Ex Parte McCray et al

Patent Trial and Appeal Board

Jan 18, 2017

12433659 (P.T.A.B. Jan. 18, 2017)

United States Patent and Trademark Office
UNITED STATES DEPARTMENT OF COMMERCE
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APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
12/433,659 04/30/2009 Paul B. McCray 17023.089US1 9544
53137 7590 01/20/2017
VIKSNINS HARRIS & PADYS PLLP
7851 Metro Parkway
Suite 325
Bloomington, MN 55425
EXAMINER
BURKHART, MICHAEL D
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
01/20/2017 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):
docketing @ vhpglobalip .com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte PAUL B. McCRAY and PATRICK L. SINN
Appeal 2014-001108
Application 12/433,659
Technology Center 1600
Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving claims to
administering a lentiviral vector encoding a therapeutic protein in at least
two consecutive dosages. The Examiner rejected the claims as obvious. We
have jurisdiction under 35 U.S.C. § 6(b). We affirm.
Statement of the Case
Background
“Mucosal innate and adaptive immune responses against the vector or
vector-encoded proteins represent a significant impediment to clinical
1 Appellants identify the Real Party in Interest as University of Iowa
Research Foundation (see App. Br. 2).
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Application 12/433,659
applications and are well documented for viral vectors such as adenovirus”
(Spec. 1:17—19). “Thus, a major limitation for gene transfer is the inability
to re-administer vectors, e.g., as transgene expression wanes, and methods
for such administration are needed” (Spec. 1:28—30).
The Claims
Claims 1—4 and 6—22 are on appeal. Independent claim 1 is
representative and reads as follows:
1. A method for treating a patient, comprising administering
a lentiviral vector that comprises a nucleotide sequence
encoding a therapeutic protein to a tissue of the respiratory
system of the patient, wherein the administration comprises
administering the lentiviral vector in at least two consecutive
dosages, wherein two consecutive dosages of the administration
are separated by an interval of more than one day.
The Issue
The Examiner rejected claims 1—4 and 6—22 under 35 U.S.C. § 103(a)
as obvious over Sinn,2 Wang,3 and Hyde4 (Ans. 2—5).
The Examiner finds that “though Sinn et al suggest the treatment of
cystic fibrosis, a disease of the airway epithelia, by gene therapy using
AcGP64-pseudotyped SIV lentiviral vectors, there is no actual disclosure of
2 Sinn et al., Persistent Gene Expression in Mouse Nasal Epithelia following
Feline Immunodeficiency Virus-Based Vector Gene Transfer, 79 J. Virology
12818-27 (2005) (“Sinn”).
3 Wang et al., Feline immunodeficiency virus vectors persistently transduce
nondividing airway epithelia and correct the cystic fibrosis defect, 104 J.
Clinical Investigation R55—R62 (1999) (“Wang”).
4 Hyde et al., Repeat administration of DNA/liposomes to the nasal
epithelium ofpatients with cystic fibrosis, 7 Gene Therapy 1156—65 (2000)
(“Hyde”).
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Application 12/433,659
targeting airway epithelial cells, or of using the CF transmembrane regulator
(CFTR) gene” (Ans. 3). The Examiner finds Wang teaches “an FIV
lentiviral vector encoding the CFTR gene” (Ans. 3). The Examiner finds
that Hyde teaches “repeat administration of CFTR DNA constructs to the
nasal epithelium of patients with cystic fibrosis, further suggesting that
repeated administration of the gene transfer vector is required for long-term
gene expression” (Ans. 4).
The Examiner finds it obvious to “introduce a variety of repeated dose
administration or escalation procedures. One would have been motivated to
do so because repeated administration of the gene transfer vector is often
required for long-term gene expression” (Ans. 5).
The issue with respect to these rejections is: Does the evidence of
record support the Examiner’s conclusion that Sinn, Wang, and Hyde render
the claims obvious?
Findings of Fact
1. Sinn teaches “[o]ne aim of gene transfer vector development is
to create vehicles to efficiently, safely, and persistently express therapeutic
genes in the appropriate cell types. For cystic fibrosis gene therapy, the goal
is to deliver the cystic fibrosis transmembrane conductance regulator
(CFTR) to surface epithelial cells of the conducting airways” (Sinn 12818,
col. 1, citations omitted).
2. Sinn teaches “an FIV pseudotype using GP64 from Autagrapha
californica multicapsid nucleopolyhedrovirus (AcMNPV) transduces
primary cultures of human airway epithelia from the apical surface and
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mediates persistent gene transfer to the respiratory epithelia of mice” (Sinn
12819, col. 1).
3. Sinn teaches “1.25 x 107 transducing units (TU) of FIV vector
in a 50-pl volume were delivered to the nasal epithelia in anesthetized mice
via direct instillation.. . . Mice received either a single dose or seven doses
over seven consecutive days” (Sinn 12820, col. 1).
4. Sinn teaches “[g]ene transfer efficacy was further evaluated
3, 9, 19, 25, 35, and 50 weeks following vector delivery. Luciferase
expression from AcGP64-Luc (with or without MC) remained constant over
the tested time period. Conversely, Ad-Luc expression dropped sharply
between the 3-week and 9-week time points” (Sinn 12822, col. 1—2).
5. Wang teaches “[g]ene therapy is the most direct means to
correct the Cl" transport defect responsible for cystic fibrosis (CF) lung
disease” (Wang R55, col. 1).
6. Wang teaches “[sjeveral problems limit the application of gene
transfer to correct the cystic fibrosis (CF) CF transport defect in airway
epithelia. These include . . . failure of transgene expression to persist, and
immune responses to vectors or vector-encoded proteins. To address these
issues, we used a feline immunodeficiency virus-based (FIV-based) vector”
(Wang R55, abstract).
7. Wang teaches:
A further encouraging result of this work was the normal
morphology of the airway tissues after gene transfer. There
was no evidence of cellular infiltration with immune effector
cells when the rabbit airways were examined at the level of
light microscopy. Although this does not eliminate the
possibility of any immune response, it contrasts with the
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cellular responses noted with adenoviral vectors. Studies with
HIV-based lentiviral vectors to date show no evidence of
cellular immune responses at the sites of administration in vivo.
Furthermore, HIV-based vectors and MuLV vectors can be
administered a second time in vivo, suggesting that humoral
immune responses may not prevent repeated dosing.
(Wang R60, col. 2; citations omitted; emphasis added).
8. Wang teaches that in “cells transduced with adenovirus,
AIsc(iBMx/Forsk) gradually declined over time. In contrast, the net
AIsc(iBMx/Forsk) in FIV transduced cells remained stable” (Wang R58, col. 2 to
3).
9. Hyde teaches “[g]ene transfer to the airways, to correct the
underlying genetic defect, is a potential treatment for CF . . . gene delivery
systems investigated to date include recombinant adenovirus, recombinant
adeno-associated virus (AAV), and cationic liposomes. All have resulted in
relatively low levels of gene expression in the airways” (Hyde 1156, col. 1—
2).
10. Hyde teaches “[tjwelve CF patients were enrolled in the study:
10 received DNA/liposomes and two received a placebo (Table 1). Each
subject attended the clinic as an outpatient on 24 occasions receiving three
doses of DNA/liposomes or placebo, administered 4 weeks apart” (Hyde
1157, col. 1).
11. Hyde teaches “adenoviral gene expression is transient,
necessitating repeat administration; clinical studies have shown that
adenoviral gene transfer results in loss of efficacy upon repeat
administration, due to the production of neutralising antibodies. AAV may
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Application 12/433,659
prove useful for CFTR airway gene transfer in the future” (Hyde 1156, col.
2; citation omitted).
Principles of Law
“The combination of familiar elements according to known methods
is likely to be obvious when it does no more than yield predictable results.”
KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “If a person of
ordinary skill can implement a predictable variation, § 103 likely bars its
patentability.” Mat417.
Analysis
We adopt the Examiner’s findings regarding the scope and content of
the prior art (Ans. 2—5; FF 1—11).
Sinn, whose aim is to treat cystic fibrosis by delivery of the CFTR
gene (FF 1), administers a lentiviral vector that expresses a marker gene to
nasal epithelia (FF 2, 4) where the lentiviral vector was administered in
seven consecutive dosages separated by an interval of one day (FF 3).
Wang also aims to treat cystic fibrosis by delivery of CFTR (FF 5)
and teaches that issues with prior vectors include immune responses (FF 6)
but that lentiviral vectors “show no evidence of cellular immune responses at
the sites of administration in vivo” “suggesting that humoral immune
responses may not prevent repeated dosing” (FF 7).
Hyde also aims to treat cystic fibrosis by delivery of CFTR (FF 9) and
teaches administering a liposomal vector in three dosages “administered 4
weeks apart” (FF 10).
We agree with the Examiner that the claimed method would have
been obvious over the teachings of Sinn, Wang, and Hyde because “repeated
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administration of the gene transfer vector is often required for long-term
gene expression” (Ans. 5; cf. FF 7).
We address Appellants’ arguments below.
Claim 1
Appellants contend, based on upon the Specification, that “local and
systemic immune responses to adenoviral and AAV vectors effectively
prevent their repeated pulmonary administration” (App. Br. 10) and that
therefore “one of skill in the art would expect that administration of viral
vectors may provide for transgene expression in vivo for a period of time but
that repeated administrations would be progressively less effective due to a
patient’s adaptive immunity” (id.).
We find this argument unpersuasive because none of the cited
references rely upon adenoviral or AAV vectors, but Sinn and Wang rather
suggest the use of lentiviral vectors (FF 2, 6). Indeed, Sinn, Wang, and
Hyde each recognize problems with adenovirus and AAV systems including
low maintenance of gene transfer (FF 4), decline of correction of the CFTR
Cl transport (FF 8) and low levels of gene expression (FF 9). While the
artisan might expect adenovirus and AAV systems to become less effective
due to adaptive immunity, the artisan would reasonably expect lentiviral
vectors to overcome these problems because Wang specifically teaches that
the lentiviral system was selected to address these issues (FF 6) and
particularly teaches that lentiviral vectors are expected avoid adaptive
immunity and allow repeated dosing (FF 7).
Appellants contend that Sinn and Hyde “do not teach or suggest
administering two consecutive dosages of the lentiviral vector, where the
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dosages are separated by an interval of more than one day” (App. Br. 11)
and that “it was surprisingly established, in view of what was known about
other viral vector systems, that gene expression could increase additively
following repeated retroviral dosages at one-week or two week intervals,
without the development of systemic or local neutralizing antibodies” (id.).
We do not find this argument persuasive because Sinn exemplifies
administering seven doses of lentiviral vectors over seven consecutive days
(FF 3) and Wang teaches that the absence of immune response allows
lentiviral vectors to be administered “a second time in vivo” (FF 7). To the
extent that “more than one day,” a period of 24 hours and one minute, differs
from the period of one day, or 24 hours, “a prima facie case of obviousness
exists when the claimed range and the prior art range do not overlap but are
close enough such that one skilled in the art would have expected them to
have the same properties.” In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir.
2003). Here, Appellants provide no reason to believe that delay of a single
minute on the administration of Sinn’s lentiviral vectors would result in any
different result.
Indeed, Appellants provide no persuasive evidence of an unexpected
result for any delivery time frame. We recognize the teaching in the
Specification that “[sjurprisingly, reporter gene expression also increased
additively following each of 7 doses of FIV delivered over consecutive
weeks (1 dose/week), without the development of systemic or local
neutralizing antibodies” (Spec. 22:27—30), but agree with the Examiner that
Hyde “suggests a variety of dose administration or escalation procedures in
order to achieve long-term gene expression” (Ans. 7). That is, we agree
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with the Examiner that the expected result of administering additional doses
would be to increase gene expression as a larger number of cells became
productively infected with the lentiviral vector. Appellants do not explain
why an additive result from adding more vector would be unexpected.
Moreover, Appellants have not provided evidence comparing this
result to the closest prior art of Sinn, showing that administration of seven
doses of lentiviral vector over seven days would not obtain the same additive
effect as that obtained over consecutive weeks. See In re Baxter Travenol
Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen unexpected results are
used as evidence of nonobviousness, the results must be shown to be
unexpected compared with the closest prior art.”).
Appellants contend
Hyde et al. teach the use of a completely different gene
transfer system than the present invention in an attempt to
overcome the problems of adaptive immunity, Hyde et al.
acknowledged the problem that researchers had discovered
with gene transfer as a possible treatment for cystic fibrosis,
namely that repeated administration of gene vector will
likely be required for long-term gene expression
(App. Br. 11).
We find this argument unpersuasive because Hyde’s concerns with
adaptive immunity are solely addressed to adenovirus vectors (FF 11), and
Wang evidences that this concern regarding immunity is not relevant to
lentiviral vectors such as those of Sinn and Wang which “show no evidence
of cellular immune responses at the sites of administration in vivo” (FF 6—7).
The Examiner solely relies upon Hyde to demonstrate that repeated
administrations of a CFTR containing vector may be performed over
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timeframes other than Sinn’s daily administration for seven days, including
administrations 4 weeks apart (FF 3, 10).
Appellants contend that in “order to circumvent these limitations of
viral-based gene transfer systems, Hyde et al. proposed that liposomes be
used an alternative system. Thus, Hyde et al. teaches away from the present
invention, namely, the use of a viral-vector administration system” (App. Br.
12).
We find the teaching away arguments unpersuasive. A teaching away
requires a reference to actually criticize, discredit, or otherwise discourage
the claimed solution. See In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004)
(“The prior art’s mere disclosure of more than one alternative does not
constitute a teaching away from any of these alternatives because such
disclosure does not criticize, discredit, or otherwise discourage the solution
claimed”). Appellants do not identify, and we do not find any teaching in
Hyde that criticizes, discredits, or discourages the use of lentiviral vectors
such as those suggested by Sinn and Wang (FF 2,6). Indeed, Hyde
specifically recognizes that AAV vectors may be useful (FF 11), suggesting
that it is only adenovirus vectors that result in neutralizing antibodies that
prevent gene transfer and never teaching away from lentiviral vectors.
We recognize, but find unpersuasive, Appellants’ contention that the
“fact that the inventors proceeded contrary to the accepted wisdom at the
time the application was filed is evidence of nonobviousness” (App. Br. 12).
Neither Appellants argument nor the Specification provide any evidence that
there was “accepted wisdom” that lentiviral vectors could not be re­
administered. Indeed, the evidence suggests the opposite as Sinn and Wang
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specifically evidence that re-administration of lentiviral vectors was not only
possible, but performed by Sinn (FF 3) and suggested by Wang (FF 7).
“[Attorney argument [is] not the kind of factual evidence that is required to
rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470
(Fed. Cir. 1997).
Appellants contend “the Examiner is using impermissible hindsight
gleaned from the Applicant’s specification in stating that one of ordinary
skill in the art at the time the application was filed would have found it
obvious to re-administer the retroviral vector using the claimed invention”
(App. Br. 12-13).
We are not persuaded. While we are fully aware that hindsight bias
may plague determinations of obviousness, Graham v. John Deere Co., 383
U.S. 1,36 (1966), we are also mindful that the Supreme Court has clearly
stated that the “combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results.” KSR, 550 U.S. at 416.
In the instant case, Sinn specifically teaches re-administration of a
lentiviral vector by administering seven doses over seven days (FF 3) and
Wang specifically teaches lentiviral vectors “can be administered a second
time in vivo” (FF 7). Thus, rather than hindsight, the prior art predictably
suggests to re-administer lentiviral vectors (FF 3, 7).
Appellants contend “the examiner must provide evidence as to why
someone of skill in the art would have expected a lentiviral system to be
different from other known viral vector-based systems, and why the skilled
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person would expect a lentiviral vector to be more similar to a liposome
system than to another viral vector system” (Reply Br. 10).
We do not find this argument persuasive because the Examiner has
provided evidence that other viral vector systems are flawed and lentiviral
systems superior in causing a reduced immune response. As already noted,
Hyde teaches that adenovirus and AAV result in low levels of gene
expression (FF 9) and Wang teaches problems with “immune responses to
vectors or vector-encoded proteins” (FF 6) that are overcome by use of
lentiviral vectors (FF 7). The Examiner substantively relies upon Hyde
simply to evidence that gene transfer vectors may be administered over
periods including four weeks (FF 10), and Hyde expressly teaches that
liposomes are a known equivalent method of viral delivery (FF 9).
Appellants provide no evidence rebutting this equivalence demonstrated by
Hyde.
Claim 15
Appellants contend “Sinn et al., Hyde el al., and Wang el al. either
singly or in combination, do not teach all of the elements of the claim 15, in
particular, repeated administration of a viral vector to respiratory tissue with
an interval of about one week between at least two of the doses” (App. Br.
13).
We are not persuaded. Both Sinn and Wang teach re-administration
of lentiviral vectors, including over intervals of one day (FF 3, 7). Hyde
teaches that re-administration of gene transfer agents may be performed four
weeks apart (FF 10). Thus, the prior art suggests varying time periods for
administration of gene transfer vectors, rendering the interval between
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administration being a routinely optimizable variable. We therefore agree
with the Examiner that “it is not inventive to discover the optimum or
workable ranges by routine experimentation” (Ans. 7). See In re Aller, 220
F.2d 454, 456 (CCPA 1955). Appellants provide insufficient evidence of
unexpected results based on a comparison of any specific administration
interval with the closest prior art of Sinn.
Claim 16
We recognize, but find unpersuasive, Appellants’ contention that
“Sinn et al., Hyde el al., and Wang el al. either singly or in combination, do
not teach all of the elements of the claim 16, in particular, repeated
administration of a viral vector to respiratory tissue with an interval of about
one month between at least two of the doses” (App. Br. 16). As discussed
above, the interval of administration is a routinely optimizable variable and
Hyde specifically teaches administration four weeks apart (FF 10). Thus, we
agree with the Examiner that “Sinn and Hyde et al clearly teach[] and
suggest[] a variety of dose administration or escalation procedures in order
to achieve long-term gene expression, which has been routine in the art at
time the instant invention was filed” (Ans. 7).
Claim 20
We recognize, but find unpersuasive, Appellants’ contention that
“Sinn et al., Hyde et al., and Wang et al. either singly or in combination, do
not teach all of the elements of the claim 20, in particular, administration of
at least 10 doses of viral vector to respiratory tissue with an interval of about
one week between at least the doses” (App. Br. 18). As with the specific
intervals of administration, the number of doses reasonably represents an
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optimizable variable, with Sinn teaching administration of either 1 or 7
doses (FF 3), Wang teaching single or multiple administration (FF 7), and
Hyde teaching administering 3 doses (FF 10). Appellants provide no
evidence of any unexpected result rebutting the prima facie case of
obviousness.
Conclusion of Law
The evidence of record supports the Examiner’s conclusion that Sinn,
Wang, and Hyde render the claims obvious.
SUMMARY
In summary, we affirm the rejection of claims 1—4 and 6—22 under
35 U.S.C. § 103(a) as obvious over Sinn, Wang, and Hyde.
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
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