Ex Parte Newton et al

Patent Trials and Appeals Board

Jun 18, 2019

13270358 - (D) (P.T.A.B. Jun. 18, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
13/270,358 10/11/2011
4743 7590 06/20/2019
MARSHALL, GERSTEIN & BORUN LLP
233 SOUTH WACKER DRIVE
6300 WILLIS TOWER
CHICAGO, IL 60606-6357
FIRST NAMED INVENTOR
Maurice Sydney Newton
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.
3 l 138/40001A 9143
EXAMINER
GREENE, NAN A
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
06/20/2019 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):
mgbdocket@marshallip.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte MAURICE SYDNEY NEWTON,
NIGEL PETER RHODES, and ALEXIS JOHN TOFT 1
Appeal 2018-004161
Application 13/270,358
Technology Center 1600
Before RYAN H. FLAX, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.
FLAX, Administrative Patent Judge.
DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134(a) involving
claims directed to methods of binding phosphate in an animal in need
thereof, treating hyperphosphataemia, or preparing a pharmaceutical for
such uses. Claims 12, 13, 15, 18, 20, 21, 24, 25, 34--37, 40, and 42-51 are
on appeal as rejected under 35 U.S.C. § 112, second paragraph, and
§ 103(a). We have jurisdiction under 35 U.S.C. § 6(b ).
We reverse.
1 Appellants identify the Real Party in Interest as "OPKO Ireland Global
Holdings, Ltd." Appeal Br. 3.
Appeal 2018-004161
Application 13/270,358
STATEMENT OF THE CASE
The Specification states, "[p ]lasma phosphate levels may be reduced
by oral intake of inorganic and organic phosphate binders." Spec. 1: 14--15.
"Other aluminium compounds such as microcrystalline aluminium oxide
hydroxide (boehmite) and certain hydrotalcites have been proposed for this
use .... " Id. at 1 :20-22. Issues with aluminum toxicity and efficiency were
observed. Id. at 1-2. "To overcome the drawbacks associated with
aluminium and also problems of efficacy over a limited pH range," the
Specification states, "WO-A-99/15189 [Roberts, see infra] discloses use of
mixed metal compounds which are free from aluminium and which have a
phosphate binding capacity of at least 30% by weight of the total weight of
phosphate present, over a pH range offrom 2-8." Id. at 2:13-17.
Even this improved compound presented drawbacks. As stated in the
Specification, "we have found that the mixed metal compounds of
WO-A-99/15189 release some of their divalent metal content in soluble
form during use." Id. at 2:22-3:2. Appellants further state, "[w]e have now
found that the release of the divalent metal, e.g. magnesium, associated with
the pharmaceutical use of compounds of WO-A-99/15189 can be
significantly reduced by heat treatment .... " Id. at 4:5-7.
Claims 12 and 21 are representative and are reproduced below:
12. A method of binding phosphate in an animal in need
thereof, comprising administering to the animal a therapeutically
effective amount of a substance comprising a phosphate binding
solid mixed metal compound of formula (I):
MII1-aMIIIaObAn-c. zH20 (I)
where Mn is at least one bivalent metal; Mm is at least one
trivalent metal selected from the group consisting of Fe(III),
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Al(III), La, and Ce; An- is at least one n-valent anion;
2+a = 2b+Lcn and Lcn < 0.9a; and z is 2 or less, wherein the
mixed metal compound is obtained by heating a starting material
comprising a layered double hydroxide structure at a temperature
of from 250 °C to 500 °C for 3 hours or less.
21. A method of preparing a pharmaceutically
acceptable substance for use as a medicament for binding
phosphate, the method comprising heating a starting material
comprising a layered double hydroxide structure at a temperature
of 250 °C to 500 °C for three hours or less, wherein the substance
comprises at least one bivalent metal and the substance is free of
a Spinel structure as determined by x-ray diffraction, and
wherein upon administration the substance releases into solution
at least 50% by weight less of the at least one bivalent metal as
compared to a release into solution of the at least one bivalent
metal from the starting material, and wherein
the starting material comprises a compound of formula
(II):
MII1-xMIIIx(OH)2An-y" mH20 (II)
where M is at least one bivalent metal selected from the
group consisting of Fe(III), Al(III), La, and Ce; Mm is at least
one trivalent metal; An- is at least one n-valent anion; x=Lny; and
0 < X :'.S 0.5, 0 :'.Sm :'.S 10.
Appeal Br. 18 (Claims Appendix). Independent claim 13 is identical to
claim 12 except its preamble recites "[a] method for treatment of
hyperphosphatemia," and it does not include Al(III) as a choice for the at
least one trivalent metal. Id. The Examiner has identified and Appellants
have not contested that Appellants
have elected the following species for examination on the merits:
( 1) a phosphate-binding, mixed metal compound comprising
iron(III) and magnesium(II), wherein a is 0.21, b is 1.08, c is
0.22, z is 0.15, and A is carbonate (satisfying the election
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requirement for (A)) and (2) a mixed metal compound
comprising iron(III) and magnesium(II), wherein x is 0.21, y is
0.14, m is 1.85, and A is carbonate (satisfying the election
requirement for (B)), in the reply filed on 04/22/2013.
Final Action 2. Pursuant to this election and using the indicated values for
the recited variables, we understand the elected species covers
Mgo_79Feo.2101.os(C02-3)0.22·0.15H20, as formula (I), i.e., the post-heat-
treatment composition, and Mgo_79Feo.21(0H)2(C02-)o.14· l .85H20, as formula
(II), i.e., the pre-heat-treatment starting material. We limit our analysis to
the elected species. See Ex parte Ohsaka, 2 USPQ2d 1460, 1461 (BP AI
1987) ( appropriate to limit discussion on ex parte appeal to elected species;
if reversing, taking no position on broader generic claims, and, if affirming,
all claims including the species are unpatentable for same reasoning as for
elected species).
The following rejections are appealed:
Claim 49 stands rejected under 35 U.S.C. § 112, second paragraph, as
indefinite. 2 Answer 3.
2 The indefiniteness rejection as directed to claims 48 and 51 was
withdrawn. Answer 3.
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Claims 12, 13, 15, 18, 20, 21, 34--37, 40, 43--46, 48, 49, and 51 stand
rejected under 35 U.S.C. § 103(a) over Zhu, 3 Hibino,4 Forano, 5 Chatelet, 6
Roberts,7 and Fernandez. 8 Answer 4; Final Action 5-12.
Claims 21, 24, 25, 42, 47, and 50 stand rejected under 35 U.S.C.
§ 103(a) over Hibino, Fernandez, Forano, Schutz,9 and Roberts. Answer 4--
5; Final Action 21-25.
DISCUSSION
"[T]he examiner bears the initial burden, on review of the prior art or
on any other ground, of presenting aprimafacie case ofunpatentability. If
that burden is met, the burden of coming forward with evidence or argument
shifts to the applicant." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992).
3 H. Zhu et al., Different Mg to Fe Ratios in the Mixed Metal MgFe
Hydroxy-Carbonate Compounds and the Effect on Phosphate Binding
Compared With Established Phosphate Binders, 91 J. PHARMA. SCI. 53---66
(2001) ("Zhu").
4 T. Hibino & A. Tsunashima, Calcination and rehydration behavior of Mg-
Fe-C03 hydrotalcite-like compounds, 19 J. MAT. SCI. LETT. 1403---05 (2000)
("Hibino").
5 Claude Forano, Environmental Remediation Involving Layered Double
Hydroxides, in CLAY SURFACES: FUNDAMENTALS AND APPLICATIONS 426-58
(F. Wypych & K.G. Satayanarayana eds., 2004) ("Forano").
6 L. Chatelet et al., Competition between monovalent and divalent anions for
calcined and uncalcined hydrotalcite: anion exchange and adsorption sites,
111 COLLOIDS & SURFACES A: PHYSIOCHEM. & ENGINEERING ASPECTS 167-
7 5 ( 1996) ("Chatelet").
7 WO 99/15189 (published Apr. 1, 1999) ("Roberts").
8 Jose Maria Fernandez et al., The effect of iron on the crystalline phases
formed upon thermal decomposition of Mg-Al-Fe hydrotalcites, 8(11) J.
MATER. CHEM. 2507-14 (1998) ("Fernandez").
9 US 5,153,156 (issued Oct. 6, 1992) ("Schutz").
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I. INDEFINITENESS
For claims under examination, "a claim is indefinite when it contains
words or phrases whose meaning is unclear," i.e., "ambiguous, vague,
incoherent, opaque, or otherwise unclear in describing and defining the
claimed invention." In re Packard, 751 F.3d 1307, 1310-13 (Fed. Cir.
2014).
The Examiner's position appears to have wavered on the facts upon
which this rejection is based, however, the Examiner ultimately found,
"claim 49 continues to recite 'the bivalent metal' in line two. The examiner
maintains that this limitation renders the claim indefinite because it is
unclear which one of the 'at least one bivalent metals' is referenced by the
phrase 'the bivalent metal."' See Answer 3, 5; compare with Final Action
3-5, and Advisory Action dated Oct. 4, 2017.
Appellants argue "[i]t is submitted that the skilled person would
understand that 'the bivalent metal' refers to the 'at least one bivalent metal'
recited in claim 13." Reply Br. 2.
Claim 49 depends from claim 13. Independent claim 13 is
substantially similar to claim 12, reproduced above, and recites, in pertinent
part, "a phosphate binding solid mixed metal compound of formula (I):
M 111-aMmaObAn-c. zH20 (I)," "where M11 is at least one bivalent metal."
Appeal Br. 18 ( emphasis added). Dependent claim 49 recites:
49. The method of claim 13, wherein upon
administration, the compound releases into solution at least 50%
by weight less of the bivalent metal as compared to a release
into solution of the at least one bivalent metal from the starting
material, and wherein the starting material comprises a
compound of formula (II):
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M111-xMIIIx(OH)2An-y" mH20 (II)
where MII is at least one bivalent metal selected from the
group consisting of Fe(III), Al(III), La, and Ce; Mm is at least
one trivalent metal; An- is at least one n-valent anion; x=I.ny; and
0 < X :'.S 0.5, 0 :'.Sm :'.S 10.
Id. at 20-21 (emphasis added).
Upon considering the Examiner's and Appellants' positions and
reading the claim language above, we conclude Appellants hold the better
position. Although it could benefit from a clarifying amendment, we agree
that a plain reading of the language of claim 49 is that the claim's first
instance of reciting "the bivalent metal" clearly enough refers to the Mn
element first recited by independent claim 13 at formula (I) and the claim's
second instance reciting "the at least one bivalent material from the starting
material" clearly enough refers to the Mn element recited immediately
thereafter in dependent claim 49 at formula (II). Therefore, we do not
sustain the indefiniteness rejection.
II. OBVIOUSNESS
"The combination of familiar elements [ or steps] according to known
methods is likely to be obvious when it does no more than yield predictable
results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007). The
discovery of an optimum value of a variable in a known process is normally
obvious. In re Aller, 220 F.2d 454 (CCPA 1955). Exceptions to this rule
include ( 1) the results of optimizing a variable were unexpectedly good and
(2) the parameter optimized was not recognized in the prior art as one that
would affect the results. In re Antonie, 559 F.2d 618, 620 (CCPA 1977).
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"One way for a patent applicant to rebut a prima facie case of
obviousness is to make a showing of 'unexpected results,' i.e., to show that
the claimed invention exhibits some superior property or advantage that a
person of ordinary skill in the relevant art would have found surprising or
unexpected." In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995). "Evidence that
a compound is unexpectedly superior in one of a spectrum of common
properties ... can be enough to rebut a prima facie case of obviousness." In
re Chupp, 816 F.2d 643, 646 (Fed. Cir. 1987) (evidence showed
unexpectedly superior properties of an herbicide when used on com and
soybeans, which overcame a prima facie case of obviousness even though
claims were not limited to use on those plants).
The same findings of fact and arguments are presented for the Board's
consideration and are determinative for both obviousness rejections.
Therefore, we address both rejections together.
The Examiner determined that claims 12, 13, 15, 18, 20, 21, 34--37,
40, 43--46, 48, 49, and 51 would have been obvious over the prior art
combination of Zhu, Hibino, Forano, Chatelet, Roberts, and Femandez. 10
Answer 4--15; Final Action 5-21. The Examiner also determined that claims
21, 24, 25, 42, 47, and 50 would similarly have been obvious over the prior
art combination of Hibino, Fernandez, Forano, Schutz, and Roberts. 11
Answer 4--15; Final Action 21-25. Whether Zhu is included in the prior art
combination or not, the Examiner's position is that Zhu and Roberts each
10 See generally Answer and Final Action for the Examiner's specific
citations to these references.
11 See supra note 10.
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teach the usefulness of mixed metal compounds as pharmaceutical anion
(phosphate) absorbers, such as the starting material recited by independent
claim 21, which, when heat treated ( calcinated), as taught or suggested by
other cited references, becomes the compound of independent claims 12 and
13. The Examiner also determined that Hibino, Chatelet (whether included
in combination or not), Fernandez, and Forano teach or suggest how to and
the advantages of calcinating such materials, which enhances their anion
exchange capabilities, which relatedly enhances their phosphate absorption.
The Examiner determined that these references teach or suggest the claimed
temperature range for such calcination and suggest the heating duration, e.g.,
Hibino teaches calcination at 400 °C, 450 °C, and 500 °C, and Hibino
references Fernandez, which discloses calcinating at 450 °C or 750 °C for
2 hours.
The Examiner has woven a tapestry of prior art that points to, if in a
strained fashion, the claimed subject matter. For example, while Zhu
teaches a hydrotalcite compound - a relevant starting compound - and
control of serum phosphate using such a material, it also suggests that
heating that compound ( although not to as high temperatures as used for
calcination) "caused an increase in the crystallinity of the compounds, which
seemed to reduce the phosphate binding capacity." Zhu 63. While Hibino
teaches calcination of hydrotalcite-like compounds (mixed metal, laminar
solids) at temperatures falling within the ranges claimed, it also discloses
that calcination at such temperatures causes spinel formation; spinel
formation is something that both the Examiner and Appellants appear to
agree is undesirable. Hibino 1403---05. Chatelet teaches the ability to
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increase anionic exchange capacity by thermally treating hydrotalcite
compounds and that the related decomposition is reversible if calcination
temperatures do not exceed 500-600 °C, but it also suggests that the thermal
treatment should occur for 18 hours, which is 15 hours longer than allowed
by the appealed claims. Chatelet 167---68. Forano likewise teaches that
calcinated hydrotalcite materials display higher adsorption properties, such
as for adsorbing phosphates, and describes a range of temperatures between
200-500 °C for calcination, where such enhancement can occur before
spinel formation, but Forano is not explicit about heating duration. Forano
430,431,442. Fernandez, a reference cited by Hibino, and upon which the
Examiner relies for the presumed duration of Hibino 's heat treatment,
teaches thermal decomposition of hydrotalcites for a 2 hour duration at
temperatures of 450 QC and 750 °C; however Fernandez also indicates that
thermal decomposition in air at 450 °C and 7 50 °C leads to spinel formation.
Fernandez 2507, 2510, 2513.
Although hinting at it, in much the same way they are ambiguous
regarding the here-uncontested undesirability of spinel formation, the
references are not explicitly clear why thermal decomposition that occurs on
calcination, and which is studied in Fernandez, is specifically desirable with
respect to the starting materials of Zhu or Roberts. The cited prior art
combination(s) is also ambiguous and vague as to what calcination
temperatures and durations are advantageous or disadvantageous. Given
these vagaries and ambiguities of the prior art, without resort to hindsight
reasoning, we surmise it would take an exceptionally adroit skilled artisan,
as opposed to one of ordinary skill, to recognize, and we conclude that the
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Examiner has not sufficiently established that a skilled artisan would have
recognized, the significance of and relationships between the teachings of
the cited prior art so as to achieve the claimed subject matter.
Appellants do not argue the Examiner has inappropriately used
hindsight reasoning. Appellants argue that, contrary to the Examiner's
rationale, Roberts does not teach a calcinated mixed-metal compound for
phosphate binding. Appeal Br. 6-7. Appellants are correct that Roberts
does not teach or suggest calcination, but this is not determinative because,
arguably, the other cited prior art references teach it and provide motivation
to use such a thermal treatment. See, e.g., In re Keller, 642 F.2d 413, 426
(CCPA 1981) ("[O]ne cannot show non-obviousness by attacking references
individually where, as here, the rejections are based on combinations of
references."). Furthermore, in the same argument, Appellants concede that
Roberts and Zhu teach the Specification's disclosed and claimed (at claim
21) starting material. Appeal Br. 8.
Appellants argue that the combined teachings of Hibino and Chatelet
do not suggest that thermal treatments ( calcination) would increase
phosphate binding in the mixed-metal compounds (they do not connect the
enhanced anionic exchange capacity with phosphate binding) or that such
compounds would be suitable as pharmaceutical phosphate binders. Appeal
Br. 8-11 (citing Newton Declaration 12 ,r,r 15, 16, 19 as support for
contention that in vivo phosphate binding is not solely controlled by anion
exchange). These arguments are not persuasive because the natural
12 Declaration of Maurice S. Newton, Ph.D Under 37 C.F.R. § 1.132 dated
Aug. 7, 2014 ("Newton Declaration").
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correlation between anion exchange and phosphate binding in mixed-metal
compounds is taught by other references. See Zhu 54; see also generally
Forano (phosphates are non-metal oxoanions absorbable by hydrotalcite-like
compounds and calcination enhances adsorption). Also, Roberts is clear that
its mixed-metal compounds, which are the claimed starting material here,
are advantageous for pharmaceutical use. See, e.g., Roberts Abstract.
Appellants also argue that the Examiner's theory of rehydration in
vivo does not support obviousness (it does not support combining and
modifying the cited art). Appeal Br. 11. This is also not a persuasive
argument because as discussed above, even absent in vivo rehydration, the
prior art supports that calcinating mixed-metal compounds, as claimed,
makes them better at absorbing phosphates, which would have been reason
enough to heat treat the starting materials of, e.g., Roberts and Zhu.
Appellants also argue that Hibino, Fernandez, and Forano fail to teach
or suggest the claimed thermal treatment duration of no more than 3 hours
because Hibino and F orano teach no durations and Fernandez offers no
reason why its disclosed 2 hour duration was selected. Appeal Br. 13.
Appellants also argue that Schutz adds nothing of further relevance. Id. The
former argument has some weight. The only reference to disclose a
calcination duration approaching the 3 hour maximum range of the appealed
claims is Fernandez; however, Fernandez disclosed that such thermal
treatments resulted in spinel formation even at its lowest 450 °C
temperature, which claim 21 forbids, and which is understood to also be
undesirable for the compounds used in the methods of claims 12 and 13.
Fernandez 2507, 2509.
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Finally, Appellants argue the Specification evidences that the claimed
invention produces the unexpected result of "a reduced release of bivalent
metal in solution, while improving phosphate binding capacity." Appeal Br.
14--17 (citing Spec. 4:5-10, 43 (Table 1), 55 (Table 4); also citing Newton
Declaration ,r,r 20-25). While the skilled artisan may have expected the
exemplified improvements in phosphate binding capacity based on the
disclosures of, e.g., Chatelet and Forano, the Examiner has not cited support
in the record that the exemplified reduction in Mgn release would have also
been expected. What the Specification describes at these cited portions is
that, when starting materials (which the Specification identifies as Batches A
and B -see Spec. 37) were calcinated at the claimed temperature and
duration, reductions in Mgn release were observed compared to uncalcinated
materials or materials calcinated outside the claimed time/temperature
ranges. Significantly, in view of the claimed 3-hours-or-less claim
limitation, the Specification's Table 4 shows that 5 minute and 3 hour heat
treatments at 500 °C provided respective Mg releases of, e.g., 0.15 and 0.1
mmol/L, while a heat treatment at the same temperature, but for 16 hours
resulted in an Mg release of 1.05 mmol/L, or about 10 times greater.
Uncalcinated material had an Mg release of, e.g., 5.9 mmol/L, or about 60
times greater.
The Newton Declaration states that such results were significant and
unexpected. Newton Declaration ,r,r 21-24. The Examiner responds that
such results amount to mere recognition of latent properties of the prior art.
Answer 14--15.
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The Newton Declaration also states that "the inventive methods and
compounds" produced the discussed results and "a mixed metal compound
as we claim demonstrates a significant reduction in the release of the
bivalent metal as compared to the uncalcinated starting material," and that
the "unexpected results" illustrated by the Specification's Table 1 and Table
4 are "of our invention." See Newton Declaration ,r,r 9, 21, 23, 24. We note
that the compounds identified in the Specification as Batch A and Batch B
(Spec. 3 7) are not identical to the starting material of, for example, claim 21,
and otherwise indicated to result in the elected species for claimed
formula (I) of claims 12 and 13. For example, the Specification's Batches A
and B include S04 and Na2S04 in the pre-calcinated starting material, but
the formula (II) starting material of claim 21 does not, nor does the
compound of Roberts that Appellants identify as the starting material of the
claimed invention. Further, the amounts of H20 are not the same when
comparing Batches A and B to the elected species. Although we note these
discrepancies, the Examiner does not contend that Appellants' evidence of
unexpected results is not commensurate in scope with the claims or
otherwise refute Appellants' position that the alleged unexpected results are
achieved by the claimed invention. See Answer 13-15.
In view of the tenuous combination of prior art cited against the
claims here, and its sometimes conflicting and often ambiguous disclosures
concerning relevant subject matter, we conclude that the balance of evidence
on appeal favors Appellants' position. The evidence of unexpected results
appears to be sufficient to rebut a prima facie case for obviousness, if indeed
one was made by the Examiner here. Such unexpected results address a
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known issue with prior art mixed-metal phosphate binders used to treat
conditions such as hyperphosphataemia. Zhu explains that prior art
phosphate binders were effective, but were associated with high ionic Mg
release, resulting in diarrhea and hypermagnesemia. Zhu 54. Furthermore,
we find a lack of identified evidence that the claimed heat treatment duration
(no more than 3 hours) was recognized in the prior art to be a result effective
variable that would be optimized. See, e.g., In re Antonie, 559 F.2d at 620
(finding variable not result-effective because the prior art did not recognize
it as relevant to the desired property). Therefore, there is a lack of definitive
evidence that the cited prior art would have been modified to utilize the
claimed heat treatment parameters.
In view of the above findings, we conclude the balance of evidence
supports that Appellants have rebutted the Examiner's case for obviousness.
SUMMARY
The indefiniteness rejection under 35 U.S.C. § 112, second paragraph,
is reversed.
The obviousness rejections under 35 U.S.C. § 103(a) are each
reversed.
REVERSED
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