Ex Parte Baltimore et al

Patent Trial and Appeal Board

Dec 9, 2016

13151053 (P.T.A.B. Dec. 9, 2016)

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.
13/151,053 06/01/2011 David Baltimore CALTE.045C1 4222
20995 7590 12/13/2016
KNOBBE MARTENS OLSON & BEAR LLP
2040 MAIN STREET
FOURTEENTH FLOOR
IRVINE, CA 92614
EXAMINER
WILSON, MICHAEL C
ART UNIT PAPER NUMBER
1632
NOTIFICATION DATE DELIVERY MODE
12/13/2016 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):
jayna.cartee@knobbe.com
efiling @ knobbe. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DAVID BALTIMORE, MARK BOLDIN, and
KONSTANTIN TAGANOV1
Appeal 2015-000943
Application 13/151,053
Technology Center 1600
Before ERIC B. GRIMES, ULRIKE W. JENKS, and RYAN H. FLAX,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35U.S.C. § 134 involving claims to a
transgenic mouse, which have been rejected as lacking patentable utility.
We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.
STATEMENT OF THE CASE
“MicroRNA (miRNA) represent a newly discovered class of
endogenous ~22-nt RNAs encoded by biological species. Owing to their
1 Appellants identify the Real Party in Interest as California Institute of
Technology. (Appeal Br. 4.)
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Application 13/151,053
ability to post-transcriptionally regulate expression of nearly any target gene,
miRNA have been implicated in a variety of processes in plants and
animals.” (Spec. 19.) “When miR-146a or miRNA-146b is delivered into
cells of the innate immune system, among other things it dampens the
production of pro-inflammatory cytokines like TNF and IL-6.” (Id. 134.2)
“Delivery of molecules that inhibit miR-146 activity, such as antisense
molecules, can be used to upregulate activity of the immune system where
appropriate.” (Id.)
The Specification discloses that “[kjnockout (KO) mice were
produced to investigate the biological role for miR-146a miRNA.” (Id.
1117.) The Specification states that “[smarting at about 6 month of age
miR-146a KO mice developed an autoimmune-like disorder that was
characterized by splenomegaly and lymphoadenopathy, and as a result died
prematurely.” (Id. 1119.) The KO mice showed a variety of changes in the
distribution and activity of their immune system cells. (Id. Tflf 119—123.)
Claims 1—5 and 7—18 are on appeal. Claim 1 is the only independent
claim and reads as follows:
1. A transgenic mouse, wherein the genome of the transgenic mouse
comprises a homozygous disruption of the endogenous miRNA-146 gene,
and wherein the transgenic mouse exhibits one or more phenotypes of an
autoimmune disorder.
DISCUSSION
The Examiner has rejected all of the claims on appeal under 35 U.S.C.
§ 101 on the basis that they are not supported by a patentable utility. (Ans.
2 The Specification and the references discussed below use “miR” and
“miRNA” interchangeably as shorthand for “microRNA.”
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3—19.) The Examiner has also rejected all of the claims on appeal under 35
U.S.C. § 112, first paragraph, on the same basis. {Id. at 19—21.)
The Examiner finds that the claimed KO mice cannot be used as a
model of a human disease because the phenotypes described for the mice in
the Specification “do not reflect a disease state in humans” {id. at 9) and “the
human disease conditions resulting from miR-146 disruption as claimed
were unknown” {id. at 10). The Examiner also concludes that the KO mice
cannot be used to determine compounds that modulate miR-146 expression
because they do not express miR-146. {Id. at 11.)
The Examiner finds that using the KO mice to determine compounds
that modulate miRNA-146 expression is not a specific utility because the
Specification does not link any of the immune system phenotypes described
for the mice to any specific disease. {Id.) The Examiner also finds that such
a use “is not a specific or substantial utility because determining compounds
that alter a phenotype may not reveal the function of the protein” (id. at 12)
and is also not substantial “because compounds that alter a phenotype may
not be therapeutic in humans.” {Id. at 13.)
Finally, the Examiner finds that miRNA-146 KO mice “did not have a
‘well-known utility’ to study the function of miRNA-146.” {Id. at 15.) The
Examiner finds that “further study of the mouse itself would be required to
determine . . . how to use the mouse to determine the role of miRNA-146
gene in autoimmunity or innate immune reaction, and such a utility is not
‘specific’ or ‘substantial.’” {Id. at 19.)
Appellants argue, among other things, that “because the
immunomodulatory function of miRNA-146a has been well documented at
the time of filing so that a person of ordinary skill in the art would
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Application 13/151,053
immediately recognize the utility of the miRNA-146a knockout mouse
claimed.” (Appeal Br. 10.) Specifically, Appellants argue that a “role of
miRNA-146a in inflammation was understood at the time of filing of the
present application.” (Id.) Appellants point to Sonkoly3 as evidence that
“miRNA-146a was reported to be involved in inflammation and other
processes that function in the innate immune system.” (Id.) Appellants
point to Sheedy4 as evidence that “[t]he expression of miRNA-146a was
known to be up-regulated by inflammatory factors such as IL-1 and TNF-a
and is a mediator of inflammation.” (Id. at 10—11.5)
Appellants also cite the Second Boldin Declaration6 as evidence that
“[sjince miRNA-146a is known to play a role in immune disorders, one of
ordinary skill in the art would recognize that the claimed miRNA-146a
knockout mouse can be utilized to study the role of miRNA-146a in human
autoimmune disorders and to investigate possible treatments that impact
some portion of the observed phenotypes.” (Id. at 15.) Appellants also cite
the Second Boldin Declaration as evidence that
3 Sonkoly et al., MicroRNAs and immunity: Novel players in the regulation
of normal immune function and inflammation, 18 Sem. Cancer Biology
131-140 (2008).
4 Sheedy et al., Adding fuel to fire: microRNAs as a new class of mediators
of inflammation, 67 (Suppl. Ill) Ann. Rheum. Dis. iii50—iii55 (2008).
5 As the Examiner has pointed out (Ans. 23), Sonkoly and Sheedy were
published after the effective filing date of the instant application. However,
both Sonkoly and Sheedy are review articles that reflect the state of the art
near this application’s effective filing date, and both cite publications from
before that date as the source of most of their discussion of miR-146. Thus,
Sonkoly and Sheedy reflect the knowledge of those skilled in the art as of
the effective filing date.
6 Declaration under 37 C.F.R. § 1.132 of Mark Boldin, signed Nov. 6, 2013.
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[t]he miRNA-146a knockout mouse is an ideal animal model for
screening for compounds capable of mimicking the function of
miRNA-146a in vivo without the interference of endogenous
miRNA-146a function. . . . Therefore, although wild-type mice
may be used for screening compounds that increase miRNA-
146a expression . . . , one of ordinary skill in the art would
consider using the miRNA-146a knockout mouse to identify
miRNA-146a mimics in vivo since it is advantageous to do so as
compared to using wild-type mice.
(Id. at 15—16.)
We agree with Appellants that the claimed invention is supported by a
patentable utility. The claimed mice need not provide an animal model of a
specific human disease in order to have patentable utility. See In re Fisher,
421 F.3d 1365, 1371 (Fed. Cir. 2005) (The courts “have required a claimed
invention to have a specific and substantial utility to satisfy § 101.”). “[T]o
satisfy the ‘substantial’ utility requirement, an asserted use must show that
that claimed invention has a significant and presently available benefit to the
public.” Id. A “specific” utility requires “an application [to] disclose a use
which is not so vague as to be meaningless” or a “showing] that th[e]
claimed invention can be used to provide a well-defined and particular
benefit to the public.” Id.
Here, the Specification discloses that miRNA-146a knock-out (KO)
mice developed an autoimmune-like disorder, and that peripheral T cells in
the KO mice consistently showed an activated status. (Spec. 1119.) The
Specification states that “[t]he activated status of peripheral T cells is a
characteristic for many autoimmune/inflammatory diseases, where T cells
cause damage to peripheral tissues in response to autoantigen stimulation.”
(Id. 1120.) The Specification also states that macrophages in the KO mice
secrete “significantly higher levels of proinflammatory cytokines, including
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Application 13/151,053
TNFa, IL-6 and IL-ip after LPS [lipopolysaccharide] stimulation, indicating
that miRNA-146a plays a role of negative regulator of inflammation and
macrophage function.” {Id. 1122.) Thus, the Specification provides a
reasonable evidentiary basis to show that the claimed mice show the
increased inflammation that is characteristic of many autoimmune/
inflammatory diseases.
Appellants’ evidence also shows that the role of miRNA-146 in
inflammation was known at the time the instant application was filed.
Sonkoly states that “[rjecently, a role for microRNAs has been proposed in
the regulation of innate immune responses in monocytes and macrophages.”
(Sonkoly 135, left col.) Sonkoly cites a paper published in 2006 as
disclosing that miRNA-146a is induced by ligands of toll-like receptors
(TLRs) that recognize bacterial products, as well as by TNF-a and IL-ip.
{Id.) Sonkoly states that miRNA-146’s “expression may be critical in
preventing excess inflammation. Interestingly, we recently found this
miRNA to be associated with psoriasis, a chronic inflammatory skin
disease.” {Id., citing a paper published in 2007.) Finally, Sonkoly discloses
that “[rjecent evidences show” that miR-146 acts as a suppressor of TLR-
and TNF-a signaling in the intracellular signaling cascade that results in
inflammation. {Id. at 136, legend to Figure 2.)
Similarly, Sheedy states that early studies indicated a role for
microRNAs in the immune response and inflammation. (Sheedy iii50
(abstract).) Sheedy states that “investigators are examining their role in the
pathogenesis of inflammatory diseases. miR-146 and miR-155 have been a
particular focus for investigators, and these two miRNAs have been shown
to be induced by proinflammatory stimuli such as interleukin 1, tumour
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Application 13/151,053
necrosis factor a (TNFa) and Toll-like receptors (TLRs).” (Id.) Sheedy
states that “TLRs and other proinflammatory stimuli have been implicated in
the pathogenesis of RA [rheumatoid arthritis] for some time.” (Id. at iii54,
left col.) Sheedy concludes that “[t]he potential of miRNAs for improving
our understanding of the pathogenesis of diseases such as rheumatoid
arthritis, and for developing potentially new treatments for these diseases, is
substantial.” (Id. at iii50 (abstract).)
Thus, the evidence shows that, as of the instant application’s effective
filing date, those skilled in the art understood that miRNA-146 played a role
in the inflammatory pathway, and more specifically that it functioned to
suppress TLR- and TNF-a signaling in the signal pathway that results in
inflammation, and thus that expression of miRNA-146 prevents excess
inflammation, as discussed in Sonkoly. The evidence also shows that, as of
the critical date, those skilled in the art understood that excess inflammation
plays a role in the pathogenesis of RA, and that agents that prevent such
excess inflammation are promising treatments for RA, as discussed in
Sheedy.
In addition, Dr. Boldin provides a reasoned basis for concluding that
the claimed mice provide an effective tool for identifying mimics of miR-
146a:
Reversal of phenotypic changes (splenomegaly, lymph-
adenopathy, tissue inflammation, cytokine production, etc.) upon
injection of miRNA-146a mimic compound (for example, a short
double-stranded oligonucleotide) into the miRNA-146a
knockout mice provides a robust and easy way to screen for the
most efficacious and specific miRNA-146a mimic compound.
Results obtained in such an experiment (in contrast to
experiments using wild-type mice) can be interpreted in a rather
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Application 13/151,053
straight forward manner, because of the lack of interference from
the function of endogenous miRNA-146a gene.
(Second Boldin Declaration 17.)
We conclude that the Examiner’s rejection is not supported by a
preponderance of the evidence of record because the evidence shows that the
claimed mice would have been recognized by persons of ordinary skill in the
art as having utility as a research tool to perform research on the miRNA-
146a gene and to screen compounds for activity in mimicking the in vivo
activity of miRNA-146a. These uses provide a significant and presently
available benefit to the public, as well as a well-defined and particular
benefit to the public. They therefore satisfy the requirement of a specific
and substantial utility, and are credible based on what was known in the art
regarding miRNA-146 and what is disclosed in Appellants’ Specification.
The Examiner concludes that “[studying the role of miRNA-146 in
autoimmune disorders would require further research of the mouse itself.”
(Ans. 24—25.)
We disagree. Using the claimed mice to conduct further research on
miRNA-146 or to identify compounds that mimic miRNA-146 does not
constitute carrying out research to determine a use for the claimed invention
itself, but rather using the claimed mice to carry out other research. Cf.
Fisher, 421 F.3d at 1373 (“[A] microscope has the specific benefit of
optically magnifying an object to immediately reveal its structure. . . .
Accordingly, while a microscope can offer an immediate, real world benefit
in a variety of applications, the same cannot be said for the claimed ESTs.”).
The Examiner also concludes that using the claimed mice to screen
for mimics of miRNA-146a is not a specific or substantial utility, because
(a) it was not disclosed in the Specification as filed, (b) the steps of the
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screening method are not disclosed, and (c) such screening could be carried
out using wild-type mice. (Ans. 27—28.)
We do not agree with the Examiner’s reasoning. Although the
Specification does not disclose using the claimed mice to identify mimics of
miRNA-146a, this utility would have been readily apparent to those skilled
in the art, in view of the existing knowledge that miRNA-146 prevents
excessive inflammation by suppressing TLR- and TNF-a signaling in the
inflammatory signaling cascade (Sonkoly) and the fact that “TLRs and other
proinflammatory stimuli have been implicated in the pathogenesis of RA for
some time” (Sheedy). The Examiner has not cited evidence showing that
such screening would have required undue experimentation for those of skill
in the art, even in the absence of a disclosed series of method steps.
Finally, the fact that the screening could also be carried out using
wild-type mice does not mean that this utility is not specific. A “specific”
utility requires “a use which is not so vague as to be meaningless” or “a
well-defined and particular benefit to the public,” In re Fisher, 421 F.3d at
1371, not a utility that is unique to the claimed invention. For the reasons
discussed above, we conclude that the claimed invention is supported by a
utility that is substantial, specific, and credible.
SUMMARY
We reverse the rejection of claims 1—5 and 7—18under 35 U.S.C.
§ 101 and 35 U.S.C. § 112, first paragraph.
REVERSED
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