Ex Parte Suzuki

Patent Trial and Appeal Board

Jul 20, 2018

13716469 (P.T.A.B. Jul. 20, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/716,469 12/17/2012 Kazuo Suzuki
33432 7590 07/20/2018
KIL YK & BOWERSOX, P.L.L.C.
400 HOLIDAY COURT
SUITE 102
WARRENTON, VA 20186
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.
3190-182 2010
EXAMINER
SCHWADRON, RONALD B
ART UNIT PAPER NUMBER
1644
MAIL DATE DELIVERY MODE
07/20/2018 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 KAZUO SUZUKI
Appeal2017-007074
Application 13/716,469
Technology Center 1600
Before RICHARD M. LEBOVITZ, JEFFREY N. FRED MAN, and
RICHARD J. SMITH, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to an
artificial polyclonal immunoglobulin composition. The Examiner rejected
the claims as failing to comply with the enablement requirement. We have
jurisdiction under 35 U.S.C. § 6(b). We reverse.
Statement of the Case
Background
"Immunoglobulin (lg) is a generic term for antibodies and proteins
structurally or functionally related to the antibodies" (Spec. ,r 2). A
"clinically used immunoglobulin preparation is a blood preparation obtained
by concentrating immunoglobulins extracted from human blood ... used for,
1 Appellant identifies the Real Party in Interest as National University
Corporation Chiba University (see App. Br. 3).
Appeal2017-007074
Application 13/716,469
for example, idiopathic thrombocytopenic purpura, agammaglobulinemia,
the acute phase of Kawasaki disease" (Spec. ,r 3). A modified version,
termed "'IVIg therapy' involving high dose intravenous administration of
immunoglobulins has been frequently employed" and "is extremely effective
for a high-severity disease and a refractory disease of unknown cause.
Further, IVIg is a useful therapeutic method also because of having virtually
no side effects" (id.).
However, the "immunoglobulin preparation clinically used at present
is a blood preparation, and hence always involves such a risk that an
unknown pathogen such as a virus derived from a raw material may be
mixed therein" (Spec. ,r 5). Also, "with an increase in the number of
diseases to be treated, a shortage of blood serving as a raw material is
predicted" (id.).
The Specification teaches "a production method for an artificial
polyclonal immunoglobulin, the method including preparing a mixture of
vectors for expressing plural kinds of genes each encoding a single chain
variable fragment (ScFv) comprised of a heavy chain variable region, heavy
chain constant region 1, and hinge region (VH-CHl-hinge) of an
immunoglobulin" (Spec. ,r 10).
The Claims
Claims 1-3 are on appeal. Independent claim 1 is representative and
reads as follows:
1. An artificial polyclonal immunoglobulin composition,
comprising, as active ingredients, polypeptides represented by
amino acid sequences set forth in SEQ ID NOS: 1 to 204 of the
sequence listing.
2
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Application 13/716,469
The Rejection
The Examiner rejected claims 1-3 under 35 U.S.C. § 112, first
paragraph as failing to comply with the enablement requirement (Ans. 2---6).
The Examiner finds the "specification is not enabling for the claimed
polyclonal immunoglobulin with the recited polypeptides as an active
ingredient or pharmaceutical composition thereof wherein said compositions
are used to treat human disease" (Ans. 2). The Examiner addresses the
factors in In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), finding "there
are no working examples in the specification using the claimed invention to
treat disease in humans"; "the claimed inventions are used to treat disease in
vivo in humans"; and "there is a high degree of unpredictability in the art"
(Ans. 4--5).
The issue with respect to enablement is: Does the evidence of record
support the Examiner's conclusion that the claims fail to comply with the
enablement requirement?
Findings of Fact
Breadth of Claims
1. Claim 1 is drawn to an artificial polyclonal immunoglobulin
composition, Claim 2 is drawn to a "pharmaceutical composition for treating
an inflammatory disease" and Claim 3 is drawn to a "pharmaceutical
composition for treating vasculitis" with each claim limited to SEQ ID Nos:
1-204 (see App. Br. 16, Claims 1-3).
Presence of Working Examples
2. The Specification teaches the "mixture comprised of plural
kinds of hScFvs produced in Example 1 was investigated for the therapeutic
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effect on vasculitis by using SCG/Kj mice as spontaneous vasculitis model
mice" (Spec. ,r 48).
3. The Specification teaches
administration of the hScFv mixture gave a reduction in the
MPO-ANCA level in serum that is an indicator for vasculitis
(FIG. 3). Further, a decreasing tendency of the spleen weight
was observed (FIG. 4). In addition, the leukocyte count,
lymphocyte count, monocyte count, granulocyte (neutrophil)
count, and platelet count in peripheral blood decreased (FIGS.
5-A, 5-B, and 5-C). The above-mentioned results confirmed
the therapeutic effect of the hScFv mixture.
(Spec. ,r 50).
Amount of Direction or Guidance Presented
4. The Specification teaches "artificial polyclonal
immunoglobulin composition according to the present invention is useful for
the treatment of a disease for which a therapy by immunoglobulin
administration, e.g., IVIg is effective. Examples of such disease may
include an infectious disease, an inflammatory disease" (Spec. ,r 30).
5. The Specification teaches: "Each of those polypeptides is a
human single chain variable fragment (hScFv) comprised of a heavy chain
variable region, heavy chain constant region 1, and hinge region (VH-CHl-
hinge) of a human gamma globulin" (Spec. ,r 19).
6. The Specification teaches:
Dosage range of the artificial polyclonal immunoglobulin
composition according to the present invention is not
particularly limited, and is suitably selected depending on, for
example, effectiveness of the ingredients contained therein, an
administration form, an administration route, the type of
disease, the properties of a subject (such as a body weight, an
age, a condition, and whether a subject is taking other
pharmaceutical agents), and a judgment by a doctor in charge.
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Application 13/716,469
(Spec. ,r 23).
State of the Prior Art and Unpredictability of the Art
7. Anthony2 teaches: "It is well established that high doses of
monomeric immunoglobulin G (IgG) purified from pooled human plasma
[intravenous immunoglobulin (IVIG)] confer anti-inflammatory activity in a
variety of autoimmune settings" (Anthony 373, abstract).
8. Anthony teaches the "anti-inflammatory activity of IVIG is
dependent on a precise glycan structure on the Fe" which "further supports
the model we have previously advanced - one in which a specific receptor
for the sialylated Fe, and not a canonical Fe receptor, is involved in this
pathway" (Anthony 375, col. 3; citations omitted).
9. Wu 3 teaches "IVIg is a highly purified globulin preparation
obtained from the pooled plasma of thousands of healthy donors. Although
initially given as replacement therapy for patients with primary and
secondary immunodeficiency states, IVIg has proven to be effective in the
treatment of various autoimmune and inflammatory disorders" (Wu 1 ).
10. Loeffler4 teaches "repeated Ivlg administration to
immunocompetent mice induces a strong humoral immune response and
hematologic deficits of unknown etiology. These factors could cause the
2 Anthony et al., Recapitulation of !VIG Anti-Inflammatory Activity with a
Recombinant IgG Fe, 320 Science 373---6 (2008).
3 Wu et al., The Mystery of IV!g, the-rheumatologist.org/article/the-mystery-
of-ivig (2012).
4 Loeffler et al., Development of Antihuman IgG Antibodies and
Hematologic Deficits but Not Clinical Abnormalities in C57BL/6 Mice after
Repeated Administration of Human Intravenous Immunoglobulin, 62
Comparative Medicine 31---6 (2012).
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effects of Iv lg preparations in mouse models of human disease to differ from
their effects in the human disorder" (Loeffler, abstract).
11. Hamano5 teaches:
The spontaneous crescentic glomerulonephritis-forming/Kinjoh
(SCG/Kj) mouse is a model of human crescentic
glomerulonephritis and vasculitis associated with the
production of the myeloperoxidase (MPO)-specific
antineutrophil cytoplasmic autoantibody (MPO-ANCA).
Although the disease is mediated initially by mutation of the
Fas gene (lpr), SCG/Kj mice also have non-Fas predisposing
genetic factors. To define these factors, genome-wide
quantitative trait locus (QTL) mapping was performed on
female (B6 x SCG/Kj) F2 intercross mice. Fourteen non-Fas
QTLs were identified.
(Hamano, abstract).
12. Dr. Suzuki6 states
We used the mouse models because they are understood to be
predictive of safety and efficacy in humans. The ability of a
treatment to improve vasculitis in a mouse would be understood
by one of ordinary skill in the art to be evidence that the
treatment would have similar effects in a human subject,
otherwise we would not have used the mouse model.
(Suzuki Deel. ,r 4, 1/17/2014).
13. Dr. Suzuki7 states:
To further support the data presented in the application,
additional experiments were performed consistent with the
5 Hamano et al., Genetic Dissection of Vasculitis, Myeloperoxidase-Specific
Antineutrophil Cytoplasmic Autoantibody Production, and Related Traits in
Spontaneous Crescentic Glomerulonephritis-Forming/Kinjoh Mice, 176 J.
Immunology 3662-73 (2006).
6 Declaration of Dr. Kazuo Suzuki, dated Jan. 17, 2014.
7 Declaration of Dr. Kazuo Suzuki, dated July 23, 2015.
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description of the application ... Figure 4 shows histological
observations in recovery of inflammation in lung by the
treatment with the hScFv proteins . . . In the control SCG/Kj
mice without treatment of the hScFv proteins, the histology
showed that vasculitis, hemorrhage and lymphoid follicle were
observed. By the treatment with the hScFv proteins, the tissue
appeared almost normal.
(Suzuki Deel. ,r,r 5, 10, 7/23/2015).
14. Dr. Suzuki states: "Red pulp and white pulp in spleen were
clearly shown in SCG/Kj mice treated with the hScFv proteins at a
concentration of 10 mg/Kg/day, 20 mg/Kg/day, or 40mg/Kg/day for 5 days,
whereas those in spleen were not clear in control SCG/Kj mice treated with
solvent" (Suzuki Deel. ,r 11, 7/23/2015).
Quantity of Experimentation
15. The Examiner makes no findings with regard to the quantity of
experimentation required.
Skill in the Art
16. The Examiner makes no findings with regard to skill in the art.
17. The authors in Wu are either medical doctors or Ph.Ds working
in a medical center (see Wu 8), while the authors in Anthony work in
university research departments (see Anthony 38, notes 1--4). This supports
a finding of a high level of skill in the art.
Principles of Law
Factors to be considered in determining whether a disclosure
would require undue experimentation ... include (1) the
quantity of experimentation necessary, (2) the amount of
direction or guidance presented, (3) the presence or absence
of working examples, ( 4) the nature of the invention, ( 5) the
state of the prior art, ( 6) the relative skill of those in the art,
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(7) the predictability or unpredictability of the art, and (8)
the breadth of the claims.
Wands, 858 F.2d at 737.
Analysis
Appellants contend "the SCG/Kj mouse is a valid model of human
disease that has been long accepted by those of ordinary skill in the art and is
directly relevant to the claimed invention. Furthermore, levels of MPO-
ANCA antibodies are a valid indicator of the effectiveness of the claimed
composition" (App. Br. 8).
The Examiner responds "the intended use of the claimed invention is
treatment of human disease (see [0011 ]). Furthermore, there is no evidence
of record that the ScFV found in the claimed compositions bind antigen
(antigen binding was never tested)" (Ans. 6). The Examiner responds that:
the functional activity of the instant invention as described by
appellants is mediated by polyclonal antibodies as is IVIG.
However, unlike IVIG, there is no evidence of record that the
ScFv in said preparation actually bind antigen. Also, said
preparation lacks the millions of different antibodies with
varying binding specificities found in IVIG and the claimed
invention lacks intact antibodies which contain Fe receptors.
(Ans. 7).
We agree with Appellants. We recognize that the working example
disclosed in the Specification, and in the Suzuki Deel. 7/23/2015, were
based on a mouse model system (FF 2, 3, 13, 14). However, even accepting
the Examiner's point based on Loeffler that model systems are not entirely
reliable (FF 10), the examples provided by Appellants provide specific
evidence which shows a positive effect of the composition of SEQ ID NOs
1-204 on markers of inflammation in several different ways in a mouse
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model system. If we accept the Examiner's argument that simply because
model systems have some limited degree of reliability, and therefore any
method based upon such systems require undue experimentation, patents
would not issue until after phase 3 clinical trials by FDA. That is not the
law. As explained in In re Brana, 51 F.3d 1560, 1567 (Fed. Cir. 1995), the
USPTO should not confuse "the requirements under the law for obtaining a
patent with the requirements for obtaining government approval to market a
particular drug for human consumption." The Brana court held that
"[ u ]sefulness in patent law, and in particular in the context of
pharmaceutical inventions, necessarily includes the expectation of further
research and development. The stage at which an invention in this field
becomes useful is well before it is ready to be administered to humans" Id. at
1568.
The Examiner's second point, that Anthony and Wu demonstrate the
claimed composition and IVIg operate by different mechanisms of action
(Ans. 5; cf FF 7-9), does not demonstrate unpredictability because there is
no requirement that the claimed invention operate using the same
mechanism of action as other, similar compositions. It is well established
that the "enablement requirement is met if the description enables any mode
of making and using the invention." Johns Hopkins Univ. v. CellPro, Inc.,
152 F.3d 1342, 1361 (Fed.Cir.1998) (emphasis added) (internal quotation
marks omitted). Here, neither Anthony nor Wu provide any specific
teachings that the polypeptides of SEQ ID Nos: 1-204 would fail to treat
inflammation or would otherwise be unpredictable. Even Anthony, which
suggests that IVIg operates through the Fe portion (FF 8), does not
demonstrate that the polypeptides of claim 1 that are composed of heavy
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chain variable, constant region 1, and hinge regions (Spec. ,r 14) fail to treat
inflammation, but rather suggests a mechanism by which Fe, composed of
heavy chain constant regions 2 and 3, performs this function.
The Examiner has provided no evidence regarding the quantity of
experimentation required nor any showing that the Specification failed to
provide significant guidance (FF 4--6, 15).
The presence of a working example, along with the evidence in the
Suzuki Declarations, the high level of skill in the art, the very narrow
breadth of the claims, the absence of any evidence requiring extensive
experimentation, weighed with some evidence of unpredictability (FF 1-1 7),
supports our conclusion that the balance of the Wands factors does not
support the Examiner's finding that undue experimentation would have been
required to make and use the claimed invention.
Conclusion of Law
The evidence of record does not support the Examiner's conclusion
that the claims fail to comply with the enablement requirement.
SUMMARY
In summary, we reverse the rejection of claims 1-3 under 35 U.S.C.
§ 112, first paragraph as failing to comply with the enablement requirement.
REVERSED
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