cited to establish that the skilled worker
knew to establish threshold values when diagnosing cancer, and its teaching
is not necessary to establish the obviousness of claims 7 and 8.

Obviousness-type double patenting rejections
Appellant relies on the same arguments for the two obviousness-type
double-patenting rejection as for the § 103 rejection. Appeal Br. 15–16. We
therefore affirm these rejections for the same reasons.

CONCLUSION
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
4, 7, 8, 15 103 Liu, Castan,
Compton
4, 7, 8, 15
4, 7, 8, 15 N/A Obviousness-type
double-patenting
4, 7, 8, 15
4, 7, 8, 15 N/A Obviousness-type
double-patenting
4, 7, 8, 15
Overall
Outcome
4, 7, 8, 15

TIME PERIOD
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv).

AFFIRMED