Ex Parte Guild et al

Patent Trial and Appeal Board

Jul 16, 2018

13800501 (P.T.A.B. Jul. 16, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/800,501 03/13/2013
147667 7590
Translate Bio, Inc.
c/o Proskauer Rose LLP
One International Place
Boston, MA 02110
07/18/2018
FIRST NAMED INVENTOR
Braydon Charles Guild
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.
MRT-1017US2 1018
EXAMINER
POPA, ILEANA
ART UNIT PAPER NUMBER
1633
NOTIFICATION DATE DELIVERY MODE
07/18/2018 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):
docketingpatentboston @proskauer.com
oandrews@proskauer.com
intellectualproperty@translate. bio
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte BRA YDON CHARLES GUILD, FRANK DEROSA, and
MICHAEL HEARTLEIN
Appeal 2016-008388
Application 13/800,501
Technology Center 1600
Before RICHARD J. SMITH, RACHEL H. TOWNSEND, and
DAVID COTTA, Administrative Patent Judges.
TOWNSEND, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of delivery of messenger RNA for in vivo production of protein, which have
been rejected as anticipated and/or obvious. 1 We have jurisdiction under 35
U.S.C. § 6(b ).
We reverse.
STATEMENT OF THE CASE
Individuals suffering from diseases that result from protein and/or
enzyme deficiencies "may have underlying genetic defects that lead to the
1 Appellant is the Applicant Shire Human Genetic Therapies, Inc., which
according to the Appeal Brief, is the real party in interest. (Appeal Br. 2.)
Appeal 2016-008388
Application 13/800,501
compromised expression of a protein or enzyme, including, for example, the
non-synthesis of the protein, the reduced synthesis of the protein, or
synthesis of a protein lacking or having diminished biological activity."
(Spec. ,r 8.) "Novel therapies that increase the level or production of an
affected protein or enzyme in target cells, such as hepatocytes, or that
modulate the expression of nucleic acids encoding the affected protein or
enzyme could provide a treatment or even a cure for metabolic disorders."
(Spec. ,r 6.) The claims at issue concern methods of intracellular delivery of
nucleic acids that can be translated into a gene product of interest following
successful delivery to target tissue. (Spec. ,r 7.)
Claims 1, 3, 4, 7, 10-14, 16, 18-28, and 30-38 are on appeal. Claim
1 is representative and reads as follows:
1. A method of delivery of messenger RNA (mRNA) for in
vivo production of protein, comprising
administering systemically to a subject in need of
delivery a composition comprising an mRNA encoding a
protein, encapsulated within a liposome such that the
administering of the composition results in the prolonged stable
expression of the protein encoded by the mRNA in the liver;
wherein the protein encoded by the mRN A is an enzyme,
a hormone, a receptor or an antibody; and
wherein the liposome comprises one or more cationic
lipids, one or more non-cationic lipids, one or more cholesterol-
based lipids and one or more PEG-modified lipids and has a
size less than about 100 nm.
(Appeal Br. 32.)
2
Appeal 2016-008388
Application 13/800,501
The following grounds of rejection by the Examiner are before us on
review:
Claims 1, 3, 4, 7, 14, 22, 31-34, and 37 under 35 U.S.C. § 102(b) as
anticipated by MacLachlan. 2
Claims 1, 3, 4, 7, 10-12, 14, 16, 18-28, and 30-38 under 35 U.S.C.
§ 103(a) as unpatentable over MacLachlan, Ye3 and Okumura. 4
Claims 1, 3, 4, 7, 10-14, 16, 18-28, and 30-38 under 35 U.S.C.
§ 103(a) as unpatentable over MacLachlan, Ye, Okumura, and Kariko. 5
DISCUSSION
Anticipation
According to the Examiner, MacLachlan teaches a method of
delivering protein-encoding messenger RNA (mRNA) encapsulated within
liposomes of the type recited in claim 1 via intravenous administration.
(Final Action 3.) The Examiner recognizes that "the preferred embodiment
in MacLachlan [] is using SNALPs6 to deliver siRNA7 to silence genes of
2 MacLachlan et al., US 2006/0008910 Al, published Jan. 12, 2006
3 Ye et al. "Prolonged Metabolic Correction in Adult Omithine
Transcarbamylase-deficient Mice with Adenoviral Vectors," 271 J. Biol.
Chem., 3639-3646 (1996).
4 Okumura et al., "Bax mRNA therapy using cationic liposomes for human
malignant melanoma," 10 J. Gene Med., 910-917 (2008).
5 Kariko et al., "Incorporation of Pseudouridine into mRNA Yields Superior
Nonimmunogenic Vector With Increased Translational Capacity and
Biological Stability," 16 (10) Mol. Ther. 1833-1840 (2008).
6 SNALP is the acronym for "stabilized nucleic acid-lipid particles."
(MacLachlan ,r,r 10, 57.)
7 siRNA is the acronym used in MacLachlan for "small-interfering RNA."
(MacLachlan ,r 77.) MacLachlan defines "interfering RNA," also called
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Appeal 2016-008388
Application 13/800,501
interest." (Ans. 6.) But the Examiner contends that MacLachlan also
teaches protein-encoding mRNA delivery with SNALP for protein
expression in vivo because (a) it indicates SNALPs "are suitable for the
delivery of nucleic acids ([0057]; [0084])," (b) it "define[s] that the term
'nucleic acid' is used interchangeably with gene, cDNA, mRNA, and an
interfering RNA ([0073])," and (c)
in [O 142] and [O 148] MacLachlan et al. specifically teach gene
(and not siRNA) delivery as follows:
"Anti-angiogenic genes are able to inhibit
neovascularization. These genes are particularly useful
to treat cancers in which angiogenesis play a role in the
pathological development of the disease". [0142]
"Tumor suppressor genes are genes that are able to
inhibit the growth of a cell, particularly tumor cells.
Thus, delivery of these genes to tumor cells is useful in
the treatment of cancer." [0148]
[ And as] clearly taught by MacLachlan et al. and as commonly
known in the prior art, inhibition of neovascularization and of
tumor cell growth requires the activity of the antiangiogenic
and tumor suppressor polypeptides/proteins, not their silencing.
Thus, MacLachlan et al. teach using SNALPs for the in vivo
delivery of genes encoding therapeutic polypeptides/proteins.
(Ans. 6-8; see also Final Action 3, 7.) The Examiner thus concludes that
"MacLachlan et al. is an anticipatory reference with respect to using SNALP
technology to deliver mRNA for protein/enzyme production in vivo." (Ans.
8 ( emphasis omitted).)
RN Ai, as "double-stranded RNA that results in the degradation of specific
mRNAs and can be used to interfere with translation from a desired mRNA
target transcript." (Id.) MacLachlan further explains the siRNA is short
RNAi that is "about 15-30 nucleotides in length." (Id.)
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Application 13/800,501
We disagree with the Examiner's factual finding that MacLachlan
discloses encapsulating protein encoding mRNA in liposomes or
systemically administering such liposomes for in vivo delivery of genes
encoding therapeutic proteins.
As Appellant points out (Appeal Br. 7-10; Reply Br. 3-8),
MacLachlan's disclosure regarding the use of SNALP technology is solely
directed to delivery of interfering RNA, notwithstanding that it broadly
defines (a) the term "nucleic acid" to be interchangeably used with cDNA,
mRNA encoded by a gene, and an interfering RNA molecule (MacLachlan ,r
73), and (b) the term "gene" as referring "to a nucleic acid ( e.g., DNA or
RNA) sequence that comprises partial length or entire length coding
sequences necessary for the production of a polypeptide or precursor ... "(id.
i175).
In the "Field of the Invention," MacLachlan states that "[t]he present
invention relates to" therapeutic delivery of encapsulated nucleic acid "to
provide efficient RNA interference." (Id. ,r 2.) MacLachlan then explains
that RNAi is a "sequence specific mechanism triggered by double stranded
RNA(dsRNA) that induces degradation of complementary target single
stranded mRNA and 'silencing' of the corresponding translated sequences."
(Id. ,r 3.) In MacLachlan's "Brief Summary of the Invention" it is stated:
The present invention comprises novel, stable nucleic acid-lipid
particles (SNALP) encapsulating one or more interfering RNA
molecules, methods of making the SNALPs and methods of
deliver[in]g and/or administering the SNALPs.
(Id. ,r 12.) In the "Detailed Description of the Invention," MacLachlan
states:
The present invention demonstrates the unexpected success of
encapsulating short inteifering RNA (siRNA) molecules in
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Application 13/800,501
SNALPs comprising cationic lipids of Formula I, II, or mixture
thereof. The SNALPs described herein can be used to deliver
an siRNA to a cell to silence a target sequence of interest.
SN ALP comprising any of a broad range of concentrations of
additional cationic lipids, noncationic lipids, and other lipids
can be used to practice the present invention. The SNALP can
be prepared with any nucleic acid comprising an inteifering
RNA sequence, from any source and comprising any
polynucleotide sequence ....
(Id. ,r 53 (emphasis added).)
"Interfering RNA sequence" or "RNAi" is defined by MacLachlan as
referring to "double-stranded RNA that results in the degradation of specific
mRNAs and can be used to interfere with translation from a desired mRNA
target transcript" and siRNA is defined as being about "15-30 nucleotides in
length" and is considered short RN Ai. (Id. ,r 77 .)
MacLachlan goes on to describe the SNALP constituents in the
Detailed Description of the Invention section: the Lipid portion (Section
III.A. and B. of the "Detailed Description of the Invention"), (Id. i-fi-f86-92),
the Bilayer Stabilizing Component (Section III.C.), (Id. ,r,r 93-117) and, the
Nucleic Acid Component (Section III.D.), (Id. ,r,r 118-148). In the
introductory paragraph of section III.D., the "Nucleic Acid Component" of
the SNALP, MacLachlan again specifies that "[t]he nucleic acid component
of the present invention comprises an interfering RNA that silences ( e.g.,
partially or completely inhibits) expression of a gene of interest." (Id. f
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Application 13/800,501
119.)8 This section III.D. is divided into three further subsections, the first
two being a discussion of selecting siRNA sequences (III.D.1) (Id. i-fi-fl20-
124) and generating siRNA (III.D.2) (Id. ,r,r 125-131 ). The third section,
III.D.3. (Id. i-fi-fl33-148), is a potential list of genes of interest that the RNAi
might target so as to silence expression of that gene of interest. That list of
genes of interest to silence expression of includes, inter alia, genes
associated with viral infection and survival (Id. i-fi-fl34-135), genes
associated with metabolic diseases and disorders (Id. ,r,r 136-137),
angiogenic and anti-angiogenic genes (Id. ,r,r 140-142), and tumor
suppressor genes (Id. ,r,r 147-148). Contrary to the Examiner's position,
these are not identified as genes or mRNA to be encapsulated for delivery to
target tissue.
In light of the foregoing, we disagree with the Examiner that delivery
of interfering RNA, such as siRNA, is merely the preferred embodiment of
MacLachlan (Ans. 11 ), and that using SNALPs for delivery of other types of
nucleic acid such as mRNA encoding a gene of interest is embraced; rather,
delivery of interfering RNA is "the invention" of MacLachlan and is all that
is described.
MacLachlan discusses the preparation of SNALPs with the foregoing
constituents in section IV (Id. ,r,r 149-202) and administration of the
8 MacLachlan notes that the:
interfering RNA can be provided in several forms. For example
an interfering RNA can be provided as one or more isolated
small-interfering RNA (siRNA) duplexes, longer double-
stranded RNA (dsRNA) or as siRNA or dsRNA transcribed
from a transcriptional cassette in a DNA plasmid.
(MachLachlan ,r 119.)
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Application 13/800,501
SNALPs in section V (Id. ,r,r 203-209). While MacLachlan refers to the
encapsulated genetic material as nucleic acid generally ( or the plasmid) in
sections IV and V, it is clear from MacLachlan' s description of "the present
invention" throughout the Specification that the nucleic acid generically
referred to in sections IV and Vis necessarily RNAi. (See, e.g., id. at
abstract, ,r,r 2, 12 ("The present invention comprises novel, stable nucleic
acid-lipid particles (SNALP) encapsulating one or more interfering RNA
molecules, methods of making the SNALPs and methods of deliver[in Jg
and/or administering the SNALPs."), 17, 53 ("The SNALP can be prepared
with any nucleic acid comprising an interfering RNA sequence, from any
source and comprising any polynucleotide sequence, and can be prepared
using any of a large number of methods."), 119 ("The nucleic acid
component of the present invention comprises an interfering RNA that
silences ( e.g., partially or completely inhibits) expression of a gene of
interest").) In short, sections IV and V concern making and using the
stabilized nucleic acid-lipid particles encapsulating one or more interfering
RNA molecules- i.e., the invention in the MacLachlan patent. Sections IV
and V do not concern making and using stabilized nucleic acid-lipid
particles encapsulating mRNA or other non-interfering RNA molecules.
In light of the foregoing, we agree with Appellant that MacLachlan
does not disclose delivering protein encoding mRNA using SN ALP.
Consequently, we conclude that the Examiner has not provided evidence that
MacLachlan discloses every limitation of the claimed invention. Thus, we
reverse the Examiner's rejection of independent claim 1, and claims 3, 4, 7,
14, 22, 31-34, and 37 depending therefrom, under 35 U.S.C. § 102(b) as
being anticipated by MacLachlan.
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Appeal 2016-008388
Application 13/800,501
II
Obviousness
The Examiner's assertion that the combination of MacLachlan, Ye,
and Okumura renders claims 1, 3, 4, 7, 10-12, 14, 16, 18-28, and 30-38
obvious applies MacLachlan as discussed above in connection with
anticipation, and relies on Ye and Okumura for teaching the limitations of
claims 10-12, 16, 18-21, 23-28, 30, 35, 36, and 38 and rendering those
claims obvious. (Final Action 5 ("The teachings of MacLachlan et al. are
applied as above for claims 1, 3, 4, 7, 14, 22, 31-34, and 37."); see, e.g.,
Ans. 13-14 (
As set forth above, MacLachlan et al. do teach using SNALPs
to deliver an mRNA encoding an enzyme for therapeutic
purposes; prolonged stable expression in the liver necessarily
follows intravenous administration as taught by MacLachlan et
al. For this reason, the argument that the cited secondary
references do not cure the deficiencies of MacLachlan et al. is
not found persuasive; there is no deficiency to be cured in the
teachings of Maclachlan et al.);
Ans. 21 ("the primary reference already anticipates in vivo delivery of
liposomal mRNA"); Ans. 22 ("using SNALP technology to deliver mRNA
is anticipated by MacLachlan et al."); Ans. 27 ("expression in liver must
necessarily follow systemic administration as taught by MacLachlan et al.
because all that is required to achieve expression in liver is to systemically
administer SNALPs encapsulating mRNA"); Ans. 30-31 (
At the time the instant invention was made, systemic delivery
of an enzyme-encoding mRNA encapsulated into 50 nm
cationic liposomes comprising one or more cationic lipids, one
or more neutral lipids (i.e., non-cationic lipids), cholesterol (i.e.,
cholesterol-based lipid), and one or more PEG-modified lipids
was taught and thus anticipated by MacLachlan et al.).)
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Application 13/800,501
Likewise, in addressing claim 13 as being obvious over MacLachlan,
Ye, Okumura, and Kariko, the Examiner continues to apply MacLachlan as
discussed above with respect to anticipation, relying on Kariko for
disclosure of the limitation added by claim 13. (Final Action 6 ("The
teachings of MacLachlan et al., Ye et al., and Okumura et al. are applied as
above for claims 1, 3, 4, 7, 10-12, 14, 16, 18-28, and 30-38."; see also Ans.
23: ("Kariko et al. cannot discourage from pursuing a method already used
by the primary reference.") (emphasis omitted).)
For the reasons discussed above, we disagree with the Examiner's
assertion that MacLachlan discloses using SNALP technology to
encapsulate mRNA for in vivo delivery or administering such an
encapsulated mRNA, and reverse the Examiner's determination that
MacLachlan anticipates claims 1, 3, 4, 7, 14, 22, 31-34, and 37. The
Examiner does not rely on Ye or Okumura to remedy the noted deficiency of
MacLachlan's disclosure. 9 As such, to the extent that the Examiner has
rejected these claims and claims 10-12, 16, 18-21, 23-28, 30, 35, 36, and 38
as obvious over the combined teachings of MacLachlan, Ye, and Okumura,
9 We take no position on whether delivering protein-encoding messenger
RNA (mRNA) encapsulated within liposomes of the type recited in claims 1
and 25 via intravenous administration would have been obvious in view of
the references cited by the Examiner or made of record by Appellant (see,
e.g., Ans. 28:
In fact Lu et al. teach successful mRNA transfection in vivo at
comparable or higher levels than DNA transfection by using the same
cationic liposomes. Lu et al. teach that gene therapy could be
achieved by using mRNA (see Abstract; p. 250, column 2, first
paragraph; p. 251, Fig. 7 and paragraph bridging columns 1 and 2),
as that rejection is not before us.
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Application 13/800,501
we reverse. Furthermore, the Examiner does not rely on Kariko to remedy
the noted deficiency ofMacLachlan's disclosure regarding claims 1, 3, 4, 7,
14, 22, 31-34, and 37 discussed above. As such, to the extent that the
Examiner has rejected these claims and claims 10-13, 16, 18-21, 23-28, 30,
35, 36, and 38 as obvious over the combined teachings MacLachlan, Ye,
Okumura, and Kariko, we reverse.
SUMMARY
We reverse the rejection of claims 1, 3, 4, 7, 14, 22, 31-34, and 37
under 35 U.S.C. § 102(b) as anticipated by MacLachlan.
We reverse the rejection of claims 1, 3, 4, 7, 10-12, 14, 16, 18-28,
and 30-38 under 35 U.S.C. § 103(a) as unpatentable over MacLachlan, Ye
and Okumura.
We reverse the rejection of claims 1, 3, 4, 7, 10-14, 16, 18-28, and
30-38 under 35 U.S.C. § 103(a) as unpatentable over MacLachlan, Ye,
Okumura, and Kariko.
TIME PERIOD FOR RESPONSE
No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136(a).
REVERSED
11