Ex Parte Finn et al

Patent Trial and Appeal Board

Nov 27, 2017

13882773 (P.T.A.B. Nov. 27, 2017)

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.
13/882,773 05/01/2013 M.G. Finn 613.201US 4812
90187 7590 11/28/2017
T .p.wis Knhn & Walker T T P EXAMINER
15030 Avenue of Science CARLSON, KAREN C
Suite 201
San Diego, CA 92128 ART UNIT PAPER NUMBER
1656
MAIL DATE DELIVERY MODE
11/28/2017 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte M.G. FINN, STEVEN BROWN, and JASON FIEDLER
Appeal 2017-0011181
Application 13/882,773
Technology Center 1600
Before JEFFREY N. FREDMAN, TAWEN CHANG, and
TIMOTHY G. MAJORS, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an Appeal under 35 U.S.C. § 134 involving claims to a
synthetic capsule construct for providing a protected chemical milieu. The
Examiner rejected the claims as anticipated and as obvious. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse and enter a new ground of
rejection.
Statement of the Case
Background
“Artificial encapsulation or immobilization on solid supports has been
shown to confer stability as well as facilitate purification and reuse” (Spec.
1:20—21). “One aspect of the present invention is directed to protein nano-
1 Appellants identify Qapsule Technologies, Inc. as the real party in interest
(see App. Br. 3).
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Application 13/882,773
particles that encapsulate cargo proteins within an enclosure containing a
protected chemical milieu. Encapsulation within such protected chemical
milieu can impart enhanced employability and performance to cargo
proteins, particularly within otherwise harsh chemical environments” (Spec.
3:3-7).
The Claims
Claims 1—8, 11—18, 31—36, and 38 are on Appeal.2 Independent claim
1 is representative and read as follows:
1. A synthetic capsule construct for providing a protected
chemical milieu, the construct comprising:
a shell having a plurality of shell proteins, said plurality
of shell proteins being assembled with one another for forming
said shell and defining an enclosure therein, each of said shell
proteins, when assembled for forming said shell, having an
interior surface facing inwardly toward said enclosure and an
exterior surface facing outwardly away from said enclosure,
said shell serving to restrict permeability to and from said
enclosure for providing the protected chemical milieu therein,
said shell proteins being recombinant;
a cargo protein, said cargo protein being recombinant and
optionally including a peptide tag; and
a bifimctional polynucleotide having both a first
aptameric activity for binding said cargo protein and a second
aptameric activity for retaining said bifimctional polynucleotide
within said enclosure by assembly with the interior surface of
said shell protein,
said bifimctional polynucleotide being non-naturally
occurring; said bifimctional polynucleotide serving to link said
cargo protein within said enclosure for providing the said cargo
protein with the protected chemical milieu therein.
2 Claim 37 is objected to, but is not subject to a rejection (see Final Act. 8).
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The Issues
A. The Examiner rejected claims 1—5, 7, 8, 11—18, 31—33, 35, and 38
under 35 U.S.C. § 102(b) as anticipated by Young3 (Final Act. 3—6).
B. The Examiner rejected claims 1—3, 5, 7, 8, 13—18, and 31—36 under 35
U.S.C. § 103(a) as obvious over Young and Brown4 (Final Act. 6—7).
C. The Examiner rejected claims 1,5, and 6 under 35 U.S.C. § 103(a) as
obvious over Young, Brown, Lim,5 and Spingola6 (Final Act. 7—8).
Because the same issue is dispositive for all of these rejections, we
will consider them together. The Examiner finds Young teaches
protein cages as delivery vehicles for selective entrapment and
release of materials [0021], wherein the proteinaceous shell
sell-assembles to form a protein cage which protein cage may
be obtained from a non-viral or viral source [0026]. The
protein cage may be linked to the therapeutic cargo agent via a
bifimctional nucleic acid linker [0112],
(Final Act. 3).
Appellants contend
1. Young does not disclose or suggest that the porosity of his
protein cages is sufficient for loading a cargo protein
therein; Young discloses loading only small molecule
imaging agents and therapeutics into his protein cages,
3 Young et al., US 2009/0041671 Al, published Feb. 12, 2009.
4 Brown et al., RNA Bacteriophage Capsid-Mediated Drug Delivery and
Epitope Presentation, 45 Intervirology 371—80 (2002)
5 Fim et al., The RNA-binding Site of Bacteriophage Qf Coat Protein, 271
J. Biological Chemistry 31839-45 (1996).
6 Spingola et al., MS2 coat protein mutants which bind Qf RNA, 25
Nucleic Acids Research 2808-15 (1997).
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Application 13/882,773
2. Young does not disclose or suggest a recombinant cargo
protein and does not disclose or suggest that, if the cargo
were a recombinant protein, then the cargo and capsule
proteins would be biosynthesized simultaneously in the
same organism and self-assembled therein. Nor does Young
disclose or suggest that intracellular self-assembly might be
advantageous.
3. Young does not disclose a recombinant cargo protein
having a peptide tag.
4. Young does not disclose a bifunctional polynucleotide.
5. Young does not disclose a bifunctional polynucleotide
having a first aptameric activity for binding the cargo
protein.
6. Young does not disclose a bifunctional polynucleotide
having a second aptameric activity for retaining the
bifunctional polynucleotide within the enclosure by
assembly with the interior surface of the shell protein.
(App. Br. 14—15).
The issue with respect to this rejection is: Does the evidence of
record support the Examiner’s conclusion that Young or Brown teach a
polynucleotide having “a first aptameric activity for binding said cargo
protein and a second aptameric activity for retaining said bifimctional
polynucleotide” as required by claim 1 ?
Findings of Fact
1. Young teaches “protein cages can be used as constrained
reaction vessels for the selective entrapment and release of materials”
(Young 121).
2. Young teaches:
By “delivery agent” herein is meant a proteinaceous shell that
self-assembles to form a protein cage (e.g. a structure with an
interior cavity which is either naturally accessible to a solvent
or can be made to be so by altering solvent concentration, pH,
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Application 13/882,773
equilibria ratios, etc.), and contains imaging and therapeutic
agents
(Young 126)
3. Figures 1A and IB of Young are reproduced below:
JigZia
~fig!w
Figure 1 of Young “illustrates the basic principle of introducing
soluble material such as a medical imaging agent into a protein cage.”
(Young 115.) Young teaches that
pH can be used to control the expansion and contraction of the
protein cage . . . When the cage is expanded, i.e., opened, pores
are formed allowing for the free exchange of soluble material
between the inside and outside of the cage (see FIG. 1 A).
When the cage is contracted, i.e., closed, the pores are closed
and any material in the cage is trapped within (see FIG. IB).
(Young 121).
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Application 13/882,773
4. Young teaches “a corresponding therapeutically active agent is
chosen. These agents will be any of a wide variety of drugs” (Young 196).
5. Young teaches “therapeutic agents of the present invention may
be attached to the protein cage via a linker” (Young 1112).
6. Young teaches:
In a preferred embodiment, the linker used to attach the
imaging agent and therapeutic agents to a protein cage is a
polymer . . . The character of the polymer will vary, but what is
important is that the polymer either contain or can be modified
to contain functional groups for the attachment of the
nanoparticles of the invention. Suitable polymers include . . .
nucleic acids and their analogs including those with modified
ribose-phosphate backbones.
(Young 11113-114).
7. The Specification states: “For purposes of the present
disclosure, the term ‘aptamer’ is defined herein to mean an oligonucleotide
having binding affinity and/or specificity for a protein tag or a protein
binding site” (Spec. 39:23—25).
8. Brown teaches: “To use our knowledge of the three-
dimensional structure and self-assembly mechanism of RNA bacteriophage
capsids to develop novel virus-like particles (VLPs) for drug delivery and
epitope presentation” (Brown 371, Abstract).
9. Brown teaches: “Covalent conjugation has also been used to
generate RNA stem-loops attached to the toxin, ricin A chain, or to
nucleotide-based drugs, that are still capable of stimulating self-assembly of
the capsid in vitro” (Brown 371, Abstract).
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Principles of Law
A prior art reference can only anticipate a claim if it discloses all the
claimed limitations “arranged or combined in the same way as in the claim.”
Wm. Wrigley Jr. Co. v. Cadbury Adams USALLC, 683 F.3d 1356, 1361
(Fed. Cir. 2012).
Analysis
We begin with claim interpretation because before a claim is properly
interpreted, its scope cannot be compared to the prior art. In this case, the
dispute centers over the term “aptamer” in claim 1.
Appellants contend “[cjovalent conjugation is not the same as
aptameric binding activity” (App. Br. 18) and neither Young nor Brown
discloses polynucleotides with aptameric binding activity (see App. Br. 15,
18).
The Examiner responds “Young et al. teach that the linker is a nucleic
acid polymer, that the nucleic acid polymer is bifimctional binds to or
attaches to the cargo protein (therapeutic agent) and to the protein cage
(shell protein)” (Ans. 12).
We find that Appellants have the better position. While every
“aptamer” is a polynucleotide, consistent with Appellants’ definition (FF 7),
not every polynucleotide is an “aptamer” with the capability of binding a
protein and the capability of binding shell proteins involved in capsid
formation. We also agree with Appellants that the ordinary artisan, familiar
with the term “aptamer”, would recognize that aptameric binding is
reasonably understood as noncovalent, hydrogen bonding that is based on
the unique primary, secondary, and/or tertiary structures formed by the
polynucleotide.
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Application 13/882,773
Young teaches covalent attachment of the polymers, specifically that a
“polymer either contain or can be modified to contain functional groups for
the attachment of the nanoparticles of the invention” (FF 6). There is no
indication in Young that the attachment would be by noncovalent aptameric
binding. Similarly, Brown teaches covalent attachment to nucleic acids (FF
9). Therefore, neither reference suggests aptameric binding, and the
evidence does not support an inherency position that such binding
necessarily occurs. “Inherency . . . may not be established by probabilities
or possibilities. The mere fact that a certain thing may result from a given
set of circumstances is not sufficient.” MEHL/Biophile Int 7. Corp. v.
Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999).
The Examiner provides no specific teaching to use aptameric binding,
or any specific reference that inherently and reasonably relies upon
aptameric binding to the cargo protein and to the shell protein.
Conclusion of Law
The evidence of record does not support the Examiner’s conclusion
that Young or Brown teach a polynucleotide having the aptameric activities
as required by claim 1.
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New Ground of Rejection
Under the provisions of 37 C.F.R. § 41.50(b), we enter the following
new ground of rejection.7 Claims 1, 2, 5, 7, 13—15, 31, 33—35, and 38 are
rejected under 35 U.S.C. § 102(b) as anticipated by Perez8 as evidenced by
Mair,9 Ye,10 and Gonzalez.11
Findings of Fact
10. Perez teaches: “PB1 and PA interact to assemble influenza
virus transcription and replication complexes, which also include PB2. . . .
[W]e engineered a set of nested deletion mutants within the PB1 N-terminal
48 amino acids” (Perez 8129, col. 2).
11. Table 1 of Perez shows recombinant viruses with PB1
mutations, and is reproduced below:
7 As the Board’s function is primarily one of review and not search, we leave
to the Examiner the determination of whether there is additional prior art to
address the remaining dependent claims.
8 Perez et al., Functional Analysis of PA Binding by Influenza A Virus PB1:
Effects on Polymerase Activity and Viral Infectivity, 75 J. Virology 8127—
36 (2001).
9 Mair et al., Receptor binding and pH stability — How influenza A virus
hemagglutinin affects host-specific virus infection, 1838 Biochimicaet
Biophysica Acta 1153-68 (2014).
10 Ye et al., Association of Influenza Virus Matrix Protein with
Ribonucleoproteins, 73 J. Virology 7467—73 (1999).
11 Gonzalez et al., Characterization of Influenza Virus PB1 Protein Binding
to Viral RNA: Two Separate Regions of the Protein Contribute to the
Interaction Domain, 73 J. Virology 631—7 (1999).
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Application 13/882,773
TABLE 1, Functional assessment of FA-binding mutants of FBI®
Strain or
iBUlaBl
% FA bsMAg
Own-hybrid)*'
PS polymerase
activity (CAT)
FBI mutani:
vires yield
(PFU/sd)
Plaque
purified arsd
sequenced
WT 100 100 4.0 X 10- X
D2V 53 ± 7 0 0 —
V3D 2:1 ± 8 0 a ....
N4D > > -4- \.vv.iv ___ 24 ± 1 4.o x or X
P51 ■ Nir 1.0 X 103 ~
T6D 75 ± 5 56 ± 4 5,1 X Of X
L7D'" 0 21 ± 2 2,0 X 1(U -A
L8D 0 0 —
F9D 0 3 ± 1 0 —
LETT 0 15 ± 5 2.0 X !0 " ■X
K11D .35 ± 7 48 ± 2 3.0 X 10 " X
VI 2D 40 ±5 54 ± 7 4.5 X 10' X
FDD 100 ± 2 78 ± 2 1.9 X Of X
AMD 100 ±. 2 0 0 _
“[W]e were able to rescue mutant viruses that displayed detectable and
significant polymerase activity. The exception is mutant F9D, which had
only a 3% polymerase activity of the WT (Table 1) and thus might be too
low for virus rescue” (Perez 8132, col. 1 and 2).
12. Mair, a postfiling date reference,12 is solely cited to evidence
the inherent structure of the influenza virus, with figure 1, panel A,
reproduced below:
12 MPEP § 2131.01(111) “Extra Reference or Evidence Can Be Used To
Show an Inherent Characteristic of the Thing Taught by the Primary
Reference.”
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Fig. 1. (A) Schematic representation of an influenza A vims
particle. The spike proteins hemagglutinin (HA, blue),
neuraminidase (NA, green) and the proton channel protein M2
(violet) are embedded in the lipid envelope (turquoise) of the
vims. The membrane is lined with the Ml capsid protein at the
inside (yellow). The viral genome consists of eight
ribonucleoprotein particles (RNPs, red), with each segment
formed by viral RNA (vRNA), the nucleoprotein (NP) and the
viral polymerase proteins (PB1, PB2 and PA, colored in gray).
(Mair 1155).
13. Ye is cited to evidence that the influenza vims Ml capsid (or
shell) protein binds to the viral RNA, specifically teaching: “Two domains
in Ml have been shown to affect the disposition of RNA. One domain
residing in a palindromic stretch of basic amino acids (101RKLKR105) has
been shown to bind vRNA” (Ye 7467, col. 2).
14. Gonzalez is cited to evidence that the influenza PB1 protein
specifically binds to the viral RNA, teaching: “Both PB1 and PB2 subunits
of the virion core could be cross-linked to the 39-terminal sequence of the
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Application 13/882,773
vRNA, and all three subunits were cross-linked to the vRNA 59-terminal
sequence” (Gonzalez 631, col. 2; citations omitted).
15. Gonzalez teaches “we show that PB1 protein on its own binds
preferentially the 59-terminal sequence of vRNA” (Gonzalez 636, col. 2).
Principles of Law
[I]t is elementary that the mere recitation of a newly
discovered function or property, inherently possessed by
things in the prior art, does not cause a claim drawn to those
things to distinguish over the prior art. Additionally, where
the Patent Office has reason to believe that a functional
limitation asserted to be critical for establishing novelty in
the claimed subject matter may, in fact, be an inherent
characteristic of the prior art, it possesses the authority to
require the applicant to prove that the subject matter shown
to be in the prior art does not possess the characteristic relied
on. . . . Whether the rejection is based on “inherency” under
35 U.S.C. § 102, on “prima facie obviousness” under 35
U.S.C. § 103, jointly or alternatively, the burden of proof is
the same, and its fairness is evidenced by the PTO’s inability
to manufacture products or to obtain and compare prior art
products. [Citation omitted].
In re Best, 562 F.2d 1252, 1254-55 (CCPA 1977) (footnote omitted);
Analysis
We begin our analysis with claim construction. We construe each of
the structural elements required by claim 1.
“shell”
The Specification states “the term ‘shell protein’ is defined herein to
mean any protein or set of proteins capable of self-assembly or directed-
assembly to form a ‘shell’ of a capsule . . . shell proteins may be either viral
or non-viral” (Spec. 40:26—30). We therefore interpret the term “shell” and
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Application 13/882,773
“shell protein” as encompassing viral proteins, such as the Ml protein of
influenza virus, that self-assemble into virion particles (FF 12).
“cargo protein ”
The Specification states “the term ‘cargo protein’ is defined herein to
mean any recombinant protein capable of being incorporated into a synthetic
capsule construct” (Spec. 42:1—3). We therefore interpret the term “cargo
protein” as encompassing any recombinant protein, including the mutated
and recombinant PB1 protein of Perez (FF 10) that is assembled into
recombinant virus (FF 11) that inherently comprises both the viral RNA
polynucleotide and the PB1 protein (FF 12).
“bifunctional polynucleotide ”
The Specification states “the term ‘bifunctional polynucleotide’ is
defined herein to mean a polynucleotide having two or more aptameric
activities” (Spec. 41:20-22). As already discussed, the Specification defines
an “aptamer” as “an oligonucleotide having binding affinity ... for a protein
tag or a protein binding site” (Spec. 39:23—25).
As applied to claim 1, the bifimctional polynucleotide must be capable
of having two binding affinities, one for the cargo protein and one for the
shell protein. An additional requirement of claim 1 is that the bifimctional
nucleotide is “non-naturally occurring.”
Prior art
Perez teaches a recombinant influenza virus particle construct (FF 10—
11) that inherently comprises the Ml shell protein (FF 12), PB1 as a “cargo
protein” where PB 1 is recombinant due to the presence of engineered
mutations (FF 11), and bifimctional polynucleotides including the eight viral
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RNA segments, one of which is the viral RNA polynucleotide encoding PB1
(FF 12).
Based on the claim interpretation above, we find that the influenza
virus Ml protein reasonably satisfies the requirement for the “shell” proteins
forming a shell of a capsule construct. We find the mutated and
recombinant PB1 protein reasonably satisfies the requirement for a “cargo”
protein.
We also find that the vRNA encoding the mutant PB1 inherently
satisfies the requirements for the “bifunctional polynucleotide.” This vRNA,
which is inherently incorporated into the influenza virus particle (FF 12), is
non-naturally occurring because it contains mutations in the PB1 nucleic
acid sequence that were “engineered” by Perez (FF 10).
In addition, the influenza vRNA polynucleotide inherently is capable
of binding to both the Ml shell protein (FF 13) and to the PB1 protein (FF
14—15) noncovalently, inherently satisfying the requirement of the
bifimctional polynucleotide of claim 1 to have an aptameric, or “protein
binding site” activity for the “shell” protein and for the “cargo” protein (FF
13-15).
We therefore conclude that the influenza virus particles of Perez with
mutated PB1 protein and vRNA inherently anticipate the requirements of
claim 1.
With regard to claims 2 and 31, the PB 1 protein of Perez is a
polymerase enzyme involved in virus transcription and replication (FF 10).
With regard to claims 5, 33, and 34, the Ml shell protein is a viral
capsid protein (FF 12).
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With regard to claims 7 and 35, the Ml shell protein is derived from
influenza virus, a single stranded RNA virus (FF12).
With regard to claim 13, the bifimctional polynucleotide is an RNA
(FF 10-12).
With regard to claims 14 and 38, the bifimctional polynucleotide is
transcribed RNA from a viral genome (FF 12).
With regard to claim 15, the Ml shell protein has a binding site for the
vRNA polynucleotide (FF 13).
SUMMARY
In summary, we reverse the rejections of claims 1—5, 7, 8, 11—18, 31—
33, 35, and 38 under 35 U.S.C. § 102(b) as anticipated by Young; of claims
1—3, 5, 7, 8, 13—18, and 31—36 under 35 U.S.C. § 103(a) as obvious over
Young and Brown; and of claims 1,5, and 6 under 35 U.S.C. § 103(a) as
obvious over Young, Brown, Lim, and Spingola.
We enter a new ground of rejection of claims 1, 2, 5, 7, 13—15, 31,
33—35, and 38 under 35 U.S.C. § 102(b) as anticipated by Perez as
evidenced by Mair, Ye, and Gonzalez.
This decision contains a new ground of rejection pursuant to 37
C.F.R. § 41.50(b). Section 41.50(b) provides “[a] new ground of rejection
pursuant to this paragraph shall not be considered final for judicial review.”
Section 41.50(b) also provides:
When the Board enters such a non-final decision, the
appellant, within two months from the date of the decision,
must exercise one of the following two options with respect to
the new ground of rejection to avoid termination of the appeal
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Application 13/882,773
as to the rejected claims:
(1) Reopen prosecution. Submit an appropriate
amendment of the claims so rejected or new Evidence relating
to the claims so rejected, or both, and have the matter
reconsidered by the examiner, in which event the prosecution
will be remanded to the examiner. The new ground of rejection
is binding upon the examiner unless an amendment or new
Evidence not previously of Record is made which, in the
opinion of the examiner, overcomes the new ground of rejection
designated in the decision. Should the examiner reject the
claims, appellant may again appeal to the Board pursuant to this
subpart.
(2) Request rehearing. Request that the proceeding be
reheard under § 41.52 by the Board upon the same Record. The
request for rehearing must address any new ground of rejection
and state with particularity the points believed to have been
misapprehended or overlooked in entering the new ground of
rejection and also state all other grounds upon which rehearing
is sought.
Further guidance on responding to a new ground of rejection can be
found in the Manual of Patent Examining Procedure § 1214.01.
REVERSED: 37 C.F.R, $ 41.50(b)
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