Ex Parte Hilt et al

Patent Trial and Appeal Board

Nov 30, 2017

10805530 (P.T.A.B. Nov. 30, 2017)

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.
10/805,530 03/22/2004 Dana Hilt 088734-1108 8526
22428 7590 12/04
Foley & Lardner LLP
3000 K STREET N.W.
SUITE 600
WASHINGTON, DC 20007-5109
EXAMINER
KLINKEL, KORTNEY L
ART UNIT PAPER NUMBER
1611
NOTIFICATION DATE DELIVERY MODE
12/04/2017 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):
ipdocketing @ foley. com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte DANA HILT, VALERIE MASINI,
RICHARD FEDYNEC, and BRIGITTE TARAVELLA1
Appeal 2016-002775
Application 10/805,530
Technology Center 1600
Before JOHN G. NEW, TIMOTHY G. MAJORS,
and DAVID COTTA, Administrative Patent Judges.
NEW, Administrative Patent Judge.
DECISION ON APPEAL
appellants state that the real party-in-interest is Besins Healthcare
Luxembourg SARL. App. Br. 3.
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Application 10/805,530
SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 45—68. Claims 45—68 are rejected
under 35 U.S.C. § 103(a) as being unpatentable over the combination of H.
Pujol et al., Phase I Study of Percutaneous 4-Hydroxy-Tamoxifen with
Analyses of 4-Hydroxy-Tamoxifen Concentrations in Breast Cancer and
Normal Breast Tissue, 36 Cancer Chemother. Pharmacol. 493-98
(1995) (“Pujol”), M.E. Brewster et al., Isomeric Interconversions in
Tamoxifen and Related Compounds: An AMI study, 53 Int’l
J. Quantum Chem. 343—52 (1995) (“Brewster”), D.W. Robertson et al.,
Synthesis of the E and Z Isomers of the Antiestrogen Tamoxifen and Its
Metabolite, Hydroxytamoxifen, in Tritium-Labeled Form, 47 J.. Organic
Chem. 2387—93 (1982) (“Robertson”), J.A. Katzenellenbogen et al., Facile
Geometric Isomerization of Phenolic Non-Steroidal Estrogens and
Antiestrogens: Limitations to the Interpretation of the Experiments
Characterizing the Activity of Individual Isomers, 22 J. Steroid Biochem.
589-96 (1985) (Katzenellenbogen), and J. McMurry et al., Chemistry (2d
ed.) at Section 13.1 (1998) (“McMurry”).
Claims 45—68 also stand rejected as unpatentable under 35 U.S.C.
§ 103(a) as being obvious over the combination of Pujol, Brewster,
McMurry, and Ansel et al., Pharmaceutical Dosage Forms and Drug
Delivery Systems (7th ed.) at 84—87 (1999) (“Ansel”), as evidenced by the
Declaration of Olivier Raux, March 6, 2008 (the “Raux Declaration”).
Claims 45—68 also stand provisionally rejected as unpatentable under
the judicially-created doctrine of obviousness-type double patenting over
claims 1—18 of copending Application Ser. No. 11/249122, and non-
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provisionally over claims 1—16 of Le Nestour (US 8,048,927 Bl, November
1, 2011) (“Le Nestour”) either alone or, alternatively, in combination with
Brewster, and/or Ansel, and as evidenced by the Raux Declaration.
We have jurisdiction under 35 U.S.C. § 6(b).
We REVERSE and enter a NEW GROUND of rejection pursuant to
37 C.F.R. § 41.50(b).
NATURE OF THE CLAIMED INVENTION
Appellants’ invention is directed to a class of chemically stable 4-
hydroxy tamoxifen compositions characterized by roughly equal amounts of
the Z-4-hydroxy tamoxifen and E-4-hydroxy tamoxifen isomers, such that
the potency of the compositions is not affected adversely by the
isomerization that occurs between these two forms. Abstract.
REPRESENTATIVE CLAIM
Claim 45 is representative of the claims on appeal and recites:
A pharmaceutical composition that comprises 4-hydroxy
tamoxifen, wherein 45%-55% of said 4-hydroxy tamoxifen
exists in the Z isomeric form and the remainder of the 4-hydroxy
tamoxifen exists in the E isomeric form, and wherein the
composition is at an equilibrium state of Z:E isomer ratio.
App. Br. 20.
ISSUES AND ANALYSES
We decline to adopt the Examiner’s findings of fact and conclusions
that the appealed claims are obvious over the cited prior art and we enter a
NEW GROUND of rejection. We address the arguments raised by
Appellants below.
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A. Rejection of claims 45—68 over Pujol Brewster, Robertson,
Katzenellenbogen, and McMurry
Issue
Appellants argue that the Examiner erred in finding that the combined
prior art cited by the Examiner teaches or suggests the limitation of claim 45
reciting: “wherein the composition is at an equilibrium state of Z:E isomer
ratio.” App. Br. 10.
Analysis
The Examiner finds, in relevant part, that Pujol teaches a 4-
hydroxtytamoxifen hydroalcoholic gel composition identical to the
composition claimed in the most specific dependent claims with the
exception that the Z:E ratio of the 4-hydroxy tamoxifen isomers is not
reported or mentioned. Final Act. 4. The Examiner also finds that the
Declaration of Olivier Raux (the “Raux Declaration”) avers that the Z and E
isomer ratio was dynamic throughout the duration of the clinical trial
disclosed by Pujol.2 Id.
The Examiner finds further that Brewster teaches that 4-
hydroxytamoxifen is known to exist in two different isomeric
configurations: the E and the Z isomers. Final Act. 4. The Examiner finds
2 Besins Iscovesco Laboratories, the predecessor to the real party-in-interest
in this appeal, provided the 4-hydroxytamoxifen used in the studies
disclosed by Pujol. See Raux Deck 1 5; Pujol 494.
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that Brewster further teaches that the reversible equilibrium of 4-
hydroxytamoxifen is well known, and that the equilibrium proportion of Z:E
is predicted to be 1:1, based upon the fact that the fact that the ground state
free energies of the E and Z isomers are nearly identical (5.54 and 5.55
respectively).3 Id. at 4—5 (citing Abstr., 348, 350, Table II). The Examiner
also finds that Brewster teaches that the thermodynamic data presented
predicting a 50:50 isomeric ratio is consistent with experimental data, citing
Robertson for support. Id.
The Examiner finds that Katzenellenbogen teaches the isomerization
of the E isomer to the Z isomer as well as the isomerization of the Z isomer
to the E isomer of 4-hydroxy tamoxifen. Ans. 6. The Examiner finds that
Katzenellenbogen further teaches that approximately 20% of a 99.9% trans
4-hydroxytamoxifen solution converts to the cis form in two days (78:22
trans'.cis) and, similarly that roughly 20% of a 99.9% pure cis 4-
hydroxytamoxifen solution converts to the trans form in two days (17:83
cis'.trans). These data suggest that the rate of the cis to trans conversion is
roughly equivalent to the trans to cis conversion rate out to two days. Id.
The Examiner therefore concludes that it would have been obvious to
a person of ordinary skill in the art to formulate a 4-hydroxytamoxifen
composition at its equilibrium state containing a 1:1 ratio of Z:E isomers
with a reasonable expectation that doing so would result in an effective
therapeutic composition. Id. at 6—7.
3 The Examiner notes that Brewster and several of the other references use
cis/trans nomenclature rather than E/Z.
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In response, Appellants adduce, as prior art, C. Malet et al., Effect of
4-hydroxytamoxifen Isomers on Growth and Ultrastructural Aspects of
Normal Human Breast Epithelial (HBE) Cells in Culture, 82 J. Steroid
Biochem. & Mol. Biol. 289-296 (2002) (“Malet”). App. Br. 8. According
to Appellants, Malet reports experimental data showing that compositions of
4-hydroxytamoxifen formulated in ethanol equilibrated to a Z:E (trans'.cis)
percent ratio of 70:30, in solution, in culture medium, and as extracted from
cells. Id. at 9 (citing Malet 291). Appellants assert that Malet is more
probative of nonobviousness than Brewster, because Malet is more
contemporaneous to the invention, and also because Malet reports actual
experimental data regarding 4-hydroxytamoxifen isomerization and
equilibration. Id.
Appellants point next to the 2012 and 2014 Declarations of Dr. Alan
Cutler (the “First” and “Second Cutler Declaration”). App. Br. 9. Dr. Cutler
states, inter alia, that the discussion section of Malet: “concludes that
‘whatever the storage or culture conditions, a spontaneous equilibrium was
reached at a trans/cis ratio of 70/30 and trans to cis conversion never
exceeded 35%.’” Id. at 10 (quoting Second Cutler Decl. 110).
Appellants contend that, given the divergence between Malet’s
experimentally-observed equilibrium ratios and Brewster’s theoretical
prediction, the distinction between experimental data and theoretical
calculations is important. App. Br. 10. Appellants assert that experimental
data involve qualitative or quantitative observations of an actual experiment,
whereas theoretical calculations involve predicting properties of various
molecules based on a set of assumptions, approximations, or generalizations.
Id. According to Appellants, Brewster expressly teaches the assumptions,
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approximations, and generalizations regarding structure, energy damping,
ionization potentials, rotational barriers, etc., that underlie its calculations
and predictions. Id. Appellants therefore assert Dr. Cutler’s opinion that:
“[A] person skilled in the art looking to formulate [4-hydroxytamoxifen] in a
pharmaceutical composition ... would have been more likely to rely on the
actual experimental data reported in Malet and Katzenellenbogen, rather
than the theoretical calculations presented in Brewster.” Id. (quoting Second
Cutler Decl. 1 8).
Appellants further dispute the Examiner’s characterization of the
teachings of Robertson, which, Appellants argue, the Examiner cites as
providing experimental evidence of a 1:1 equilibrium ratio of Z:E isomers of
4-hydroxytamoxifen. App. Br. 11. However, Appellants contend, the
Examiner mischaracterizes Robertson’s disclosure, because that reference
does not teach or suggest a 1:1 equilibrium ratio of 4-hydroxytamoxifn Z:E
isomers. Id.
Appellants argue that Robertson is directed to a method by which a
brominated intermediate compound was obtained at a 1:1 E:Z ratio. App.
Br. 11 (citing Robertson 2389 (reporting the production of an intermediate
“product 11” at a 1:1 E:Z ratio)). Appellants assert that, although Robertson
reports that the intermediate was treated “to give a mixture of
hydroxytamoxifen (3) and its cis isomer,” it does not report the E:Z isomer
ratio of that final product, or indicate that the final 4-hydroxytamoxifen
product had a 1:1 ratio of isomers. Id. Rather, Appellants argue, Robertson
teaches that “[b]y this procedure 167 mCi of cA-[3H]hydroxytamoxifen and
231 mCi of [3H]hydroxytamoxifen were isolated,” suggesting that the ratio
was not 1:1. Id. Appellants quote Dr. Cutler as emphasizing that Robertson
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“does not study the equilibrium state of the isomers over time. Rather,
Robertson reports that as soon as the isomers were prepared they were stored
in THF containing BHT at -25°C to prevent isomeric conversion.” Id.
(quoting Second Cutler Decl. 117). Therefore, Appellants argue, Robertson
does not provide experimental evidence of a pharmaceutical composition
that comprises 4-hydroxytamoxifen at a 1:1 equilibrium ratio of E:Z
isomers.
With respect to Katzenellenbogen, which the Examiner cites as
teaching “roughly equivalent” rates of E —> Z and E <— Z isomerization
reactions after two days, Appellants point to the Second Declaration of Dr.
Cutler, who cites Katzenellenbogen and a related reference, B.S.
Katzenellenbogen et al., Bioactivities, Estrogen Receptor Interactions, and
Plasminogen Activator-inducing Activities of Tamoxifen and
Hydroxytamoxifen Isomers in MCF-7 Human Breast Cancer Cells, 44
Cancer Research, 112-19 (1984) (“Katzenellenbogen 1984”). App. Br.
11-12.
Dr. Cutler opines that both references: “report studies that started with
either radiolabeled trans-4-OHT or radiolabeled c/s-4-OHT and assessed
conversion to the other isomer.” Id. at 12 (citing Second Cutler Decl. 111).
Appellants argue that both Katzenellenbogen references therefore teach
parallel isomer conversion studies, and report that the isomer ratio reached
after 48 hours depended on the starting isomer. Id. Specifically, Appellants
point to Dr. Cutler’s opinion that: “As reported in Katzenellenbogen (1984),
after 48 hours in culture media maintained at 37°C, the ‘trans’ isomer
preparation contained 17% cis isomer, while the ‘cis’ isomer preparation
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contained 25% trans isomer.” Id. (quoting Second Cutler Decl. 111).
Appellants point out that Dr. Cutler also observes that: “Katzenellenbogen
[...] reports similar data for a trans-4-OHT composition, observing 16% cis
after 2 days in culture media.” Id. According to Appellants, the
Katzenellenbogen references therefore corroborate Malet’s conclusion,
regarding Z:E 4-OHT equilibrium. Id. Appellants emphasize that Dr. Cutler
also opines that: “the results reported in Malet for the pure ‘trans’ (Z)
starting composition are consistent with the results reported in
Katzenellenbogen for its pure ‘trans’ (Z) starting compositions.” Id.
(quoting Second Cutler Dec. 112).
Appellants further observe that Dr. Cutler opines that the teachings of
both Katzenellenbogen references, as well as those of the McMurry
reference, do not provide any scientific basis for the Examiner’s finding that
the Katzenellenbogen data reported for day 2 can be: “extrapolate[d] ... to
arrive at an equilibrium state of cis(E):trans(Z) of roughly 1:1” App. Br. 13
(quoting Second Cutler Decl. 116).
The Examiner responds that Malet teaches only that “spontaneous
isomerization of trans- into cis-4[-]OHT occurred within 24-48 h, but
stabilized rapidly at a trans/cis ratio of 70/30, whether in stock solution,
culture medium or cultured cells.” Ans. 6 (quoting Malet Abstr.). The
Examiner contrasts the teachings of Malet with those of Brewster, which
teaches that: “[theoretical evaluation indicated that both cis- and trans -
tamoxifen[,] as well as the 4-hydroxytamoxifen isomeric pair[,] were very
close in energy, confirming experimental results suggesting nearly
equivalent populations of the two isomers under equilibrium conditions.” Id.
(quoting Brewster Abstr.).
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The Examiner finds Brewster points to the teachings of Robertson in
support of Brewster’s finding of a 1:1 E:Z isomer ratio of 4-
hydroxytamoxifen. Ans. 7 (citing Final Act. 5—6). The Examiner finds that
Robertson teaches experimental data demonstrating that tamoxifen, 4-
hydroxytamoxifen, and their brominated and tritium-labeled derivatives
equilibrate at E:Z ratios of approximately 1:1. Id. The Examiner further
finds that Brewster teaches that when trans-tamoxifen (the parent compound
to the 4-hydroxytamoxifen metabolite) is refluxed in an ethanolic solution of
HC1, it isomerizes to a 1:1 mixture of the cis and trans isomers. Id.
The Examiner finds further that additional experimental support
suggesting an E:Z equilibrium ratio of 1:1 is taught by Katzenellenbogen, as
supported by the teachings of McMurry. Ans. 7. The Examiner finds
Katzenellenbogen teaches the isomerization of the E to the Z isomer as well
as the reverse Z to E isomerization reaction of 4-hydroxytamoxifen. Id. The
Examiner finds Katzenellenbogen teaches that roughly 20% of a 99.9% pure
trans 4-hydroxytamoxifen solution converts to the cis form in two days
(78:22 trans'.cis); and that roughly 20% of a 99.9% pure cis 4-
hydroxytamoxifen solution converts to the trans form in two days (17:83
cis'.trans). Id. The Examiner therefore finds that these data suggest that the
rate of the cis to trans conversion is roughly equivalent to the trans to cis
conversion rate after two days. Id. The Examiner finds that, because the
rates of isomerization, as taught by Katzenellenbogen, are roughly
equivalent, a person of ordinary skill could extrapolate this data to arrive at
an equilibrium state of cis(E):lrans(Z) of roughly 1:1, as taught by
McMurry. Id. Therefore, the Examiner finds, as the cis to trans
isomerization and the reverse are roughly the equivalent rate after two days,
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the equilibrium can be determined to be essentially 1:1 given enough time to
reach this point. Id.
The Examiner finds that Malet teaches establishment of a 70:30
cis'.trans ratio from an initially pure //vm.s-4-hydroxy tamoxifen solution after
48 hours, which remains stable for 7—8 days, but does not report what
happens subsequent to 8 days. Ans. 8. However, the Examiner finds, the
reversible equilibrium of 4-hydroxytamoxifen is well known and Brewster
predicts an equilibrium proportion of Z:E of 1:1, based on upon
thermodynamic data. Id. (citing Brewster Abstract, 348—350).
The Examiner therefore concludes, based upon the combined
teachings of Brewster, Robertson, Katzenellenbogen, and McMurry, that it
would have been obvious to one of ordinary skill in the art to formulate a 4-
hydroxytamoxifen composition containing, at its equilibrium state, a 1:1
ratio of Z:E isomers with a reasonable expectation that doing so would result
in an effective therapeutic composition. Ans. 9.
We are not persuaded by the Examiner’s findings and conclusions.
As an initial matter, we are not persuaded by the Examiner’s finding, based
upon the alleged teachings of McMurry, that because Robertson allegedly
teaches cis to tram and trans to cis conversion rates that are approximately
equal, this predicts a 1:1 cis'.trans ratio. See Ans. 7. McMurry teaches that
an equilibrium is attained when “the rates of the forward and reverse
reactions become equal,” but this does not necessarily require that the ratio
of the concentrations of the equilibrium reactants be equal when equilibrium
is achieved. McMurry 515 (emphasis in original); see also Fig. 13.1.
Malet teaches, inter alia, that:
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When [3H] -tra«s-40HTam was stocked in ethanol (10'3 M
solution) at -20°C, or diluted to 10 6 or 10 8 M in culture medium
maintained at 4°C, isomerization to the cw-isomer occurred as
early as 24-48 h and remained stable at a cis/trans ratio of 30/70
during the 7—8 days of treatment
and that:
[WJhatever the storage or culture conditions, a spontaneous
equilibrium was reached at a trans/cis ratio of 70/30 and trans to
cis conversion never exceed 35%. This trans/cis ratio and the
100-fold higher affinity of /r