Ex Parte Stewart

Patent Trial and Appeal Board

May 10, 2018

14030000 (P.T.A.B. May. 10, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/030,000 09/18/2013
63467 7590
Ramey & Schwaller, LLP
5020 Montrose Blvd.
Suite 750
Houston, TX 77006
05/14/2018
FIRST NAMED INVENTOR
Duncan John Stewart
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.
20200.0002.PCUS02 1029
EXAMINER
KELLY, ROBERT M
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
05/14/2018 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):
uspto@rameyfirm.com
wramey@rameyfirm.com
bwilliams@rameyfirm.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Exparte DUNCAN JOHN STEWART 1
Appeal2016-007734
Application 14/030,000
Technology Center 1600
Before FRANCISCO C. PRATS, JOHN G. NEW, and
JOHN E. SCHNEIDER, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
1 Appellant identifies Northern Therapeutics, Inc. as the real party-in-
interest. App. Br. 3.
Appeal2016-007734
Application 14/030,000
SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner's Final Rejection of claims 21, 23-25, and 28 as unpatentable
under 35 U.S.C. § 112, first paragraph, for lack of enablement.
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.
NATURE OF THE CLAIMED INVENTION
Appellant's invention is directed to a cell-based therapy comprising
administration to the lung, by injection into the blood system, of viable,
mammalian cells effective for alleviating or inhibiting pulmonary disorders.
Abstract.
REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
21. A process for alleviating or inhibiting the
progression of mechanically induced acute lung injury in a
mammalian patient comprising administration of syngeneic or
allogeneic or autologous mesenchymal stem cells, smooth
muscle cells, fibroblast cells or a combination thereof to the lung
by injection into the pulmonary circulation of the mammalian
patient suffering from the disorder wherein the administration
results in alleviation or inhibition of the progression of the acute
lung injury.
App. Br. 25. Appellant has selected, as the elected species under
examination and on appeal, non-transformed mesenchymal stem cells
("MSCs"), and ARDS ""Acute Respiratory Distress Syndrome") (as the
acute lung injury). Final Act. 2 (citing Reply Br. December 17, 2014).
2
Appeal2016-007734
Application 14/030,000
ISSUE AND ANALYSIS
We agree with, and adopt, the Examiner's findings and conclusion
that the appealed claims are not enabled by Appellant's Specification.
Issue 1
Appellant argues that the Examiner erred in finding that Appellant's
Specification, although being enabling for treatment of LPS-induced
ALI rodent models of ARDS, does not reasonably provide enablement for
treatment of ALI in other species. App. Br. 12 (citing Final Act. 5).
Analysis
The Examiner finds that Appellant's Specification discloses that
administered mesenchymal stem cells lodge in the lung at the capillaries,
and thereby effect treatment. Final Act. 5. The Examiner finds Example 22
of the Specification discloses that such cell therapy works in mice with ALI
that has been induced by lipopolysaccharides ("LPS"). Id. The Examiner
further finds that the Specification discloses the treatment of ARDS and a
description of its clinical manifestations. Id. (citing Spec i-fi-1 6-9). The
Examiner finds that human subjects are specifically included for treatment
Id. (citing, e.g., Spec. i1288). However, the Examiner finds, the bulk of
Appellant's Specification is directed to the administration of transgenic
cells, wherein the transgene has the claimed therapeutic effect. Final Act. 5.
The Examiner points to several references in support of the findings
of fact. Final Act. 6. The Examiner finds that G. Matute-Bello et al.,
Animal Models of Acute Lung Injury, 295 AM. J. LUNG CELL MOL. PHYSIOL.,
L379-99 (2008) ("Matute-Bello") teaches the effects of LPS-induced
3
Appeal2016-007734
Application 14/030,000
models for ARDS/ ALI in several animals are evaluated as models of ARDS.
Id. (citing Matute-Bello L384-86). The Examiner finds that Matute-Bello
teaches that the response to an LPS insult is species specific, requiring
varying administration dosages of LPS, and that the model, in general, "does
not cause the severe endothelial and epithelial injury that occurs in humans
with ARDS." Id. (citing Matute-Bello L386).
The Examiner then points to D.N. Kotton, et al., Bone Marrow-
Derived Cells as Progenitors of Lung Alveolar Epithelium, 128
DEVELOPMENT' 5181-88 ("Kotton"). Final Act. 6. The Examiner finds
Kotton teaches a different model of ALI, bleomycin-induced ARDS, for
which treatment with a simple administration of mesenchymal stem cells
("MSCs") was ineffective. Id.
The Examiner next points to S.H.J. Mei et al., Prevention of LPS-
Induced Acute Lung Injury in Mice by Mesenchymal Stem Cells
Overexpressing Angiopoietin 1, 4(9) PLoS MEDICINE, 1525-37 (2007)
("Mei")2. The Examiner finds that Mei expressly states that: "it should be
emphasized that the animal model used here is not a precise parallel of
ARDS in humans, and that more research remains to be done before human
studies of this sort could be considered." Id. (quoting Mei 15 3 7).
The Examiner therefore concludes that a person of ordinary skill,
comprehending the data disclosed by Appellant's Specification, would have
considered that more information would be required to reasonably predict
treatment in other species, particularly humans, without having to perform
2 The Examiner notes that Appellant is one of the authors of this reference.
Final Act. 6.
4
Appeal2016-007734
Application I 4/030,000
undue experimentation. Final Act. 6. The Examiner finds that the cited
references and Appellant's Specification collectively teach that the various
models are not entirely accurate models of ARDS because they do not
completely reproduce the features of ARDS and, therefore, that the claimed
treatment would not be equally effective across the approximately 5500
extant species of mammal. Id.
Appellant argues that there are at least three working examples in the
application that provide enablement for at least Claim 2 I. App. Br. I 4.
According to Appellant, at least Examples I9, 22, and 23 teach one of skill
in the art to make and use the subject matter of claim 2 I. Id. Appellant
contends that Example I 9 teaches treating ARDS in rats with smooth muscle
cells expressing Angiopoeitin- I. Id. Example 22, asserts Appellant, teaches
preventing ALI (an important underlying cause of human ARDS) in mice
with mesenchymal cells overexpressing Ang- I. Id. Appellant argues that
Example 23 teaches treating ARDS in rats and mice with fibroblast cells
expressing Ang-I. Id.
Appellant quotes our reviewing court, stating that: "it has long been
recognized that when experimentation on human subjects is inappropriate, as
in the testing and development of drugs and medical devices, the enablement
requirement may be met by animal tests or in vitro data." App. Br. I4
(quoting Edwards Lifesciences AG v. Core Valve, Inc., 699 F.3d I305,
I309-IO (Fed. Cir. 20I2). Appellant argues that the fact pattern of the
instant appeal is congruent with those in Edwards: both sets of claims relate
to medical therapies or devices that were tested in animal models. App. Br.
I 5. Appellant notes that the Federal Circuit's decision in Edwards supports
Appellant's position that an enablement rejection requiring testing in
5
Appeal2016-007734
Application 14/030,000
humans, simply because more developmental work is required at the time of
filing the application, is improper. Id.
With respect to the references cited by the Examiner, Appellant
argues that the Examiner's reliance on Matute-Bello fails to specifically
address the claims and in doing so, has failed to show that the claims are not
enabled for treatment of ALI. App. Br. 16. Appellant points to Claim 21 as
being directed to treating ALI. Id. Appellant specifically points out that the
first sentence of Matute-Bello teaches that ALI is not the same as ARDS:
"Acute lung injury (ALI) and its most severe manifestation, the acute
respiratory distress syndrome (ARDS), is a clinical syndrome defined by
acute hypoxemic respiratory failure, bilateral pulmonary infiltrates
consistent with edema, and normal cardiac filling pressures." Id. (quoting
Matute-Bello 379). Appellant asserts, therefore, that Matute-Bello teaches
that ARDS is ALI but not all ALI is ARDS. Id. (emphasis added).
With respect to Kotton, Appellant argues that the Examiner has not
demonstrated where Kotton teaches that no treatment was found by
administration of MSCs. App. Br. 16. Appellant contends that Kotton is not
evidence that the disclosure of the present application fails to make and use
the claimed invention. Id. Appellant also points to Exhibit 11, a declaration
filed by the inventor in a related application, US Ser. No. 11/696,039, April
16, 2012 (the "Stewart Declaration"), which explains that one cannot
determine whether Kotton discloses a method of treating ARDS with
mesenchymal stem cells based upon the time of various aspects of the
experiment. Id. Appellant contends that the Stewart Declaration also states
that LPS administration in a mouse model to initiate ARDS symptoms
correlates with ARDS symptoms in humans. Id. at 16-1 7.
6
Appeal2016-007734
Application 14/030,000
With respect to Mei, Appellant notes that the editor of the reference
states that the mouse model was not "a precise parallel" to the human
condition. App. Br. 17. It is not necessary that an animal model be a precise
parallel to enable a claim to humans, argues Appellant, but, rather, "all that
is required is a reasonable correlation between the activity and asserted use."
Id. (quoting MPEP § 2107.03.I.
Appellant adduces several references to show that the rat model of
ALI/ ARDS using LPS-induced pulmonary inflammation is accepted by
persons of skill in the art. App. Br. 19. Appellant points first to D. Rocksen,
ACUTE LUNG INWRY: STUDY OF PATHOGENESIS AND THERAPEUTIC
INTERVENTIONS (2003) ("Rocksen") as teaching that:
Experimental animal models are useful tools for better
understanding of the underlying mechanisms of ALI/ ARDS and
may be helpful in development of therapy to prevent the human
disease. A plethora of models has been used to elicit ALI/ ARDS
in animals, but the most extensively used is inhalation exposure
or systemic administration of bacterial endotoxin
(lipopolysaccharide: LPS),
Id. (quoting Rocksen 29). Appellant notes that Rocksen also teaches that:
"Exposure to moderate doses LPS has been used as a prototypic model of
ALI in several studies and intratracheal administration of high doses in rats
has been suggested as a relevant model of ARDS in one study." Id. (quoting
Rocksen 30) (references omitted). Appellant quotes Rocksen as concluding
that: "[W]e have demonstrated that the generalized Shwartzman reaction in
mice exhibits a lung pathology that resembles clinical features of ARDS, as
evidenced by acutely impaired respiratory function leading to mortality as
well as characteristic hallmarks of ARDS such as lung edema and interstitial
neutrophil infiltration" and that "In this thesis, experimental animal models
7
Appeal2016-007734
Application 14/030,000
of ALI/ ARDS have been used in order to achieve a comprehensive
knowledge of which cells and mediators are involved in the pathogenesis of
the syndrome." Id. (quoting Rocksen 44--45, 55).
Appellant also points to S. Lax et al., Using a Non-Invasive
Assessment of Lung Injury in a Murine Model of Acute Lung Injury, 1 BMJ
OPEN RESP. RES., 1-8 (2014) ("Lax"), as teaching that: "Intratracheal (IT)
LPS is a very reproducible technique which models many of the features in
human ALI, typified by significant infiltration of neutrophils into the
alveolar air spaces and expression of pulmonary inflammatory cytokines"
and that: "Animal models are used to replicate pathological, physiological
and histological changes in human ALI/ARDS. 3" App. Br. 19 (quoting Lax
1)
Appellant next points to D. Rittirsch et al., Acute Lung Injury Induced
by Lipopolysaccharide is Independent of Complement Activation, 180 J.
IMMUNOL., 7664--72 (2008) ("Rittirsch"), which states: "Therefore, lung
injury induction by LPS in rodents represents a frequently used ALI model,
mimicking many features of ALI/ ARDS in humans." App. Br. 20 (quoting
Rittirsch 7670).
Finally, Appellant argues that "[g]rants received from a funding
source indicate that an animal model is accepted as predictive of clinical
efficacy. Grant proposals may request funding for conducting in vivo
experiments on animal models or for clinical experiments." App. Br. 20.
Appellant points to a number of grants and grant proposals as indicative that
3 Appellant notes that, whereas Lax was published in 2014, the article was
received and accepted by the journal in 2013 and, therefore, Appellant
contends that it indicates the thoughts of an artisan in 2013. App. Br. 20.
8
Appeal2016-007734
Application I 4/030,000
animal models using mesenchymal stem cells in the development of
treatments for, inter alia, LPS-induced ALI and treatment of ARDS in
clinical trials. Id. at 20-2I (citing Exs. I2-I4).
We are not persuaded by Appellant's arguments. Appellant has
chosen, as the elected species of claim 2 I, non-transformed MSCs as the
cells to be administered for the alleviation or inhibition of the progression of
ARDS. Final Act. 25. It is, therefore, this species which we must determine
whether Appellant's Specification enables.
Appellant points primarily to Examples I 9, 22, and 23 of the
Specification as enabling disclosures of claim 2 I. See App. Br. I 4.
Example I 9 of the Specification is directed to using transfected smooth
muscle cells derived from the pulmonary artery and expressing angiopoeitin-
I ("Ang-I") to treat mechanically-induced ALI (pulmonary edema) in rats.
Spec. i-fi-12 I 8-220. Claim I 9 is therefore not directed to the elected species
because it does not employ either non-transformed or transformed
mesenchymal stem cells in the treatment of ARDS, which is the human
clinical correlate of severe ALI. See Spec. i1 6.
Similarly, claim 23 is directed to the use of transfected fibroblast cells
expressing Ang-I in the treatment ofLPS-induced ALI in rats. Spec. i-fi-1
265-267. Appellant contends that this LPS-induced model is recognized as a
close model of ARDS in humans. See App. Br. I9. However, we again find
that this example is not enabling for the claims because it does not disclose
the use of MS Cs, either transformed or non-transformed.
Claim 22 of the Specification is directed to the treatment of LPS-
induced ALI in rats with transfected MSCs expressing Ang- I. Spec. i-fi-1
259-59. This is the sole example in the Specification disclosing the use of
9
Appeal2016-007734
Application 14/030,000
MSCs in the treatment of ALI. Furthermore, Example 23 discloses the use
of both transformed and non-transformed (i.e., control) MSCs and further
discloses that the non-transformed MSCs had a beneficial effect on the LPS-
induced ALI. See Spec. i-f 262 ("Treatment with MSCs alone reduced total
protein, albumin and IgM levels modestly"); see also Figs. 33A---C. Claim
22 thus discloses the use of non-transformed MS Cs in the treatment of LPS-
induced ALI, which, Appellant asserts, is a close, and therefore enabling,
model for human ARDS.
However, that is not the end of our analysis. Appellant's claim 21 is
directed to: "A process for alleviating or inhibiting the progression of
mechanically induced acute lung injury in a mammalian patient." (Emphasis
added). Example 19 of the Specification discloses the use of smooth muscle
cells in treating mechanically-induced ALI and is therefore not enabling for
the elected species (i.e., non-transformed MSCs ). Example 22 discloses the
use of non-transformed (and transformed) MSCs in the treatment of LPS-
induced ALI, which Appellant asserts is a close and enabling model for
ARDS. Claim 22, however, is not by itself enabling on claim 21 because it
does not teach treatment of mechanically-induced (as opposed to LPS-
induced) ALI or ARDS. Thus, none of the Examples relied upon by
Appellant are directly enabling for claim 21.
We therefore address the question of whether some combination of
the Examples, or other disclosures of the Specification, are enabling for the
elected species of claim 21. We conclude that they do not. Appellant has
adduced a number of references, i.e., Rocksen, Lax, Rittirsch, and Exhibits
12-14, to argue that LPS-induced ALI is an accurate model for human
ARDS, the latter of which is also part of the Appellant's elected species.
10
Appeal2016-007734
Application 14/030,000
However, Appellant has adduced no persuasive evidence of record to
demonstrate that a person of ordinary skill in the art would understand that
mechanically-induced ALI, as recited in claim 21, in rats is a sufficiently
precise model of human ARDS to enable the claim. Indeed, Appellant
directly admits that Matute-Bello teaches that not all models of ALI in rats
are the same as human ARDS, which is the elected species. See App. Br. 16
("Matute-Bello teaches that ARDS is ALI but not all ALI is ARDS").
Absent evidence of record that a person of ordinary skill in the art
would understand that mechanically-induced ALI is ARDS, or a reasonably
predictive model of ARDS, we conclude that Appellant's Specification is
not enabling for claim 21. The Specification provides no examples or
embodiments of the elected species, nor are there other any disclosures of
the Specification, that suggest that mechanically-induced ALI in rats is a
model of human ARDS such that it could be treated by non-transformed
MSCs. We consequently affirm the Examiner's rejection of claim 21.
Furthermore, Appellant relies upon the same arguments with respect
to dependent claims 23-25 and 28. App. Br. 23-24. We therefore, and for
the same reasons, affirm the Examiner's rejection of these claims.
DECISION
The Examiner's rejection of claims 21, 23-25, and 28 as unpatentable
under 35 U.S.C. § 112, first paragraph, for lack of enablement is affirmed.
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a)(l). See 37 C.F.R.
§ 1.136(a)(l )(iv).
11
Appeal2016-007734
Application 14/030,000
AFFIRMED
12