Ex Parte Sharp et al

Patent Trials and Appeals Board

Jun 26, 2019

13128800 - (D) (P.T.A.B. Jun. 26, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/128,800 11/18/2011
32425 7590 06/28/2019
NORTON ROSE FULBRIGHT US LLP
98 SAN JACINTO BOULEVARD
SUITE 1100
AUSTIN, TX 78701-4255
FIRST NAMED INVENTOR
Zelton Dave Sharp
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.
UTSK.P0408US/l 000086950 3489
EXAMINER
SIMMONS, CHRIS E
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
06/28/2019 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):
aoipdocket@nortonrosefulbright.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte ZEL TON DA VE SHARP, JOHN R. STRONG,
VERONICA GALVAN, SALVA TORE ODDO, and
HERBERT G. WHEELER1
Appeal 2018-008436
Application 13/128,800
Technology Center 1600
Before DONALD E. ADAMS, ERIC B. GRIMES, and RYAN H. FLAX,
Administrative Patent Judges.
GRIMES, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
method of extending the lifespan of a mammal, which have been rejected as
indefinite and obvious. We have jurisdiction under 35 U.S.C. § 6(b ).
We affirm.
1 Appellants identify the Real Parties in Interest as The Board of Regents of
The University of Texas System and Southwest Research Institute. Br. 1.
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Application 13/128,800
STATEMENT OF THE CASE
"[T]he invention relates to microcapsules that include an inhibitor of
the mammalian target of rapamycin (mTOR), and methods of treating or
preventing age-related diseases, disorders, and conditions in a subject using
[the] microcapsules." Spec. 1. "The inhibitor of mTOR may be rapamycin."
Id. at 4.
The Specification states that "[ m ]icroencapsulation improves
therapeutic efficacy compared to formulations that are not encapsulated." Id.
at 2-3. The microcapsules can include a core that is encased in a coating. Id.
at 3. In some embodiments, "the coating provides for delayed release of the
inhibitor of mTOR and/or preferential release of the therapeutic agent in the
intestinal tract of a subject (i.e., an enteric coating)," such as "Eudragit S 100,
cellulose acetate phthalate (CAP), a methyl acrylate-methacrylic acid
copolymer," etc. Id.
The Specification states that, "[ f]or example, ... microencapsulated
rapamycin fed late in life extends lifespan in genetically heterogenous [sic]
mice." Id. at 2. "Prolongation of lifespan ... refers to a greater lifespan of
the subject than the subject would otherwise live in the absence of the
microcapsules." Id. at 7. "An estimate of the lifespan the subject would have
otherwise lived in the absence of the microcapsules can be obtained, for
example, from demographic studies, Social Security Administration Life
Tables, and scientific literature concerning lifespan." Id.
Claims 57, 62, 67----69, 73-79, 81, and 86-88 are on appeal. Claim 86
is representative and reads as follows:
86. A method for extending lifespan in a mammalian subject
comprising administering to the subject an effective amount of
a pharmaceutical or nutraceutical composition comprising
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microencapsulated rapamycin, wherein the rapamycin is
encased in a coating that includes a water insoluble polymer,
wherein the water insoluble polymer is a methyl methacrylate-
methacrylic acid copolymer, and wherein the lifespan is
extended to greater than the life expectancy of the mammalian
subject.
The claims stand rejected as follows:
Claims 57, 62, 67----69, 73-79, 81, and 86-88 under 35 U.S.C. § 112,
second paragraph, as indefinite (Ans. 3) and
Claims 57, 62, 67----69, 73-79, 81, and 86-88 under 35 U.S.C. § I03(a)
as obvious based on Sehgal, 2 Bedrosian, 3 Penhasi, 4 and Blagosklonny5
(Ans. 4).
I
The Examiner has rejected all of the claims on appeal on the basis that
"the limitation, 'wherein the lifespan is extended to greater than the life
expectancy of the mammalian subject' ... renders the claims indefinite
because it is not controlled via a positive, pro-active step other than
administering the claimed composition and, therefore, is indefinite for not
being further limiting." Ans. 3.
The Examiner also reasons that
one cannot reasonably know the life expectancy of any given
person with any true accuracy given that several methods may
be chosen. There are various approaches to determining an
individual's likely longevity with varying results .... Moreover,
physicians do poorly at predicting life expectancy and tend to
2 Sehgal et al., US 5,066,493, iss. Nov. 19, 1991.
3 Bedrosian, US 2007/0185150 Al, pub. Aug. 9, 2007.
4 Penhasi, US 2006/0251720 Al, pub. Nov. 9, 2006.
5 Blagosklonny, WO 2008/022256 A2, pub. Feb. 21, 2008.
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underestimate how long patients have left to live .... Clearly,
one of ordinary skill in the art is not apprised of the metes and
bounds of the claimed invention.
Id. The Examiner cites Shavelle6 and Leung7 in support of this position. Id.
We agree with the Examiner that the claims are indefinite because it is
unclear what is encompassed by "life expectancy." The Specification states
that "[a]n estimate of the lifespan the subject would have otherwise lived in
the absence of the microcapsules can be obtained, for example, from
demographic studies, Social Security Administration Life Tables, and
scientific literature concerning lifespan." Spec. 7. That statement, however,
refers to the "lifespan" of a subject, not "life expectancy," and the terms
apparently are not synonymous, since the claims state that "the lifespan is
extended to greater than the life expectancy of the mammalian subject."
Claim 86 ( emphasis added). Clearly, lifespan cannot be greater than life
expectancy if the two terms mean the same thing. The Specification does not
define the term "life expectancy."
Appellants argue that the "wherein" clause of the claims "is supported
throughout the specification," and cite pages 33-34 and Figure 1 as showing
"an extension of lifespan of. . rapamycin-treated mice past the life
expectancy of the mice." Br. 4.
Appellants also argue that
[ w ]hile there may be other methods to determining an
individual's life expectancy, the current claims particularly point
6 Shavelle et al., Rating the Raters: Evaluating the Predictions from a Life
Expectancy Rating Service, 41 J. INSUR. MED. 178-90 (2009).
7 Leung et al., Challenging the 10-year rule: The accuracy of patient life
expectancy predictions by physicians in relation to prostrate cancer
management, 6 CAN. UROL. Assoc. J. 367-73 (2012).
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out and distinctly claim "life expectancy of the mammalian
subject". Accordingly, a general definition of "life expectancy",
such as that defined by the Organization for Economic Co-
operation and Development (OECD), suffices to define the
metes and bounds of the currently claimed subject matter.
Id. at 5. 8
These arguments, however, are inconsistent. The Specification, at
pages 33-34, 9 discusses the "median and maximum life-span" of mice that
were fed encapsulated rapamycin, compared to control mice. Spec. 33. The
Specification states that, "mice fed rapamycin were longer lived than controls
(P<0.0001) in both males and females .... Expressed as life expectancy at
600 days (the age of first exposure to rapamycin), the effect sizes were 28%
for males and 38% for females." Id. The Specification's use of "life
expectancy," therefore, refers to rapamycin-treated subjects compared to
otherwise identical subjects that were not treated with rapamycin.
The OECD definition that Appellants point to, on the other hand,
refers to "life expectancy" in a much broader context. It states: "Life
expectancy at birth and ages 40, 60, 65 and 80 is the average number of
years that a person can be expected to live, assuming that age-specific
mortality levels remain constant." Br., Exhibit A. The OECD definition thus
does not refer to a certain cohort of subjects who are exposed to certain
conditions, as compared to an otherwise identical cohort of subjects exposed
to different conditions. Thus, the term "life expectancy" is apparently used
8 In their arguments regarding the § 103 rejection, Appellants point to an
OECD "glossary of statistical terms" that was submitted during prosecution.
Br. 5---6.
9 The results shown graphically in Figure 1 are the same as those discussed
at page 33 of the Specification.
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to mean two different things in the two sources of support cited by
Appellants.
In addition, even assuming the OECD definition is applicable, it is
unclear how it would be applied to the claimed method, because it states that
people have life expectancies at birth and at ages 40, 60, 65, and 80, which
implies that people have different life expectancies at different ages. With
respect to the claimed method, it is unclear whether the subject's "life
expectancy" refers to their life expectancy at the time they were born, or
their life expectancy based on their age when they were first administered
rapamycin, or their life expectancy based on their age each time they are
administered rapamycin, or something else.
In short, the claim language does not make clear what effect is
required in order for a method of administering rapamycin to fall within the
scope of claim 86. Claims 57 and 67, the other independent claims, also
include the language discussed above. Thus, all of the claims on appeal are
indefinite for the reasons discussed above. We affirm the rejection of claims
57, 62, 67----69, 73-79, 81, and 86-88 under 35 U.S.C. § 112, second
paragraph.
II
The Examiner has rejected all of the claims on appeal as obvious
based on Sehgal, Bedrosian, Penhasi, and Blagosklonny. The Examiner finds
that "Sehgal teaches methods of using rapamycin ... to reduce the tumor
size and prolong the survival time of mammal[s]." Ans. 5. "Sehgal
specifically demonstrated that rapamycin inhibits growth of colon tumor and
extended the lifespan of mice with colon tumors." Id.
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The Examiner finds that "Sehgal does not expressly teach
microencapsulated rapamycin encased in methyl methacrylate-methacrylic
acid copolymer," but "Bedrosian is directed to methods for treating cancer
in a patient with rapamycin analogs," including rapamycin itself, and "[ o ]ral
administration of the drug is of particular interest." Id. at 6. "Solid dosage
forms are often preferred for oral administration and include ... tablet[s]."
Id. "The tablet may further comprise a film-coat such as an enteric layer."
Id. "The enteric layer comprises a methacrylic acid methyl methacrylate
copolymer." Id. at 7. The Examiner also cites Penhasi as disclosing a
methacrylic acid methyl methacrylate copolymer as an enteric coating. Id.
The Examiner concludes that it would have been obvious to "treat[]
colon cancer and prolong extend [sic] the life expectancy of a mammal with
the cancer by administering rapamycin as disclosed by Sehgal by
encapsulated nanoparticles of the rapamycin in an enteric coating to control
the release of the rapamycin as suggested by Bedrosian." Id.
The Examiner reasons that "[t]he 'extending lifespan' limitation is
considered a function or property of the drug because when the drug is
administered to a subject, the function of prolongation of the lifespan of the
subject cannot be separated from the drug." Id. The Examiner also notes that
"Blagosklonny states the following: ' ... rapamycin can be used in the
methods of the invention to delay, prevent, or treat age-related diseases and
prolong human life span by inhibiting aging."' Id. at 7-8. Finally, the
Examiner finds that "Sehgal demonstrated that administration of rapamycin
increased the lifespan of mice afflicted with several different cancer types,
including colon cancer" and concludes that "it is clear that rapamycin was
known for increasing the lifespan." Id. at 8.
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We agree with the Examiner that the claimed method would have
been obvious to a person of ordinary skill in the art based on the cited
references. Sehgal discloses that "rapamycin reduces tumor size in and
prolongs the survival time of tumor bearing mammals." Sehgal 1 :43--45.
Sehgal discloses that rapamycin can be administered in capsules or tablets.
Id. at 1 :56-59. Sehgal determines survival time in reference to control
(untreated) animals. 10
Bedrosian discloses "administration of an mTOR inhibitor to a patient
in need thereof, especially to a cancer patient." Bedrosian ,r 1. Bedrosian
states that "mTOR inhibitors include, among others, sirolimus (rapamycin)."
Id. ,r 2. "Oral administration of the drug, e.g., in tablet or capsule form, is of
particular interest." Id. ,r 12. "The tablet may further comprise a film-coat to
control the release of the rapamycin analog." Id. ,r 38. "The film coating may
also be an enteric layer comprising an enteric polymer, for delayed release of
the rapamycin analog .... Suitable enteric polymers are well known to those
of skill in the art (WO O 1/051031) and include, without limitation, methyl
metacrylate [sic] polymers, methacrylic acid co-polymers," etc. Id. ,r 39.
Enteric coatings include those made from "poly(methacrylic acid, methyl
methacrylate) 1: 1." Penhasi ,r 62.
Blagosklonny discloses "methods for treating or preventing an age-
related disease, condition, or disorder comprising administering a
therapeutically effective amount of an inhibitor of TOR to a patient in need
thereof." Blagosklonny 5 :21-23. "In one embodiment of the invention, the
1° For example, Sehgal states that "T/C % = Median Survival Time (MST) in
days of treated animals (T)/control animals (C) x 100." Sehgal 3:22-24.
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Application 13/128,800
aging process is inhibited or retarded by administering a therapeutically
effective amount of an inhibitor of the TOR pathway (a TOR inhibitor) to a
patient. In this manner, cell aging, organism aging, or age-related diseases
are treated or prevented." Id. at 12:27-30.
"Direct inhibitors of TOR include rapamycin." Id. at 12:34. "Thus,
rapamycin can be used in the methods of the invention to delay, prevent, or
treat age-related diseases and prolong human life span by inhibit aging." Id.
at 7:31-33.
Based on these teachings, it would have been obvious to administer
rapamycin to a mammalian subject such as a mouse (Sehgal) or a human
patient (Bedrosian, Blagosklonny) in order to prolong the survival of a
subject with cancer (as taught by Sehgal) or to inhibit the aging process,
prevent organism aging, and prolong human life span (as taught by
Blagosklonny). In addition, it would have been obvious to administer the
rapamycin in a dosage form (e.g., a tablet 11) coated with a methyl
methacrylate-methacrylic acid copolymer, because that copolymer is a
known enteric polymer (Bedrosian, Penhasi) and Bedrosian expressly
suggests using an enteric coating to allow "delayed release of the rapamycin
analog." Bedrosian ,r 39. The cited references thus would have made
obvious the method of claim 86.
11 Although claim 86 recites "microencapsulated" rapamycin, the
Specification states that "microcapsules may be of any size .... For
example, the maximum diameter of the microcapsule may be about ... 1. 0
cm or greater." Spec. 4. The Specification also states that, in some
embodiments, "the microcapsule includes a single core that is encased in a
coating." Id. at 3. The broadest reasonable interpretation of
"microencapsulated" rapamycin therefore includes a standard-sized tablet.
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Appellants argue that "[ n Jone of Sehgal, Blagosklonny, or Bedrosian
teach or exemplify an extension of lifespan past life expectancy." Br. 6.
Specifically, "[a]ccording to the OECD ... , the definition of life expectancy
is the average number of years that a person can be expected to live .... The
life expectancy is a statistical measure of the average time an organism is
expected to live, based on their current age and other demographic factors."
Id. at 5---6. Appellants argue that "none of the cited art teaches an extension
of lifespan beyond life expectancy, as exemplified by the current
application." Id. at 6.
As discussed above with respect to the indefiniteness rejection, the
evidence that Appellants point to in the Specification is not consistent with
the proffered OECD definition of "life expectancy." Regardless of which
definition is applied, however, the cited prior art suggests that administering
rapamycin will achieve it: Sehgal states that rapamycin prolongs the survival
time of tumor-bearing mice compared to untreated control mice, and
Blagosklonny states that a therapeutically effective amount of rapamycin
will inhibit the aging process, prevent organism aging, and prolong human
life span. Thus, the cited references suggest, even if they don't exemplify,
extending the life span of a mammalian subject to greater than its life
expectancy by administering rapamycin.
Appellants also argue that, "[a]s shown in the evidence presented in
the declaration of record (Declaration of Dr. Sharp dated Sept. 17, 2015) and
reproduced below, eRapa (the currently claimed composition) shows
unexpected properties compared to that what [sic] is seen in the prior art
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(compare with RADOOl data from Fujishita et al.; cited in an IDS on
9/17 /2015)." Br. 6-7. 12
This argument is unpersuasive, for several reasons. First, the
declaration states that the graph that is reproduced in the Appeal Brief shows
the survival of F AP mice ( mice modeling the disease of familial
adenomatous polyposis ) .... This chart shows data of
microencapsulated rapamycin ( eRapa) from our lab that was
published and presented as Exhibit D in the declaration filed
February 18, 2015. Also included in this chart is data from
Fujishita ... , which shows the survival of PAP mice treated
with unencapsulated everolimus.
Sharp Deel. ,r 3.
The graph in the Appeal Brief thus does not represent a side-by-side
comparison of mice treated with two different compositions, but a
comparison of results from an experiment using eRapa under certain
conditions, with results from a different experiment using a different active
agent, unencapsulated, under other conditions. It is therefore unclear what
probative value the submitted data have with respect to nonobviousness.
In addition, the reference that is cited in the Sharp Declaration
("Exhibit D in the declaration filed February 18, 2015") 13 describes "enteric-
targeted rapamycin ( eRapa)" or "microencapsulated rapamycin"
(Exhibit D, pages 2, 4), but does not describe the eRapa composition as
rapamycin encapsulated with a methyl methacrylate-methacrylic acid
12 Citing the declaration under 37 C.F.R. § 1.132 of Zelton Dave Sharp
("Sharp Deel."), filed Sept. 17, 2015, and Fujishita et al., Inhibition of the
mTORCJ pathway suppresses intestinal polyp formation and reduces
mortality in Apcf1716 mice, 105 PNAS 13544--49 (2008).
13 Declaration under 37 C.F.R. § 1.132 ofZelton Dave Sharp, filed Feb. 18,
2015, Exhibit D.
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copolymer, as required by the claims on appeal. Thus, it is unclear whether
the results shown in the graph represent those of the composition recited in
the claims.
To the extent that Appellants are relying on the evidence as showing
unexpected results, it is deficient for additional reasons. First, Exhibit D
shows administration of microencapsulated rapamycin to mice that "exhibit
multiple intestinal neoplasia" (Exhibit D, abstract) and so the closest prior
art would appear to be Sehgal, which administered unencapsulated
rapamycin to tumor-bearing mice, rather than Fujishita, which administered
unencapsulated everolimus. "To be particularly probative, evidence of
unexpected results must establish that there is a difference between the
results obtained and those of the closest prior art, and that the difference
would not have been expected by one of ordinary skill in the art at the time
of the invention." Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752
F.3d 967,977 (Fed. Cir. 2014).
Second, the claims encompass treating any mammalian subject,
including healthy subjects, and the proffered evidence only shows results for
mice that have a mutation in the adenomatous polyposis coli (APC) gene
that makes them susceptible to intestinal neoplasia. Id. Appellants have
presented no evidence or sound technical reasoning to establish that the
results shown are commensurate in scope with the claims. "Evidence of
unexpected results must be reasonably commensurate with the scope of the
claims." In re Huai-Hung Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011).
Appellants also argue that "the use of rapamycin for achieving the
effect described in the current claims is not a property of the drug," but of
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rapamycin microencapsulated in a methyl methacrylate-methacrylic acid
copolymer, as shown by
post-filing data with APCMinJ+ mice using a different rapamycin
formulation [that] did not achieve the recited effect ( see, Koehl
et al., Exhibit B; cited in an IDS on November 18, 2011), shows
that only about 30% of the APCMinJ+ -treated mice are alive at
364 days (Koehl et al., FIG. 2). This is in stark contrast to
treatment of APCMinJ+ mice with the composition of the current
claims, where 100% are alive at 364 days (Hasty et al., FIG.
2A; submitted in an IDS on September 17, 2015).
Br. 7-8.
This argument also fails, because Appellants have not identified the
evidence it is based on. Appellants cite a reference by Koehl et al. as Exhibit
B in an Information Disclosure Statement (IDS) filed November 18, 2011,
but the official record of the instant application does not include an IDS filed
on November 18, 2011. Appellants provide no other identification of the
Koehl et al. reference. Thus, even if the graph shown in the Appeal Brief
accurately depicts the data shown in the cited Hasty et al. reference,
Appellants have not identified the source of the data alleged to be shown in
the Koehl et al. reference, and therefore it is unclear what probative value, if
any, the cited evidence has with respect to nonobviousness.
For the reasons discussed above, we affirm the rejection of claim 86
under 35 U.S.C. § 103(a) based on Sehgal, Bedrosian, Penhasi, and
Blagosklonny. Claims 57, 62, 67----69, 73-79, 81, 87, and 88 were not argued
separately and therefore fall with claim 86. 37 C.F.R. § 41.37(c)(l)(iv).
SUMMARY
We affirm both of the rejections on appeal.
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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).
AFFIRMED
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