Ex Parte Elia

Patent Trial and Appeal Board

Aug 18, 2016

11986690 (P.T.A.B. Aug. 18, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
111986,690 11/26/2007
45018 7590 08/22/2016
GERALD K. WHITE & ASSOCIATES, P.C.
13414 W. Oakwood Ct.
Suite 100
Homer Glen, IL 60491-8154
FIRST NAMED INVENTOR
James P. Elia
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
1000-10-CP A 3786
EXAMINER
GAMETT, DANIEL C
ART UNIT PAPER NUMBER
1647
NOTIFICATION DATE DELIVERY MODE
08/22/2016 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):
gkwpatlaw@aol.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JAMES P. ELIA
Appeal2014-003528
Application 11/986,6901
Technology Center 1600
Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and
JEFFREY N. FREDMAN, Administrative Patent Judges.
LEBOVITZ, Administrative Patent Judge.
DECISION ON APPEAL
This appeal involves a claim to a method of growing and integrating a
desired artery at a selected site in a body of a human patient. The Examiner
rejected the claims for lack of enablement. We have jurisdiction under
35 U.S.C. § 134. The rejection is reversed.
STATEMENT OF THE CASE
Claim 6 is the only pending claim and reads as follows:
6. A method of growing and integrating a desired artery at a
selected site in a body of a human patient comprising the steps
of locally placing living stem cells harvested from bone marrow
1 The '690 Application.
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Application 11/986,690
in a body of a human patient at said selected site and growing
said desired artery which integrates itself into said body at said
selected site.
Appellant appeals from the Examiner's final rejection of claim 6
under 35 U.S.C. § 112, first paragraph (pre-AIA), as failing to comply with
the enablement requirement. Final Rej. 2.
RELATED APPEALS
The '690 application is related to Application 09/794,456 which was
the subject of Appeal 2011-013556 appealed to the Patent Trial and Appeal
Board (PT AB). The claims in the appeal involved forming a new artery
with cells and causing a dead portion of a heart to be repaired. The claims
were rejected for lack of enablement. The appeal was decided Sept. 28,
2012. The Examiner's rejection was affirmed. The application is
abandoned.
The '690 application is also related to Application 13/038;563 which
was the subject of Appeal 2013-002510 to the PTAB. The claims in the
appeal involved treating a brain in a human patient having a damaged
portion caused by a stroke by placing a growth factor at a selected area of
the patient and forming an artery in the brain. The claims were rejected for
lack of enablement. The appeal was decided Mar. 16, 2016. The
Examiner's rejection was affirmed. The application is abandoned.
ENABLEMENT REJECTION
Section 112, first paragraph (pre-AIA), of 35 U.S.C. requires that the
specification of a patent describe "the manner and process of making and
using [the invention], in such full, clear, concise, and exact terms as to
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enable any person skilled in the art to which it pertains ... to make and use
the same." 35 U.S.C. § 112, first paragraph (pre-AIA). A specification is
not enabling if a person of ordinary skill in the art would be unable to
practice the invention without "undue experimentation." In re Wands, 858
F.2d 731, 737 (Fed. Cir. 1988). Factors relevant to a determination of
whether undue experimentation would be necessary include:
(1) the quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence of
working examples, ( 4) the nature of the invention, ( 5) the state
of the prior art, ( 6) the relative skill of those in the art, (7) the
predictability or unpredictability of the art, and (8) the breadth
of the claims.
Id. (footnote omitted).
When rejecting a claim for lack of enablement, the initial burden is on
the PTO to set forth "a reasonable explanation" of why it believes the
specification is not enabling. In re Wright, 999 F.2d 1557, 1561---62 (Fed.
Cir. 1993). The burden then shifts to the applicant to provide "suitable
proofs indicating that the specification is indeed enabling." Id. at 1562.
In this case, we begin with addressing the breadth of the claim. Claim
6 is directed to a method of "growing and integrating a desired artery at a
selected site in a body of a human patient comprising the steps of locally
placing living stem cells harvested from bone marrow." The only cell type
covered by the claims are "living stem cells harvested from bone marrow."
The Examiner raised questions about the adequacy of the written
description in the '690 Application of the use of stem cells from bone
marrow to grow artery. Answer 15-16, 41--43 (especially, paragraph
spanning pages 41--42). We reviewed the '690 Application, and as
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explained in more detail below, we conclude that claim 6 is adequately
described in it.
The '690 Application describes stem cells harvested from bone
marrow:
Living stem cells are harvested from the bone marrow, the
blood of the patient, or from cell culture techniques.
'690 Application 40: 27-28.
The '690 Application describes the use of stem cells to form organs,
such as arteries:
Organs and/ or tissues can be formed utilizing the patient's
own cells .... A cell nutrient culture may or may not be utilized
depending on the desired functional outcome (i.e., growth of an
artery, of pancreatic Islet cells, of a heart, etc.) or other
circumstances. Replantation can occur at any appropriate stage
of morphogenesis. The foregoing can be repeated without the
patient's own cells if universal donor cells such a germinal cells
are utilized. . . .
In the example above, if germinal cells (and in some cases,
stem cells) are utilized a direct differentiation and morphogenesis
into an organ can occur in vivo, ex vivo, or in vitro.
Id. at 47:22 to 48:15 (emphasis added).
The only stem cells mentioned in the '690 Application are those
harvested from bone marrow (id. at 40: 27-28). Consequently, the skilled
worker would have recognized that the specific mention of stem cells on
page 48 (see supra) to grow organs includes the disclosed "[l]iving stem
cells . . . harvested from the bone marrow" (id. at 40: 27-28). The same
passages on pages 47--48 also refer to the growth of an artery, completing
the description of providing a stem cell harvested from bone marrow to grow
an artery. In sum, these disclosures provide adequate evidence that the
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inventor had possession of the claimed subject matter as of the filing date.
Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir.
2010)(en bane).
Was it credible at the time of the invention that an artery could be grown
with bone marrow stem cells?
The Examiner acknowledged that Isner '2252 and Isner 19953 "make
it credible that arteries may form in response to constitutive expression of
VEGF." Answer 4. However, the Examiner found that these publications
"do not establish that one of ordinary skill in the art would have reasonably
expected that arteries comprising endothelial and smooth muscles would be
formed by stem cells harvested from bone marrow, or any cell placed in a
patient, as recited in the claim under consideration." Id. We note that the
only cell type "under consideration" is a living cell "harvested from bone
marrow."
To support the lack of credibility that arteries could be grown with
bone marrow stem cells, the Examiner cited Isner '8874 and Asahara. 5 Isner
'887 teaches endothelial cell ("EC") progenitor cells incorporate into arteries
and capillaries, and are found within the smooth muscle cell layer after
2 Isner, US 5,652,225, issued July 29, 1997 ("Isner '225").
3 Isner et al., Arterial Gene Therapy for Therapeutic Angiogenesis in
Patients With Peripheral Artery Disease, 91 Circulation 2687-2692 (1995)
("Isner 1995").
4 Isner et al., US 5,980,887, issued Nov. 9, 1999 ("Isner '887'')
5 Asahara et al., Isolation of Putative Progenitor Endothelial Cells for
Angiogenesis, 275 Science 964--967 (1997) ("Asahara").
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introduction into a denuded artery. Isner '887, Abstract; col. 15, 11. 35----67.
Isner '887 does not teach that the EC progenitors form arteries (id.).
Isner '887 teaches that the EC progenitor cells "may be obtained from
human mononuclear cells obtained from peripheral blood or bone marrow of
the patient" and that the cells are isolated from blood or marrow using
antibodies, such as antibodies to CD34. Id. at col. 6, 11. 49-50, 54----60. Isner
'887 also discloses:
We have now discovered a means to regulate angiogenesis, to
promote angiogenesis in certain subject populations, and to more
precisely target certain tissues. These methods all involve the use
of endothelial cell [EC] progenitors. One preferred progenitor
cell is an angioblast.
Id. at col. 5, 11. 21-25.
In contrast to angiogenesis, vasculogenesis typically begins as a
cluster formation, or blood island, comprised of EC progenitors
(e.g. angioblasts) at the periphery and hematopoietic stem cells
(HSCs) at the center. . . . In addition to this intimate and
predictable spatial association; such EC progenitors and HSCs
share certain common antigenic determinants, including flk-1,
tie-2, and CD-34.
Id. at col. 5, 11. 35--40.
We have now discovered that by using techniques similar to
those employed for HSCs, EC progenitors can be isolated from
circulating blood. In vitro, these cells differentiate into ECs.
Indeed, one can use a multipotentiate undifferentiated cell as
long as it is still capable of becoming an EC, if one adds
appropriate agents to result in it differentiating into an EC.
Id. at col. 5, 11. 48-55.
As these disclosures indicate, Isner '887 does not teach that an EC
progenitor cell is a stem cell, but rather describes it as differentiating into
only an endothelial cell (EC) (id. at col. 5, 11. 48-55 above) and distinguishes
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it from hematopoietic stem cells (HS Cs) (see id. at col. 5, 11. 35--40 above).
Consequently, we do not find Isner '887 to support the lack of credibility
about the capability of a stem cell to form an artery because the Examiner
did establish that the EC progenitor cell is a stem cell within the scope of
claim 6.
Asahara is authored by two of the inventors of Isner '887 (Isner and
Asahara). It describes isolation of endothelial cell progenitor cells from
human peripheral blood on basis of cell surface antigens. Asahara, Abstract.
Again, Asahara teaches that the progenitor cells differentiate into endothelial
cells (Asahara 967). The Examiner did not point to disclosure in Asahara
where the authors identified the EC progenitors as stem cells. Consequently,
we do not find this evidence to support the lack of credibility about the
ability of stem cells from bone marrow to form artery.
The Examiner also cited Noishiki6 (1996) as evidence that "one of
skill in the art at the 1998 filing date of the instant specification would have
reason to question whether locally placing bone marrow cells would result in
the growth of a complete artery comprising endothelial cells and smooth
muscle cells." Answer 7.
Noishiki described transplanting bone marrow cells into a
polytetrafluoroethylene vascular graft which was implanted into the
abdominal aorta position in dogs. Noishiki 90 (Abstract). Noishiki reported
that capillaries were observed in six month grafts. Id. at 92 (col. 1 ).
Noishiki found that "bFGF was always detected in capillary blood vessels,
6 Noishiki et al., Autocrine angiogenic vascular prosthesis with bone
marrow transplantation, 2 Nature Medicine 90-93 (1996) ("Noishiki
(1996)").
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marrow cells and cells adjacent to the hemopoiesis" of the implanted
vascular grafts. Id. Noishiki disclosed that the cells "continuously
synthesized cytokines such as bFGF, which has strong angiogenic
properties." Id. Isner '225 discloses that bFGF can expedite and/or augment
collateral artery development:
Recent investigations have established the feasibility of using
recombinant formulations of such angiogenic growth factors to
expedite and/or augment collateral artery development in
animal models of myocardial and hindlimb ischemia. See,
Baffour et al., J. Vase. Surg., 16:181-191 (1992) (bFGF).
Isner '225, col. 5, 11. 51-56.
Thus, while Noishiki may not have reported the formation of artery
growth, it did describe secretion of bFGF which was known to promote
collateral arteries. Moreover, as pointed out by Appellant, Noishiki's
experiments were designed to induce capillary growth into a vascular graft,
not to grow and integrate arteries as claimed. See Noishiki, Abstract. For
these reasons, we conclude that Noishiki is not persuasive evidence that one
of skill in the art would not have believed that bone marrow stem cells could
be used to grow and integrate artery in a body of a human patient.
In sum, we conclude that the Examiner erred in finding that the skilled
worker would not have found the claimed method of growing arteries with
stem cells derived from bone marrow credible at the time of the invention.
Was there a lack of predictability that the claimed invention would work?
The Examiner found that cell therapy is unpredictable, and that even
after filing date of the application, it had not been established that bone
marrow stem cells would give rise to arteries. Answer 7-11. Several post-
filing publications were discussed by the Examiner and Appellant, including
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Orlic7 (2001), Strauer8 (2002), and Ziegelhoeffer9 (2004). We begin the
discussion with these publications.
In their introduction, Orlic (2001) describes an earlier study of their
own in which implanted bone marrow cells ("BMC") had differentiated into
coronary vessels. Orlic (2001) 10344 (col. 1 ). In their present study, Orlic
(2001) used cytokines to increase and mobilize circulating bone marrow
cells (BMC) and concluded that "BMC injected [previous published study]
or mobilized to the damaged myocardium behave as cardiac stem cells,
giving rise to M [myocytes], endothelial cells, and smooth muscle cells." Id.
at 10349. Thus, Orlic (2001) provides evidence that bone marrow cells
succeeded in growing blood vessels comprising endothelial and muscle
cells.
Strauer (2002) showed that bone marrow cells aspirated from patients
and transplanted into an infracted zone of the heart (Strauer (2002) 1914)
improved heart function and myocardial perfusion (id. at 1915). Strauer
(2002) does not indicate that preparation of the BM Cs required any
treatment other than washing (Strauer (2002) 1914). Strauer (2002) did not
describe histological changes, but based on other published studies, the
7 Orlic et al., Mobilized bone marrow cells repair the infarcted heart,
improvingfunction and survival, 98 PNAS 10344--10349 (2001) ("Orlic
(2001 )").
8 Strauer et al., Repair of Infarcted Myocardium by Autologous
Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans,
106 Circulation 1913-1918 (2002) ("Strauer (2002)").
9 Ziegelhoeffer et al., Bone Marrow-Derived Cells Do Not Incorporate Into
the Adult Growing Vasculature, 94 Circ. Res. 230-238 (2004)
("Ziegelhoeffer (2004)").
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authors stated the results could be attributed, inter alia, to neovascularization
(id. at 1913), i.e., the growth of new blood vessels.
In contrast to these results, the Examiner cited "Ziegelhoeffer [2004]
[who] proposed a different mechanism, suggesting that the capability of
BMCs to promote vascular growth is unrelated to their structural
incorporation into the artery, but rather attributable to their ability to either
secrete or elicit secretion of growth factors which in tum promoted new
artery formation." Answer 10. However, claim 6 does not require the
implanted cells themselves to form the artery. Thus, as long as arteries are
formed, it is immaterial if the mechanism is by growth factor secretion or
stem cell differentiation into the artery, itself. Ziegelhoeffer (2004), in fact,
acknowledges that the latter mechanism cannot be ruled out (it is "possible
that the isolation and subsequent culture of progenitor or bone marrow-
derived cells under special conditions can change the properties of these
cells in terms of their capacity to incorporate into target tissue").
Ziegelhoeffer (2004) 237. Nonetheless, Ziegelhoeffer observed "growing
collateral arteries" after bone marrow transplantation, but attributed the new
artery growth to the secretion of growth factors ("paracrine effects"). Id.
Abstract; 23 7.
In view of the consistent results described in the post-filing
publications of Orlic (2001), Strauer (2002), and Ziegelhoeffer (2004), each
of whom described administering bone marrow cells to increase cardiac
function and achieve vascular growth, including the generation of smooth
muscle cells found in arteries (Orlic (2001)), we do not find the post-filing
publications sufficient to establish that, even after the application filing date,
it was unpredictable that bone marrow stem cells could be utilized to grow
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arteries in a human patient as claimed. Each of the aforementioned
publications are evidence that what the inventor described and enabled in the
patent application achieved success. It is not necessary the mechanism was
understood (Answer 11) because placing bone marrow cells into the desired
site achieved success in growing vessels as established by the post-published
journal articles cited by Appellant.
Is there a sufficient amount of direction in the '690 Application to enable
claim 6?
The examples in the '690 Application describe injection of a genetic
material coding for a growth factor, or the growth factor, itself, into the
desired location in the body, and confining it to the location with a
containment system. '690 Application 53 :20 to 54:4. The '690 Application
describes growth factors as encompassing "compositions ... which promote
the growth of hard tissue ... or soft tissue" (id. at 20: 11-12). Stem cells
promote the growth of soft tissue and thus would be considered growth
factors. The '690 Application also teaches that "Cellular products and their
derivatives can be growth factors," which would include cells." Id. at 37:26.
Thus, the disclosure of injecting growth factors to grow arteries is a teaching
on how to administer stem cells. Consistently, Isner '887 and Asahara,
which were published prior to the Application filing date, describe injection
of EC progenitor cells to produce EC cells integrated into capillary walls
(Isner '887, col. 14, 11. 33--48; Asahara 966), substantially the same route
disclosed in the '690 Application. See also Appeal Br. 18-19. Enablement
is determined at the time of filing. In re Hogan, 559 F.2d 595, 604 (CCPA
1977). Consequently, it is reasonable to rely on the consistent disclosures by
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Isner '887 and Asahara in determining whether there was sufficient guidance
in the '690 Application to enable the claim.
The Examiner addresses the broad disclosure in the '690 Application
involving other cell types, growth factors, and purposes (to form a kidney or
a tooth), but none of these are relevant to what is disclosed and enabled to
grow an artery. Answer 12-14. Nor do the Examiner's concerns regarding
the support in the Specification for bone marrow cells relate to enablement,
rather than written description. Answer 14--15.
The Examiner did not identify a credible defect in the '690
Application's enablement for introducing bone marrow derived stem cells
into a patient to grow an artery. We note that the level of skill in the art was
of a Ph.D. or M.D. who was active in researching blood vessel growth as
established by the many scientific publications which have been cited in this
proceeding which are authored by Ph.D. and M.D. scientists. We find that
an experienced and educated scientist would be familiar with the prior art,
such as Asahara and Isner '887 (e.g., "Background"; col. 7, 11. 16-22; col. 8,
11. 9-19), and would have known how to introduce stem cells into a patient
to grow an artery.
The Examiner states that the record "shows that extensive
experimentation had been performed ... to achieve methods that fall within
the scope of the instant claims," but even the subsequent post-filing articles
described injecting material as does the '690 Application, Isner '887, and
Asahara. Answer 20; See, e.g., Strauer (2002) (legend to Fig. 1 at 1914),
describing using a balloon catheter to inject cells into the infract-related
artery enabling the cells to infiltrate the infarcted zone.
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The Examiner also states that the "rejection of record has shown that
the persons of skill in the art considered such factors as choice of cell,
dosing, timing, means of delivery, etc. to be important for the development
of a successful method of cell therapy." Answer 44. We are not persuaded
by the evidence. As mentioned, the pre-filing evidence, including the '690
Application examples, disclosed injection as the means to introduce material
to stimulate artery growth, endothelial cell production, and capillary
formation, the same methods later shown to be successful when using bone
marrow cells (e.g., Strauer (2002)). It is true that the bone marrow cells
were enriched in several post-filing publications in the mononuclear fraction
(e.g., Strauer (2002), Dohmann10 (2005)), and such enrichment is not
disclosed in the '690 Application. However, the Examiner has not provided
evidence that enrichment is necessary or that the skilled worker would have
doubted that an unenriched bone marrow cell population would have worked
to grow an artery as claimed.
The Examiner states that the claim is not enabled because of the lack
of guidance on "which cell populations to use." Answer 44. We do not
agree. The claim requires "living stem cells harvested from bone marrow,"
so there does not appear to be a choice to be made - the population must
comprise stems cells obtained from the bone marrow - either fractionated or
unfractionated.
10 Dohmann et al., Transendocardial Autologous Bone Marrow
Mononuclear Cell Injection in Ischemic Heart Failure Postmortem
Anatomicopathologic and Immunohistochemical Findings, 112 Circulation
521-526 (2005) ("Dohmann (2005)").
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As far as dosing and timing, the Examiner has not provided evidence
that such factors required undue experimentation to determine such
parameters.
Summary
In sum, after considering the totality of evidence in the record, we are
not persuaded that the Examiner met the burden of establishing it would
require undue experimentation to practice the subject matter of claim 6. The
enablement rejection of claim 6 is reversed.
REVERSED
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