Vivex Biologics Group, Inc.

Patent Trials and Appeals Board

Dec 17, 2021

2021002099 (P.T.A.B. Dec. 17, 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.
14/706,165 05/07/2015 Theodore I. Malinin DN0262 6717
119489 7590 12/17/2021
Vivex Biologics Group, Inc.
David L. King
5131 NE County Road 340
High Springs, FL 32643
EXAMINER
FOX, ALLISON M
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
12/17/2021 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):
davidlkingsr@windstream.net
uspto@dockettrak.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte THEODORE I. MALININ, DOROTHY R. MALININ, and
WENDY W. WESTON
Appeal 2021-002099
Application 14/706,165
Technology Center 1600
BEFORE ERIC B. GRIMES, JEFFREY N. FREDMAN, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
SCHNEIDER, Administrative Patent Judge.
DECISION ON APPEAL
STATEMENT OF THE CASE
Pursuant to 35 U.S.C. § 134(a), Appellant appeals from the
Examiner’s decision to reject claims 13 and 22.1 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 Vivex Biologics Group, Inc. as the real party
in interest. Appeal Br. 3.
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CLAIMED SUBJECT MATTER
The claims are directed to a method of using cells derived from
multilineage stem cells from peripheral blood. Claim 13, reproduced below,
is illustrative of the claimed subject matter:
13. A method of using a therapeutically effective amount of a
composition or mixture having cells derived from a patient
donor, the composition or mixture having bone and osteogenic
cells, wherein the osteogenic cells are derived from a patient-
donor from isolated, post-natal, multilineage inducible,
morphologically distinct cells which express levels of CD90
and levels of CD45 similar to stem cells derived from bone
marrow while being devoid of immune cell markers HLA-DR,
a MHC class II cell surface receptor, and CD34, which are
derived from stem cells from peripheral blood of a patient-
donor to treat a bone disorder or a cartilage disorder exhibited
by the patient-donor consisting of the steps of:
(a) first obtaining fresh peripheral blood from a patient-
donor through venipuncture,
(b) collecting the blood in containers containing heparin,
(c) aliquoting the blood into centrifuge tubes,
(d) centrifuging the tubes from step (c) to obtain an adequate
amount of cells separated into rings,
(e) collecting the cells from the separated rings,
(f) pooling the cells collected from the separated rings into
tubes,
(g) filling the tubes from step (f) with PBS,
(h) centrifuging the tubes from step (g) to form a supernatant
and a cell pellet,
(i) aspirating off the supernatant,
(j) re-suspending the cell pellet in either an expansion
media, culture media or balanced salt solution,
(k) isolating cells from the cell pellet, wherein said cells
derived exclusively from the patient donor’s peripheral blood
express some level of CD90 and some level of CD45, but do
not express HLA-DR or CD34,
(l) culturing said cells of step (k) in a medium to induce
osteogenic differentiation,
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(m) contacting the osteogenic cells from step (l) with freeze-
dried, dehydrated, cryopreserved or fresh particulate bone to
create a composition or mixture of osteogenic cells from step (l)
and bone particles,
(n) placing the composition in a delivery system, said
delivery system being a pre-filled syringe or a sealed container
or vial, and
(o) administering the composition or mixture to the patient-
donor.

REFERENCES
The prior art relied upon by the Examiner is:
Ukai et al., Mesenchymal Stem Cells Derived from Peripheral Blood
Protects against Ischemia, Journal of Neurotrauma, 24, 3, 508–520,
(2007) hereinafter “Ukai”
Kim et al., Comparison of osteogenic potentials of autologous cultured
osteoblasts and mesenchymal stem cells loaded onto allogenic cancellous
bone granules, Cell Tissue Res., 347, 303–310 (2012) hereinafter “Kim”
Chong et al. , Human Peripheral Blood Derived Mesenchymal Stem Cells
Demonstrate Similar Characteristics and Chondrogenic Differentiation
Potential to Bone Marrow Derived Mesenchymal Stem Cells, Journal of
Orthopaedic Research, 30, 634–642 (2012), hereinafter “Chong”
Mapara et al., Rabbit as an animal model for experimental research,
Dental Research Journal, Vol. 9, iss. 1, 111–116 (2012), www.mul.ac.ir
last visited Nov. 2021, hereinafter “Mapara”
Fu et al., A New Source of Mesenchymal Stem Cells for Articular
Cartilage Repair, The American Journal of Sports Medicine, 42, 3, 592–
601 (2013) hereinafter “Fu”
Kotikalapudi et al., Comparative Study of the Influence of EDTS and
Sodium Heparin on Long Term Storage of Cattle DNA, Cell Journal, 17,
1, 181–186 (2015), hereinafter “Kotikalapudi”

REJECTIONS
The Examiner has rejected the claims as follows:
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Claim 13 has been rejected under 35 U.S.C. § 103 as unpatentable
over Kim in view of Chong, Ukai, Kotikalapudi and Fu.
Claim 22 has been rejected under 35 U.S.C. § 103 as unpatentable
over Kim in view of Mapara, Chong, Ukai, Kotikalapudi and Fu.
OPINION
Claim 13
The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claim 13 would have been obvious to one of ordinary skill in the art at the
time the invention was made over Kim combined with Chong, Ukai,
Kotikalapudi and Fu.
The Examiner finds Kim teaches a method for managing bone defects
by treating rabbits with undifferentiated mesenchymal stem cells (“MSCs”)
mixed with allogenic bone granules. Final Act. 6–7. The Examiner finds that
the MSCs were prepared using a method comparable with steps a–m and o
of claim 13. Id. at 7. The Examiner finds that the method taught in Kim
differs from claim 13 in that Kim does not teach isolating MSCs from
peripheral blood and Kim does not teach the step of placing the composition
in a delivery system comprising either a pre-filled syringe or in a sterile vial
or container. Id. at 8.
The Examiner finds Chong and Ukai teach that MSCs derived from
peripheral blood have the same osteogenic potential as MSCs derived from
marrow. Id. The Examiner finds
Thus one having ordinary skill in the art would have found it
prima facie obvious to have used MSCs derived from fresh
peripheral blood of the patient to be treated, in place of MSCs
from bone marrow in the method of Kim et al. This conclusion
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of obviousness is based on a motivation that would have been
apparent to one skilled in the art: harvesting of peripheral blood
. . . from a patient is less invasive than harvesting of bone
marrow. Thus, in order to reduce trauma to the
donor/recipient/patient, one would have been motivated to have
obtained MSCs from peripheral blood instead of bone marrow,
as the cell types were otherwise recognized as the same. It is
noted that peripheral blood-derived MSCs are art-recognized
equivalents for bone marrow-derived MSCs (as evidenced by
both Chong et al and Ukai et al). Both are taught to have
osteogenic potential (as evidenced by Chong et al and Ukai et
al). Alternatively the holding of obviousness can also be based
on the rationale that substitution of one element for another
known in the field is considered obvious. Again, both Chong et
al and Ukai et al indicate that MSCs from bone marrow and
peripheral blood were recognized as suitable alternatives for
one another in terms of osteogenic potential. As such, one
would have had a reasonable expectation that substitution of
one for the other would have yielded predictable results in so
far as being a precursor for generation of osteoblasts in the
method of Kim et al. One would have had a reasonable
expectation of success because both Chong et al and Ukai et al
teach that MSCs exist in peripheral blood and can be isolated
based on known techniques, and that the MSCs have osteogenic
potential.

Id.
The Examiner finds Chong does not teach the use of heparin but uses
EDTA-K2 as an anticoagulant. Id. at 9. The Examiner finds that it would
have been obvious to substitute heparin for EDTA-K2 as both are known to
be suitable anticoagulants. Id.
With respect to the phenotype of the peripheral blood- (PB-) derived
MSCs, the Examiner finds that while Chong is silent about the phenotype,
because the PB-derived MSCs are the same as the cells
described by the instant specification, noting the cells are
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isolated in the same manner as taught by the prior art, and
because cell phenotypes are inherent to the cells, then there is
reasonable basis to conclude that the PB-derived MSCs of the
prior art have identical HLA-DR expression (or lack thereof) as
the cells of the current claims. Because the Examiner has
provided basis for concluding that the prior art PB-derived
MSCs meet the current claim limitations, burden of showing
otherwise is shifted to Applicants.

Id. at 10.
Finally, with respect to the limitation calling for the composition be
loaded into a delivery device, the Examiner finds
Kim et al teach the osteoblasts are seeded onto the allogeneic
bone granules and incubated for 48 hours. Thus the osteoblasts
and bone granules are necessarily present in some sort of
container or vial. In order to transfer the osteoblasts and bone
granule composition from the container or vial to the bone
defect site, it would have been prima facie obvious to one
having ordinary skill in the art to have used a syringe. It is
noted that the composition of Kim et al includes granules of
bone, not blocks, thus the granules would be extrudable through
an appropriately sized syringe. Use of syringes to administer
biological materials to in vivo locations is well within the
purview of the artisan of ordinary skill and does not represent a
patentable distinction over the method of Kim et al. Therefore
the claimed step (n) placing the composition in a delivery
system, said delivery system being a pre-filled syringe, sealed
container or vial is considered prima facie obvious over the
prior art.

Id.
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On appeal, Appellant contends that the Examiner failed to properly
consider the declarations submitted by one of the inventors, Dr. Weston.2
Appeal Br. 18–19. Appellant contends that the Examiner improperly
discounted the affidavits because the Examiner found that the inventor had
an interest in the outcome. Id. at 18. Appellant contends Dr. Weston’s
Declarations show why the Examiner’s assumptions are in error, especially
with respect to whether rabbit blood can be compared with human blood and
why EDTA-K2 is not the same as heparin. Id. at 19.
We adopt the Examiner’s findings of fact, reasoning on scope and
content of the prior art, and conclusions set out in the Final Action and
Answer regarding this rejection. We find the Examiner has established a
prima facie showing that the subject matter of claim 13 would have been
obvious over Kim combined with Chong, Ukai, Kotikalapudi and Fu to a
person of ordinary skill in the art at the time the invention was made.
Appellant has not produced evidence showing, or persuasively argued, that
the Examiner’s determinations on obviousness are incorrect. Only those
arguments made by Appellant in the Briefs have been considered in this
Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R.
§ 41.37(c)(1)(iv) (2015).
Appellant contends that the Examiner improperly gave the
declarations of Dr. Weston little weight, arguing that the Examiner found
that Dr. Weston, as an inventor, had an interest in the outcome of this
examination. Appeal Br. 18. We are not persuaded by this argument.

2 Declaration Under 37 C.F.R. § 1.132 from Wendy W. Weston, filed July
1, 2019 (“2019 Decl.”) and Declaration Under 37 C.F.R. § 1.132 from
Wendy W. Weston, filed Jan. 10, 2020 (“2020 Decl.”).
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We have reviewed the Declarations submitted by Dr. Weston as well
as the official actions which address those declarations.3 While the Examiner
did note that Dr. Weston was an inventor and may have an interest in the
case, the Examiner made specific findings regarding the references of record
including those cited by Dr. Weston in the Declarations. See, e.g. 2020 Act.
8–10. As the Examiner noted, the Declarations were fully considered and
were found unpersuasive in light of the prior art and evidence of record.
Appellant contends that Dr. Weston specifically rebutted the
Examiner’s positions regarding rabbit blood versus human blood and why
EDTA-K2 is not the same as heparin. Appeal Br. 19. We have considered
Dr. Weston’s testimony as well as the references of record and are not
persuaded that the rejection is in error.
We begin by noting that Dr. Weston testified about whether rabbit
models could be extrapolated to humans because of differences in bone
microstructure not blood. See 2019 Decl. 2. In the 2019 Declaration, Dr.
Weston points to teachings in Wang4 and Castaneda5 that point out
differences between rabbit bones and human bones. Id. While Dr. Weston
points out the passages that suggest there are differences between human and
rabbit bone systems, we discern nothing in Dr. Weston’s Declaration to

3 Non-Final Action mailed Sept. 18, 2019 (“2019 Act.”) and Final Action
mailed March 20, 2020 (“2020 Act.”).
4 Wang et al., An interspecies comparison of bone fracture properties, 8
Bio-Med. Mat. And Eng. 1 (1998) (“Wang”).
5 Castaneda et al., Bone mineral measurements of subchronal and
trabecular bone in healthy and osteoporotic rabbits, 35 Sketetal Radiol. 34
(2006) (“Castaneda”).
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support the position that one skilled in the art would not consider rabbits a
suitable model for human systems. See 2020 Decl. 2–3.
Moreover at least three references of record support the Examiner’s
conclusion that one skilled in the art would use rabbit models as surrogates
for human subjects. Castaneda teaches “In summary, experimental models of
osteoporosis in rabbits can be very helpful, especially to investigate agents
with bone anabolic properties, because this animal has a fast bone turnover
with predominant remodeling [sic] over the modelling processes in
comparison with other species.” Castaneda, 39. Mapara teaches that rabbits
are a good model for studying bone based applications. Mapara, 117. Kim
used a rabbit model to develop its conclusions about the use of MSCs to
promote bone regeneration. See Kim, 303.
Appellant contends that Dr. Weston’s testimony rebuts the
Examiner’s conclusion that EDTA-2 is not the same as heparin. Appeal Br.
19. In support of this contention, Dr. Weston cites to Lima-Oliveira6 and
Kotikalapudi which discuss the differences between EDTA-K2 and heparin
including the potential of EDTA-K2 affecting the results of certain tests.
2020 Decl. 3.
We have considered the arguments of both the Examiner and
Appellant as well as Dr. Weston’s testimony and the references of record
and are not convinced that the rejection is in error. While Dr. Weston
testified that EDTA-K2 prevents coagulation of blood using a different
mechanism than heparin, and that in some instances it may produce different

6 Lima-Oliveira et al., Contamination of lithium heparin blood by K2-
ethylenediaminetretraacetic acid (EDTA): an experimental evaluation, 24
Biochemia Medica 359 (2014) (“Lima-Oliveira”)
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results we do not agree that this would lead one skilled in the art away from
substituting heparin for EDTA-K2 in the system taught in Chong.
As Dr. Weston testified, “[h]eparin is the normal anticoagulant used in
blood collection.” 2020 Decl. 3. Kotikalapudi teaches “Comparative studies
revealed that the DNA samples extracted from blood using [heparin and
EDTA] give more or less the same quality of results especially for
polymerase chain reaction (PCR) based applications in cattle.” Kotikalapudi
Abstract. We agree with the Examiner that it would have been obvious to
substitute heparin for EDTA-K2. Ans. 4. “[W]hen a patent claims a structure
already known in the prior art that is altered by the mere substitution of one
element for another known in the field, the combination must do more than
yield a predictable result.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416
(2007) (citing United States v. Adams, 383 U.S. 39, 50–51 (1966)).
Moreover, we do not find the teachings of Lima-Oliveira would lead
one skilled in the art away from making the substitution proposed by the
Examiner. One skilled in the art reading that the use of EDTA-K2 could
produce erroneous results would be motivated to substitute heparin for
EDTA-K2 in the method taught in Chong.
Based on the foregoing we conclude that a preponderance of the
evidence supports the Examiner’s conclusion that the subject matter of claim
13 would have been obvious to one skilled in the art at the time the invention
was made over Kim combined with Chong, Ukai, Kotikalapudi and Fu.

Claim 22
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The issue with respect to this rejection is whether a preponderance of
the evidence supports the Examiner’s conclusion that the subject matter of
claim 22 would have been obvious to one of ordinary skill in the art at the
time the invention was made over Kim combined with Mapara, Chong,
Ukai, Kotikalapudi and Fu.
The Examiner reiterates her findings with respect to Kim and Chong
as well as her conclusion with respect to the use of a delivery system. Final
Act. 11–12.
The Examiner also finds
While Kim et al use New Zealand White rabbits as an animal
model, the method of Kim et al renders obvious therapeutic
treatment of bone defects in humans. The motivation to apply
the method of Kim et al to humans is that science seeks to find
cures to human ailments, thus one would have been motivated
to apply the successful method of Kim et al to human patients
experiencing bone loss/defects/fracture. One would have a
reasonable expectation of successfully extending the method of
Kim et al to humans because New Zealand White rabbits are an
art accepted model for human bone defects (See Mapara et al).
Thus, the method of Kim et al renders obvious treating a human
patient-donor having a bone disorder (i.e. a fracture or bone
defect) with autologous MSCs differentiated into osteoblasts
and combined with allogenic bone granules.

Id. at 12.
Appellant reiterates the arguments addressed above with respect to
claim 13. Appeal Br. 21–22. For the reasons stated above, we find these
arguments unpersuasive.
Appellant also contends that none of the references show that the
isolated cells have the required cell markers and lack HLA-DR, MSC class
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II and CD34 as required by the claims. Appeal Br. 22. We are not persuaded
by this argument.
As the Examiner points out
Chong et al does describe PB-Derived MSCs as CD34- (See
Chong et al, abstract); Ukai describes PB-derived MSCs as
CD90+ with a low number of contaminating CD45+ cells (See
Ukai et al, Pg 511 “Characteristics of BM Cs and PM Cs” at
column 2, and Fig. 1D); thus the PB-derived MSCs of the prior
art do meet the limitation express levels of CD90 and levels of
CD45 and do not express CD34 marker. The prior art is silent
as to HLA-DR expression in PB-derived MSCs. However,
because the PB-derived MSCs are the same as the cells
described by the instant specification, noting the cells are
isolated in the same manner as taught by the prior art, and
because cell phenotypes are inherent to the cells, then there is
reasonable basis to conclude that the PB-derived MSCs of the
prior art have identical HLA-DR expression (or lack thereof) as
the cells of the current claims. Because the Examiner has
provided basis for concluding that the prior art PB-derived
MSCs meet the current claim limitations, burden of showing
otherwise is shifted to Applicants. See MPEP 2112(V).

Final Act. 10.
“Where . . . the claimed and prior art products are identical or
substantially identical . . . the PTO can require an applicant to prove that the
prior art products do not necessarily or inherently possess the characteristics
of his claimed product. [The] fairness [of the burden-shifting] 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). Here
Appellant has not offered any persuasive evidence that the MSCs of the
prior art do not inherently and necessarily have the characteristics recited in
claim 22.
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Finally, Appellant contends that the rejection is based on the improper
use of hindsight. Appeal Br. 22. We remain unpersuaded that the rejection is
in error.
“Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it takes into
account only knowledge which was within the level of ordinary skill at the
time the claimed invention was made and does not include knowledge
gleaned only from applicant’s disclosure, such a reconstruction is proper.”
In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971). Appellant has not
pointed to any knowledge gleaned only from Appellant’s disclosure that
serves as the basis for the rejection. As the Examiner points out, both Kim
and Ukai teach that the MSCs would have most if not all of the
characteristics of the claimed MSCs and that the differentiation methodology
used by the references is the same as the claimed method. Final Act. 10. This
supports the conclusion that the rejection is based on the teachings of the
references and not knowledge gleaned from the present disclosure.
Based on the foregoing we conclude that a preponderance of the
evidence supports the Examiner’s conclusion that the subject matter of claim
22 would have been obvious to one of ordinary skill in the art at the time the
invention was made over Kim combined with Mapara, Chong, Ukai,
Kotikalapudi and Fu.
CONCLUSION
The Examiner’s rejections are affirmed.
More specifically, the rejection of claim 13 under 35 U.S.C. § 103 as
unpatentable over Kim in view of Chong, Ukai, Kotikalapudi and Fu is
affirmed.
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The rejection of claim 22 under 35 U.S.C. § 103 as unpatentable over
Kim in view of Mapara, Chong, Ukai, Kotikalapudi and Fu is affirmed.

DECISION SUMMARY
In summary:

Claims
Rejected
35 U.S.C. § Reference(s)/Basis Affirmed Reversed
13 103 Kim, Chong, Ukai,
Kotikalapudi, Fu
13
22 103 Kim, Mapara,
Chong, Ukai,
Kotikalapudi, Fu
22
Overall
Outcome
13, 22

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