UNIVERSITE DE NANTES et al.

Patent Trials and Appeals Board

Nov 18, 2021

2021001356 (P.T.A.B. Nov. 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.
14/651,887 06/12/2015 Brigitte Dreno 007534.00054\US 1949
22910 7590 11/18/2021
BANNER & WITCOFF, LTD.
28 STATE STREET
SUITE 1800
BOSTON, MA 02109-1701
EXAMINER
PATURY, SRIKANTH
ART UNIT PAPER NUMBER
1657
NOTIFICATION DATE DELIVERY MODE
11/18/2021 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):
PTO-22910@bannerwitcoff.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte BRIGITTE DRENO, THOMAS ZULIANI, and
SORAYA SAIAGH

Appeal 2021-001356
Application 14/651,887
Technology Center 1600
Before JEFFREY N. FREDMAN, TAWEN CHANG, and
JAMIE T. WISZ, Administrative Patent Judges.

WISZ, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1–6 and 18. We have jurisdiction under
35 U.S.C. § 6(b).
We REVERSE.

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. Appellant identifies Universite de Nantes and Chu Nantes
as the real parties-in-interest. Appeal Br. 2.
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CLAIMED SUBJECT MATTER
The Specification describes compositions comprising mixtures of
foetal human keratinocyte cells and foetal human fibroblastic cells in which
the proportion of fibroblasts to keratinocytes “is precisely adapted to
effectively stimulate skin healing, notably via the secretion of growth factors
produced by fibroblasts and foetal keratinocytes.” Spec. 7.
Claim 1, the only independent claim, is illustrative of the claimed
subject matter and is reproduced below:
1. A composition for accelerating healing of a skin defect
comprising a mixture of foetal human keratinocyte cells and
foetal human fibroblastic cells in a skin healing accelerating
ratio between said keratinocyte and fibroblast cells ranging
from 1:1 to 2.5:1.
Appeal Br. i (Claims App.).
REJECTIONS
The Examiner rejected claims 1–5 and 18 under 35 U.S.C. § 103 as
being unpatentable over Baetge2 in view of Laurent-Applegate.3
The Examiner rejected claim 6 under 35 U.S.C. § 103 as being
unpatentable over Baetge in view of Laurent-Applegate and further in view
of Kemp4 as evidenced by Barash.5

2 Baetge et al., US 2002/0048563 A1, published Apr. 25, 2002 (“Baetge”).
3 Laurent-Applegate et al., US 2003/0175256 A1, published Sept. 18, 2003
(“Laurent-Applegate”).
4 Kemp et al., US 2008/0193507 A1, published Aug. 14, 2008 (“Kemp”).
5 Faith Barash, Food and Drug Administration Memorandum concerning the
Product: TISSEEL, Pediatric Safety and Utilization Review for the Pediatric
Advisory Committee (PAC) Meeting; Center for Biologics Evaluation and
Research (“Barash”).
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ISSUES AND ANALYSIS
Rejection of claims 1–5 and 18 under 35 U.S.C. § 103 as being unpatentable
over Baetge in view of Laurent-Applegate
The Examiner finds that Baetge teaches a composition wherein the
cell mixture may include 50% of keratinocytes and 50% of fibroblasts (a
ratio of 1:1) within an extracellular matrix for accelerating wound healing.
Final Act. 3 (citing Baetge ¶¶ 4, 66). The Examiner acknowledges that
Baetge does not teach a composition comprising a mixture of foetal
keratinocyte cells and foetal fibroblastic cells but finds that this limitation is
taught by Laurent-Applegate. Id. The Examiner finds that Laurent-
Applegate teaches compositions containing undifferentiated epidermal
keratinocytes and undifferentiated dermal fibroblasts integrated into a
collagen matrix. Id. (citing Laurent-Applegate abstract, ¶ 105).
The Examiner concludes that “[i]t would be obvious to one of
ordinary skill in art at the time of invention to modify the composition of
human keratinocytes and human fibroblasts in a 1:1 ratio as taught by
Baetge by using the foetal human keratinocyte cells and foetal human
fibroblastic cells as taught by [Laurent-Applegate].” Id. According to the
Examiner, one would be motivated to do so because Laurent-Applegate
teaches the advantages of using fetal skin cells over adult skin cells and one
would have a reasonable expectation of success because both Baetge and
Laurent-Applegate suggest a composition of keratinocyte cells and fibroblast
cells in a matrix for accelerating wound healing. Id. at 3–4 (citing Laurent-
Applegate ¶ 71, Figs. 3–5).
Appellant argues that the combination of Baetge and Laurent-
Applegate would not have led one of skill in the art to select the particularly
claimed ratio of foetal human keratinocyte cells to foetal human fibroblastic
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cells. Appeal Br. 4–8. Appellant also argues that the record demonstrates
unexpected results with respect to the claimed subject matter. Id. at 8–10.
First, we find that the Examiner has established a prima facie case of
obviousness. Baetge discloses the use of human keratinocyte cells and
foetal human fibroblastic cells in a 1:1 ratio to enhance wound healing.
Baetge ¶¶ 4, 66. Laurent-Applegate teaches use of foetal human
keratinocyte cells and fibroblastic cells for wound healing and discusses the
benefits of using foetal cells over adult cells. Laurent-Applegate ¶¶ 71, 105,
Figs. 3–5. Therefore, it would have been obvious to one of ordinary skill in
the art to use the foetal human keratinocyte cells and fibroblastic cells
discussed in Laurent-Applegate in the compositions of Baetge in a 1:1 ratio
to enhance wound healing and they would have done so with a reasonable
expectation of success. Appellant presents arguments disputing the prima
facie case of obviousness which we find unpersuasive. See Appeal Br. 4–8.
However, prima facie obviousness can be addressed by presenting
evidence of secondary considerations and when such evidence is submitted,
all of the evidence must be considered anew. In re Piasecki, 745 F.2d 1468,
1472–1473 (Fed. Cir. 1984). First, Appellant contends that the prior art
teaches the use of a small proportion of undifferentiated keratinocytes
relative to undifferentiated fibroblasts (i.e., a lower ratio than the 1:1 ratio of
claim 1). Appeal Br. 5–6 (citing Laurent-Applegate ¶ 105 (disclosing the
use of about 10–13.5% keratinocytes and 90–86.5% fibroblasts)). Appellant
also cites to Hirt-Burri,6 which discloses that the use of fetal skin fibroblasts

6 Nathalie Hirt-Burri et al., Wound-healing Gene Family Expression
Differences Between Fetal and Foreskin Cells Used for Bioengineered Skin
Substitutes, Artificial Organs, 32(7) 509–518 (2008) (“Hirt-Burri”).
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alone are more effective at skin healing than combined compositions, and
also cites to Applegate7 which states that, “[m]ore recently, it has been
shown that, when grafts are prepared with a majority of dermal fibroblasts in
proportion to keratinocytes, the stimulation of healing is much greater.” Id.
at 6–7 (emphasis and underling omitted) (citing Hirt-Burri 511, 517;
Applegate 67).
As evidence of unexpected results, Appellant cites to the Declaration
of Brigitte Dreno under 37 C.F.R. § 1.132 dated Feb. 2, 2019 (“Dreno
Declaration), which states that,
[i]t was unexpected that a combination of fetal fibroblasts and
fetal keratinocytes within the claimed ratio altered the amount of
skin healing factors that the combined fetal cells produced
compared to what the fetal cells would produce (or not produce)
individually and as compared to what a combination of adult cells
produced.

Appeal Br. 8 (citing Dreno Declaration ¶ 8). Appellant also points to Figure 6
of the Specification (shown below) as demonstrating that compositions in
which fibroblasts/keratinocytes are in a 75:25 ratio (as disclosed in the prior
art) exhibit a lower and slower healing effect as compared to compositions
with the claimed 1:1 ratio. Id. (citing Spec. Fig. 6).

7 L.A. Applegate et al., Whole-Cell Bioprocessing of Human Fetal Cells for
Tissue Engineering of Skin, Skin Pharmacology and Physiology, 22:63–73
(2009) (“Applegate”).
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Figure 6 of the Specification shows “the evolution of the closing of a cellular
scratch over time (between 0 and 20 hours after the scratch), for different
cellular conditions (ratio of fibroblasts/keratinocytes of 100/0, 75/25, 50/50
or 0/100)” with the 50/50 ratio having the highest percentage of scratch
closing over time. Spec. 6.
Appellant also points to Figure 7A of the Specification (shown
below), which demonstrates an increase in the percentage of significant
healing in 5 minutes with the composition comprising fibroblasts/
keratinocytes in a 1:1 ratio as compared to the composition where the ratio is
75/25. Id. at 9 (citing Spec. Fig. 7A).

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Figure 7A of the Specification “illustrates the closing percentage of the
scratch at 5 hours . . . for different cellular conditions (ratio of
fibroblasts/keratinocytes of 100/0, 75/25, 50/50 or 0/100)” with the 50/50
ratio having the highest percentage of scratch closing percentage (25%).
Spec. 6.
The Dreno Declaration also points to Figure 3A of the Specification
(shown below) which “shows that fetal fibroblasts and fetal keratinocytes
mixed in ratio 30:70 [1:2.5] produce GM-CSF at a much higher
concentration than that of a mixture of fetal fibroblasts and fetal
keratinocytes in ratio 90:10 as recommended by [Laurent-Applegate].”
Dreno Declaration ¶ 13.

Figure 3A of the Specification illustrates the production of GM-CSF in the
supernatant of keratinocyte cells (K) and foetal fibroblast (F), alone or
mixed at different ratios, with the highest concentration of GM-CSF found
in the 30:70 ratio of keratinocyte cells to fibroblasts. Spec. 5. The
Specification and the Dreno Declaration describe GM-CSF as a cytokine
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factor that plays an essential role in healing. See Spec. 7; Dreno Declaration
¶ 9.
We find that the Examiner has not provided a persuasive reason as to
why these results would have been expected. “[W]hen an applicant
demonstrates substantially improved results, as [is the case] here, and states
that the results were unexpected, this should suffice to establish unexpected
results in the absence of evidence to the contrary.” In re Soni, 54 F.3d 746, 751
(Fed. Cir. 1995) (emphasis omitted). The Examiner argues that these results
would have been expected and cites to Figure 2 of Baetge (shown below),
which, according to the Examiner, “shows that a combination of fibroblasts and
keratinocytes at 1:1 ratio produced a much greater amount of GM-CSF than the
sum of the individual fibroblasts and keratinocytes alone.” Ans. 11–12 (citing
Baetge Fig. 2).

Figure 2 of Baetge is a histogram showing the secretion of keratinocyte growth
factor (KGF), vascular endothelial growth factor (VEGF), granulocyte-
macrophage colony-stimulating factor (GM-CSF) from cultures containing
keratinocytes alone, fibroblasts alone, or co-cultured keratinocytes and
fibroblasts in fibrin paste. Baetge ¶ 24. Figure 2 of Baetge shows that the
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combination of keratinocytes and fibroblasts in fibrin paste produced the
highest amounts of GM-CSF, VEGF, and KGF.
Appellant argues that the Examiner provides no support for the
contention that Figure 2 of Baetge shows a combination of fibroblasts and
keratinocytes in a 1:1 ratio. Reply 2–3. We agree. While Baetge generally
discloses the use of fibroblasts and keratinocytes in a 1:1 ratio (Baetge ¶ 66),
there is no indication that the experimental results shown in Figure 2 depict a
composition with this ratio. See Baetge ¶¶ 24, 85–90. Further, while Figure 2
of Baetge may show that the combined use of fibroblasts and keratinocytes is
more effective than use of fibroblasts or keratinocytes alone, it does not provide
evidence that a 1:1 ratio of fibroblasts and keratinocytes would provide better
wound healing than other ratios with a higher percentage of fibroblasts as
taught in the prior art cited by Appellant. Thus, we find that the Examiner has
not provided any persuasive basis to question the unexpected results and
Appellant’s evidence of unexpected results outweigh the evidence
supporting the prima facie case of obviousness.
For the reasons discussed above, we do not sustain the rejection of
claims 1–5 and 18 as being unpatentable over Baetge and Laurent-
Applegate.
Rejection of claim 6 under 35 U.S.C. § 103 as being unpatentable over
Baetge in view of Laurent-Applegate and further in view of Kemp as
evidenced by Barash
For the same reasons as discussed above, we reverse the Examiner’s
rejection of claim 6, which was not argued separately from claims 1–5 and
18.
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DECISION SUMMARY
In summary:
Claim(s)
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1–5, 18 103(a) Baetge, Laurent-
Applegate
1–5, 18
6 103(a) Baetge, Laurent-
Applegate, Kemp,
Barash
6
Overall
Outcome
1–6, 18

REVERSED