Regenerative Sciences, LLC

Patent Trials and Appeals Board

Jul 8, 2020

2019006371 (P.T.A.B. Jul. 8, 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.
15/891,852 02/08/2018 Christopher J. Centeno BRT-004CIP 3123
26285 7590 07/08/2020
K&L GATES LLP-Pittsburgh
210 SIXTH AVENUE
PITTSBURGH, PA 15222-2613
EXAMINER
SCHUBERG, LAURA J
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
07/08/2020 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):
USpatentmail@klgates.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte CHRISTOPHER J. CENTENO
____________

Appeal 2019-006371
Application 15/891,852
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 appeal under 35 U.S.C. § 134(a) involving
claims to methods of culturing nucleated cells harvested from a patient 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.
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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. ¶ 61.
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.
Claims 5–25 are on appeal and can be found in the Claims Appendix
of the Appeal Brief. Claims 5 and 25 are illustrative of the claims on appeal.
They read as follows:
5. A method for treating an avascular zone in a patient in
need thereof, the method comprising:
culturing nucleated cells harvested from the patient in
need thereof in a culture medium under a selective pressure
of about 1% to about 10% oxygen for 1–28 days;
selecting viable mesenchymal stem cells capable of
growth in the culture medium under the selective pressure of
about 1% to about 10% oxygen; and
providing the selected, viable mesenchymal stem cells
for implantation in the avascular zone.

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25. A method for treating an avascular zone in a patient in
need thereof, the method comprising:
first culturing nucleated cells harvested from the patient
in need thereof in a culture medium under a selective
pressure of about 1% to about 10% oxygen for 1–28 days;
subsequent to the first culturing, selecting viable
mesenchymal stem cells capable of growth in the culture
medium under the selective pressure of about 1% to about
10% oxygen; and
providing the selected, viable mesenchymal stem cells
for implantation in the avascular zone.
Appeal Br. 23, 26.
Appellant seeks review of the following rejections:2
I. Claims 5–7, 12–14,3 and 18–25 under 35 U.S.C. § 103 as
unpatentable over Centeno4 and Grayson;5
II. Claims 8 under 35 U.S.C. § 103 as unpatentable over Centeno,
Grayson, and Ma;6
III. Claims 8 and 9 under 35 U.S.C. § 103 as unpatentable over Centeno,
Grayson, and Kolesnikova;7

2 The obviousness-type double patenting rejection of claims 1, 6, 11, 12, 19,
22, 23, 30–34, 39, 42, 44, 47, 49, 80, 81, 83, 84, and 86 referred to
Examiner’s Answer (see Ans. 15) was withdrawn prior to the appeal in an
Advisory Action mailed January 2, 2019.
3 It is clear that Examiner included claim 14 in the obviousness rejection of
these claims. See Final Act 5 (referring to claim 14). We likewise interpret
the Appeal Brief to include claim 14 in the arguments Appellant makes
regarding this rejection.
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 US 6,875,605 B1, issued April 5, 2005 (“Ma”).
7 RU 2323252, published April 27, 2008 (“Kolesnikova”).
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IV. Claim 10 under 35 U.S.C. § 103 as unpatentable over Centeno,
Grayson, and Toner;8
V. Claims 11 and 22 under 35 U.S.C. § 103 as unpatentable over
Centeno, Grayson, and Schallmoser;9
VI. Claims 15–17 under 35 U.S.C. § 103 as unpatentable over Centeno,
Grayson, Binette,10 and Bennett;11 and
VII. Claims 5–25 as provisionally rejected for obviousness-type double
patenting over claims 70–75, 77, 78, and 80–86 of U.S. Patent
Application No. 13/132,840 (the “’840 Application”).
Appeal Br. 8.
I. OBVIOUSNESS REJECTIONS I–VI
Issue
All of Examiner’s obviousness rejections are premised on the same
combination of Centeno and Grayson. Appellant does not present separate
arguments for Rejections II–VI, but instead relies on the same arguments it
presents for claim 5 in the first rejection. See Appeal Br. 18–21.
Accordingly, we consider the obviousness rejections together in our
analysis. We select claim 5 as representative of claims 6–24, which are not
argued separately from claim 5. 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 5

8 US 2004/0248293 A1, published Dec. 9, 2004 (“Toner”).
9 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”).
10 US 2005/0038520 A1, published Feb. 17, 2005 (“Binette”).
11 US 2003/0198687 A1, published Oct. 23, 2003 (“Bennett”).
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obvious. In addition to its arguments regarding claim 5, Appellant presents
a separate argument for claim 25 that we likewise address below.
Findings of Fact
FF1. Centero teaches methods for autologous transplantation of MSCs and
progenitor helper cells (PHC) “from bone marrow to degenerated
intervertebral discs or joints.” Centero ¶ 17; Abstr. In particular, Centero
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. Centero 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.
Centero ¶ 18.
FF3. According to Centero,
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.
Centero ¶ 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, Centero teaches that its method is
“designed to be used by operating room staff . . . during the same surgical
procedure as transplantation.” Id. ¶ 17; Abstr. However, Centero also
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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.
FF4. For example, Centero 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.” Centero ¶ 27.
Centero teaches “[t]his alternative selection method may be performed at an
on or off-site clinical lab.” Id.
FF5. Centero 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.” Centero ¶ 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.
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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
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.
Analysis
Claims 5–24
Examiner finds that Centero “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. 3–4. Examiner acknowledges that Centero “is
silent with regard to the culture conditions . . . for expansion of the selected
MSCs,” but finds that Grayson teaches culturing and expanding MSCs under
hypoxic conditions as recited in claim 5 “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
teach that these percentages provide improved expansions
characteristics for MSCs. The culturing of the MSCs under
hypoxic conditions would also provide for the selection of
MSCs capable of surviving under low oxygen conditions after
culturing for at least one day. One of ordinary skill in the art
would have had a reasonable expectation of success because
Grayson teach that hypoxic conditions select for MSCs that are
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more primitive with a higher CFU-F number that correlates
with high in vitro lifespan and extended proliferation.
Id. at 4–5.
We adopt the Examiner’s findings and reasoning regarding the scope
and content of the prior art (Final Act. 3–5; FF1–FF7) and agree that claim 5
is obvious over the articulated combination of Centero and Grayson. We
address Appellant’s arguments below.
Appellant argues that Examiner’s combination of Centero and
Grayson is “actively discouraged by Centero.” See Appeal Br. 10–16. More
specifically, Appellant contends that Examiner’s finding that Centero
“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” Centero “provides no motivation for adding an in-vitro culturing
step” and that “by relying on a single statement in Centero ’519 that
conflicts with the entirety of the remaining teachings of Centero ’519, the
Office has engaged in improper hindsight analysis.” Id. at 14–15 (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, Centero
does not actively discourage expanding MSCs prior to implanting them. To
the contrary, Centero describes a method that includes an expansion step in a
lab (i.e., in vitro) as an “alternative[]” embodiment of Centero’s invention.
FF5. It is true that in some instances Centero expresses a preference for a
selection method that can be practiced by operating room staff as part of the
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same procedure. Centero ¶¶ 5, 7, 17. However, there are also multiple
instances in which Centero 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 Centero
paragraph 5 as evidence that Centero “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 Centero” 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, Centero 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, Centero 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 Centero 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
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
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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, Centero paragraph 28 is not
setting up a strawman to distinguish its invention; rather paragraph 28
describes an alternative embodiment of Centero’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 are inconsistent and therefore
that they would “disregard the statement in paragraph [0028]” if they were
reading Centero 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
declarants, even attempt to reconcile paragraph 28 with their arguments as to
what the rest of Centero discloses. We, however, decline Appellant’s
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invitation to disregard paragraph 28 because doing so would conflict with
Centero’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 5 and therefore affirm. We affirm
the rejection of claims 6–24 for the same reasons.
Claim 25
In addition to the arguments concerning claim 5, which we determine
are unpersuasive for the reasons explained above, Appellant argues that
Centeno “clearly requires obtaining a specific population of cells comprising
MSCs via a first selecting step, which is exactly opposite the limitations of
claim 25 that recites a first culturing step followed by a selection step.”
Appeal Br. 17–18.
We are not persuaded by Appellant’s additional argument for claim
25. As Examiner correctly points out, “a selection step prior to culturing is
not excluded from claim 25 due to the transitional phrase of ‘comprising’”
and “culturing the nucleated cells under hypoxic conditions is itself a
selection step as it only allows for MSCs (which are nucleated cells) capable
of surviving under these conditions to remain viable for collections upon its
conclusion.” Ans. 12; FF6–FF7. Thus, the combination of Centero’s
harvesting and expansion steps with Grayson’s hypoxic culturing and
selection conditions, as articulated by Examiner, reads on the method of
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claim 25. See FF1–FF7. This is true even if another selection step is
performed prior to culturing and subsequently selecting the MSCs under
hypoxic conditions.
Accordingly, we likewise determine that the rejection of claim 25 is
supported by a preponderance of the evidence.
II. PROVISIONAL DOUBLE PATENTING REJECTION
In addition to the above rejections, Examiner provisionally rejected
claims 5–25 for ODP over certain claims of Appellant’s co-pending ’840
Application. Final Act. 15. Appellant argues the rejection is “premature”
and asks that the rejection be “withdrawn or stayed” at least until the claims
of the ’840 Application “issue as a patent.” Appeal Br. 21.
Appellant does not, however, present any argument that claims 5–25
are patentably distinct from the claims of the ’840 Application identified in
Examiner’s rejection. Appellant also did not file a terminal disclaimer to
moot this rejection. Thus, on this record, Appellant has not contested the
merits of Examiner’s provisional ODP rejection.
“If a ground of rejection stated by the examiner is not addressed in the
appellant’s brief, appellant has waived any challenge to that ground of
rejection and the Board may summarily sustain it.” MPEP § 1205.02 (9th
Ed., Rev. 08.2017 (Jan. 2018)).
For the foregoing reasons, we summarily affirm this rejection.

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DECISION SUMMARY
Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
5–7, 12–
14, 18–25
103 Centeno, Grayson 5–7, 12–
14, 18–25

8 103 Centeno, Grayson, Ma 8
8, 9 103 Centeno, Grayson,
Kolesnikova
8, 9
10 103 Centeno, Grayson,
Toner
10
11, 22 103 Centeno, Grayson,
Schallmoser
11, 22
15–17 103 Cenento, Grayson,
Binette, Bennett
15–17
5–25 Provisional
Obviousness-type
Double Patenting
5–25
Overall
Outcome
5–25

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