Christopher Centeno

Patent Trials and Appeals Board

Jul 10, 2020

13132840 - (D) (P.T.A.B. Jul. 10, 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.
13/132,840 06/03/2011 Christopher J. Centeno 0237.09/PCT-US 8193
7590 07/10/2020
K&L Gates LLP - Pittsburgh
210 Sixth Avenue
Pittsburgh, PA 15222-2613
EXAMINER
SCHUBERG, LAURA J
ART UNIT PAPER NUMBER
1632
MAIL DATE DELIVERY MODE
07/10/2020 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 CHRISTOPHER J. CENTENO
____________

Appeal 2020-000988
Application 13/132,840
Technology Center 1600
____________

Before DONALD E. ADAMS, ULRIKE W. JENKS, and
MICHAEL A. VALEK, Administrative Patent Judges.

VALEK, Administrative Patent Judge.

DECISION ON APPEAL
Appellant1 submits this appeal2 under 35 U.S.C. § 134(a) involving
claims to methods of treatment that involve culturing and selecting viable
mesenchymal stem cells (MSC) for implantation. 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(a). Appellant identifies Regenexx, LLC as the real party in
interest. Appeal Br. 1. Herein, we refer to the Final Action mailed March
11, 2019 (“Final Act.”); Advisory Action mailed May 23, 2019 (“Advisory
Act.”); Appellant’s Appeal Brief filed July 22, 2019 (“Appeal Br.”); and
Examiner’s Answer mailed September 5, 2019 (“Ans.”).
2 This Appeal is related to Appeal 2019-006371 (Application 15/891,852),
Decision affirming the rejections of record entered July 8, 2020.
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STATEMENT OF THE CASE
The Specification describes “methods for facilitating repair in a
damaged avascular site, for example an intervertebral disc; more
particularly, the invention provides applying environmentally conditioned
autologous stem cells . . . to avascular sites in patients in need thereof.”
Spec. ¶1. The Specification explains that MSC may be “harvested and
expand[ed] . . . under various atmospheric conditions that simulate a
damaged disc’s environment.” Id. ¶ 57.
In some cases the harvested stem cells are cultured under 3 to
10% oxygen and in other cases the harvested stem cells are
cultured under 3 to 7% oxygen. These lower oxygen conditions
replicate the hypoxic conditions present in typical damaged disc
environments. . . . Selection occurs as cells are cultured, with
viable cells that are able to survive and ultimately expand
having an advantage when implanted into a disc having a
hypoxic environment.
Id. According to the Specification, MSC may also be “cultured in vitro
under elevated carbon dioxide conditions, typically from 2-10% carbon
dioxide” to select for “viable cells that are able to survive and ultimately
expand having an advantage when implanted into a disc having an elevated
carbon dioxide environment or an elevated carbon dioxide environment
combined with a hypoxic environment.” Id. ¶ 58.
Claims 70–75, 77, 78, and 80–853 are on appeal and can be found in
the Claims Appendix of the Appeal Brief. Claim 70 is illustrative of the
claims on appeal. It reads as follows:

3 Claim 87 was canceled after the Final Action and is not at issue in this
appeal. See Appeal Br. 5, 9; Advisory Act. 1.
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70. A method for treating a degenerative intervertebral disc
in a patient in need thereof, the method comprising:
implanting selected, viable mesenchymal stem cells into
the disc to be treated;
where the implanted selected, viable mesenchymal stem
cells were prepared for implantation by at least:
culturing nucleated cells in a culture medium under one
or more of the following conditions: (1) selective pressure of
about 1% to about 10% oxygen; or (2) about 2% to about 10%
carbon dioxide; and
selecting viable, mesenchymal stem cells capable of
growth under the conditions from said culture medium after
culturing for a period of 1-28 days; and
administering to said disc, either separately or in
combination with said selected, viable, mesenchymal stem
cells, autologous platelets or platelet lysate to facilitate stem
cell viability and expansion within the damaged disc.
Appeal Br. 21.
The following rejections are before us for review:
I. Claims 70, 73, 74, 77, 82, and 83 under 35 U.S.C. § 103 as
unpatentable over Centeno4, Grayson,5 and DiGirolamo;6
II. Claims 71 and 80 under 35 U.S.C. § 103 as unpatentable over
Centeno, Grayson, DiGirolamo, and Ma;7

4 WO 2007/087519 A2, published Aug. 8, 2007 (“Centeno”).
5 Warren L. Grayson et al., Effects of Hypoxia on Human Mesenchymal Stem
Cell Expansion and Plasticity in 3D Constructs, 207 J. of Cellular
Physiology 331–339 (2006) (“Grayson”).
6 Carla M. DiGirolamo et al., Propagation and Senescence of Human
Marrow Stromal Cells in Culture: a Simple Colony-forming Assay Identifies
Samples with the Greatest Potential to Propagate and Differentiate, 107
British J. of Haematology 275–281 (1999) (“DiGirolamo”).
7 US 6,875,605 B1, issued April 5, 2005 (“Ma”).
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III. Claims 72 and 81 under 35 U.S.C. § 103 as unpatentable over
Centeno, Grayson, DiGirolamo, and Toner;8
IV. Claims 70, 73–75, 77, and 82–84 under 35 U.S.C. § 103 as
unpatentable over Centeno, Grayson, DiGirolamo, and DiMauro;9
and
V. Claims 78 and 85 under 35 U.S.C. § 103 as unpatentable over
Centeno, Grayson, DiGirolamo, and Schallmoser;10
Appeal Br. 8.
I. OBVIOUSNESS REJECTIONS I–V
Issue
All of Examiner’s rejections are premised on the same combination of
Centeno, Grayson, and DiGirolamo. See Ans. 3–4. Appellant does not
present separate arguments for Rejections II–V, but instead relies on the
same arguments it presents for the first rejection. See Appeal Br. 17–18.
Accordingly, we consider the obviousness rejections together in our
analysis. We select claim 70 as representative of the other claims on appeal,
which Appellant does not argue separately from claim 70. See 37 C.F.R.
§ 41.37(c)(1)(iv). The issue for these rejections is whether a preponderance
of the evidence supports Examiner’s conclusion that cited prior art renders
the method of claim 70 obvious.

8 US 2004/0248293 A1, published Dec. 9, 2004 (“Toner”).
9 US 2004/0229878 A1, published Nov. 18, 2004 (“DiMauro”).
10 Katharina Schallmoser et al., Human Platelet Lysate Can Replace Fetal
Bovine Serum for Clinical-scale Expansion of Functional Mesenchymal
Stromal Cells, 47 Transfusion 1436–46 (2007) (“Schallmoser”).
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Findings of Fact
FF1. Centeno teaches methods for autologous transplantation of MSCs and
progenitor helper cells (PHC) “from bone marrow to degenerated
intervertebral discs or joints.” Centeno ¶ 17; Abstr. In particular, Centeno
teaches “a[ ]procedure where target cells are harvested, then isolated, then
reimplanted into a target site, all from and into the same patient.” Id. ¶ 17.
FF2. Centeno also teaches experimental techniques
to determine which bone marrow cells should be removed via
negative selection to generate a MSC/PHC population most
likely to regenerate certain tissue types in-vitro as well as which
combination of fibrinogen and hyaluronic acid and which
degree of gel maceration provides the best matrix for in-vitro
and in-vivo regeneration of joints and intervertebral discs.
Centeno ¶ 18.
FF3. According to Centeno,
physicians will be unlikely to utilize regenerative techniques
unless the isolation can be easily performed by operating room
staff and the isolation itself can be performed during the same
surgical procedure as the actual transplantation. If expansion of
the cells is required for success, then that expansion would
preferably be carried out in a hospital or clinical lab and not a
research laboratory.
Centeno ¶ 5; see also id. ¶ 7 (distinguishing prior art methods as “not
practical for surgeons and hospitals” or “a clinical or hospital lab without
experienced research personnel”). Thus, Centeno teaches that its method is
“designed to be used by operating room staff . . . during the same surgical
procedure as transplantation.” Id. ¶ 17; Abstr. However, Centeno also
teaches that “[t]he method can be used as a two step procedure where cells
are harvested, then isolated, then reimplanted at a later time.” Id. at Abstr.
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FF4. For example, Centeno describes “an alternative embodiment” wherein
“the cell sample may be separated using the same combination of cell
surface antigens determined through experimental design discussed herein,
with flouresence activated cell sorting being utilized.” Centeno ¶ 27.
Centeno teaches “[t]his alternative selection method may be performed at an
on or off-site clinical lab.” Id.
FF5. Centeno also teaches that “[a]lternatively, the cells selected as most
likely to regenerate the target tissue may be expanded in a hospital lab
before re-injection.” Centeno ¶ 28.
FF6. Grayson describes results from experiments in which human
mesenchymal stem cell (hMSC) “were cultured under physiologically
relevant oxygen environments (2% O2) in three-dimensional (3D) constructs
for up to 1 month in order to investigate the combined effects of chronic
hypoxia and 3D architecture on hMSC tissue development patterns.”
Grayson, 331. Grayson teaches that hMSC cultured and expanded under
these hypoxic conditions “exhibited an extended lag phase in order to
acclimatize to culture conditions,” but
subsequently proliferated continuously throughout the culture
period, while maintaining significantly higher colony-forming
unit capabilities and expressing higher levels of stem cell genes
than hMSC cultured at 20% O2 (normoxic) conditions. Upon
induction, hypoxic hMSC also expressed higher levels of
osteoblastic and adipocytic differentiation markers than
normoxic controls. . . . Importantly, hMSC maintained the
ability to thrive in prolonged hypoxic conditions suggesting that
hypoxia may be an essential element of the in vivo hMSC
niche.
Id; see also id. at 338 (reporting that “hMSC in vitro proliferation is actually
enhanced by long-term chronic hypoxia” and “[o]ur results demonstrate that
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hMSC cultured at 2% O2 maintain much higher colony forming numbers
than cells cultured at 20% O2”).
FF7. Grayson teaches that colony-forming unit “numbers in hypoxic
cultures were also higher than those of the original cell population seeded
into the matrices indicating that the more primitive cells are being selected
by oxygen deprivation.” Grayson, 338.
FF8. DiGirolamo describes protocols for isolating and culturing MSC and
assaying colony-forming unit fibroblasts (CFU-F) therein. See generally
DiGirolamo 275–79. DiGirolamo teaches that “[s]amples with high colony-
forming efficiency exhibited the greatest replicative potential” and that
“CFU-U assays predict life-span in culture.” Id. at Abstr, 276; see also
Grayson 338 (“High CFU-F potential has been correlated with high in vitro
lifespan.”) (citing DiGirolamo).
Analysis
Examiner finds that Centeno “teaches a therapeutic method for
selecting autologous MSCs for administration to a degenerated intervertebral
disc” in which the cells may “be expanded in a hospital lab before re-
implantation.” Final Act. 4 (citing Centeno ¶¶ 17, 23, 28). Examiner
acknowledges that Centeno “is silent with regard to the culture conditions . .
. for expansion of the selected MSCs,” but finds that Grayson teaches that
MSCs cultured and expanded under hypoxic conditions, as recited in claim
70, “displayed significantly improved expansion characteristics while
maintaining their multi-lineage potential.” Id. at 4. Thus, Examiner
determines
one of ordinary skill in the art would have been motivated to
use 2-5% oxygen and 5% carbon dioxide for the culture of
MSCs in the method of Centeno ’519 because Grayson et al
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teach that these percentages provide improved expansion[]
characteristics for MSCs. One of ordinary skill in the art would
have had a reasonable expectation of success because Grayson
teach[es] that hypoxic conditions select for MSCs that are more
primitive with a higher CFU-F number that correlates with high
in vitro lifespan and extended proliferation.
Id. at 5.
We adopt the Examiner’s findings and reasoning regarding the scope
and content of the prior art (Final Act. 3–5; FF1–FF8) and agree that claim
70 is obvious over the articulated combination of Centeno, Grayson, and
DiGirolamo. We address Appellant’s arguments below.
Appellant argues that Examiner’s combination of Centeno with a
culturing step is “actively discouraged by Centeno.” See Appeal Br. 10–15.
More specifically, Appellant contends that Examiner’s finding that Centeno
“teaches a therapeutic method that selects and expands MSCs is based on a
single sentence . . . that generally discusses expanding cells (paragraph
[0028]) but which runs contrary to the entirety of the remaining teaching of
the reference and its objectives.” Id. at 10. Appellant urges that “read as a
whole” Centeno “provides no motivation for adding an in-vitro culturing
step” and that “by relying on a single statement in Centeno ’519 that
conflicts with the entirety of the remaining teachings of Centeno ’519, the
Office has engaged in improper hindsight analysis.” Id. at 115 (citing
Bausch & Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc., 796 F.2d 443, 448
(Fed. Cir. 1986) (“Bausch & Lomb”)).
Appellant’s argument is unpersuasive. As an initial matter, Centeno
does not actively discourage expanding MSCs prior to implanting them. To
the contrary, Centeno describes a method that includes an expansion step in
a lab (i.e., in vitro) as an “alternative[]” embodiment of Centeno’s invention.
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FF5. It is true that in some instances Centeno expresses a preference for a
selection method that can be practiced by operating room staff as part of the
same procedure. Centeno ¶¶ 5, 7, 17. However, there are also multiple
instances in which Centeno makes clear that its methods also encompass
“two step” procedures in which cells are harvested and reimplanted at a later
time. See FF3–FF5. For example, Appellant quotes a portion of Centeno
paragraph 5 as evidence that Centeno “clearly intends for its . . . methods to
be performed as a single procedure . . . not over multiple days as would be
required if a culturing step were included in the Centeno” process. Appeal
Br. 11. But the ultimate sentence in paragraph 5, which Appellant does not
quote in its brief, expressly contemplates instances in which “expansion of
the cells is required for success” and thus would be carried out in a lab––not
the operating room. FF3. In addition, Centeno describes other embodiments
in which at least portions of the selection method are performed in a
laboratory. FF4. Thus, we disagree with Appellant’s position that only a
“single sentence” in Centeno paragraph 28 (see Appeal Br. 10) supports
Examiner’s finding Centeno teaches a culturing and expanding step in its
method.
Rather, read as a whole, Centeno teaches a preferred embodiment in
which the harvesting, selection, and implantation of MSCs occurs in a single
procedure as well as alternative “two step” embodiments “where cells are
harvested, then isolated, then reimplanted at a later time.” FF3. It is as part
of these two step embodiments that Centeno teaches that MSCs may
“alternatively” be cultured and expanded before implantation. FF5.
As such, the facts here are very different from those in Bausch &
Lomb. There, the district court relied on a “single line” out of the
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specification, stating that one way in which a particular objective could be
achieved was by the use of a laser. 796 F.2d at 448. However, “the
immediately following sentences” noted that the use of a laser “is limited by
several disadvantages” and that instead the author “suggests the use of a
special class of polymer” to achieve the same objective. Id. As such, the
Federal Circuit determined “[a] complete reading demonstrates quite clearly
that [the author] is setting up a strawman and point out its disadvantages to
highlight the advantages of [the author’s] invention, that special class of
polymers.” Id. But unlike Bausch & Lomb, Centeno paragraph 28 is not
setting up a strawman to distinguish its invention; rather paragraph 28
describes an alternative embodiment of Centeno’s invention.
We are not persuaded by the testimony in the Declaration of Joseph C.
Maroon, dated August 27, 2018 (“Maroon Decl.”) and the Declaration of
Christopher J. Centeno, dated August 27, 2018 (“Centeno Decl.”). Both
declarations rely on the same teachings in Centeno paragraphs 5, 7, and 17
to conclude that the teaching in paragraph 28 is “wholly inconsistent” and
therefore that they would “disregard the statement in paragraph [0028]” if
they were reading Centeno for “instructive purposes.” Maroon Decl. ¶¶ 12,
15; Centeno Decl. ¶¶ 13, 16. The problem with the testimony in both of
these declarations is that it cannot be reconciled with the statements in
Centeno teaching “two step” embodiments. FF3–FF5; see also PharmaStem
Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1361 (Fed. Cir. 2007)
(holding the jury’s determination of non-obviousness was not supported by
the testimony of patentee’s expert because “[t]he problem with [the expert’s]
testimony about the prior art references is that it cannot be reconciled with . .
. the prior art references themselves”). Indeed, neither Appellant, nor its
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declarants, even attempt to reconcile paragraph 28 with their arguments as to
what the rest of Centeno discloses. We, however, decline Appellant’s
invitation to disregard paragraph 28 because doing so would conflict with
Centeno’s various disclosures regarding “two step procedure[s]” (see FF3–
FF5) and is contrary to precedent. See Merck & Co. Inc. v. Biocraft
Laboratories Inc., 874 F.2d 804, 807, 10 USPQ2d 1843, 1846 (Fed. Cir.
1989) (quoting In re Lamberti, 545 F.2d 747, 750, 192 USPQ 278, 280
(CCPA 1976) (“[I]n section 103 inquiry . . . ‘all disclosures of the prior art,
including unpreferred embodiments, must be considered.’”).
For these reasons, we determine the preponderance of the evidence
supports Examiner’s rejection of claim 70 and, therefore, affirm Rejection I.
Having found no deficiency in the rejection of claim 70 over the
combination of Centeno, Grayson, and DiGirolamo, we are not persuaded by
Appellant’s contentions that Ma, Toner, DiMauro, and Schallmoser fail to
make up for Appellant’s alleged deficiencies in the combination of Centeno,
Grayson, and DiGirolamo (see Appeal Br. 17–18). Because Appellant failed
to identify an error with respect to the combination of Centeno, Grayson,
DiGirolamo, together with Ma, Toner, DiMauro, or Schallmoser, we affirm
Rejections II–V as well.
DECISION SUMMARY
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
70, 73, 74,
77, 82, 83
103 Centeno, Grayson,
DiGirolamo
70, 73, 74,
77, 82, 83

71, 80 103 Centeno, Grayson,
DiGirolamo, Ma
71, 80
72, 81 103 Centeno, Grayson,
DiGirolamo, Toner
72, 81
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Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
70, 73–75,
77, 82–84
103 Centeno, Grayson,
DiGirolamo, DiMauro
70, 73–75,
77, 82–84

78, 85 103 Centeno, Grayson,
DiGirolamo,
Schallmoser
78, 85
Overall
Outcome
70–75, 77,
78, 80–85

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).

AFFIRMED