Ex Parte Moolenaar et al

Patent Trial and Appeal Board

Jul 28, 2017

11547152 (P.T.A.B. Jul. 28, 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.
11/547,152 10/20/2006 Sytske Hyke Moolenaar 2004.837US 8600
210 7590
MERCK
P O BOX 2000
RAHWAY, NJ 07065-0907
EXAMINER
MCCORMICK, MELENIE LEE
ART UNIT PAPER NUMBER
1621
NOTIFICATION DATE DELIVERY MODE
08/01/2017 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):
US-DOCKET-PATENT@merck.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte SYTSKE HYKE MOOLENAAR,
GERARDUS JOHANNES KEMPERMAN,
and KEES VAN DER VOORT MAARSCHALK1
Appeal 2015-003491
Application 11/547,152
Technology Center 1600
Before ULRIKE W. JENKS, RYAN H. FLAX, and
RACHEL H. TOWNSEND, Administrative Patent Judges.
JENKS, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a non­
sublimating solid salt of mirtazapine, and a method of producing the solid
salt. The Examiner rejects the claims as obvious. We have jurisdiction
under 35 U.S.C. § 6(b).
We AFFIRM.
1 According to Appellants, the real party in interest is Merck, Sharp and
Dohme Corp. MSD Oss B.V., a subsidiary of Merck, Sharp and Dohme
Corp. Appeal Br. 2.
Appeal 2015-003491
Application 11/547,152
STATEMENT OF THE CASE
Claims 1—9 are on appeal, and can be found in the Claims Appendix
of the Appeal Brief. Claims 1 and 5 are representative of the claims on
appeal, and read as follows:
1. A pharmaceutical formulation comprising an
enantiomerically purified form of mirtazapine, wherein the
mirtazapine is present as a pharmaceutically suitable non­
sublimating and solid salt of mirtazapine.
5. A method to prevent sublimation of mirtazapine from a
pharmaceutical formulation comprising an enantiomerically
purified form of mirtazapine in solid form, characterized by
selecting a pharmaceutically suitable non-sublimating salt of S-
or R-mirtazapine during manufacturing the pharmaceutical
formulation.
Appellants seek review of the Examiner’s rejection of claims 1—9
under 35 U.S.C. § 103(a) as unpatentable over Burg2 and Watthey3 in view
of Gould4 and Moody.5
The issue is: Does the preponderance of evidence of record support
the Examiner’s conclusion that the combination of references renders the
claims directed to a non-sublimating salt of S- or R-mirtazapine obvious?
Findings of Fact
FF1. Example 19 of Burg teaches the optical resolution of 2-methyl-
1,2,3,4,10,14b-hexahydro-benzo[c]pyrazino[ 1,2-a]pyrido[3,2-
2 William J. van der Burg, US 4,062,848, issued Dec. 13, 1977 (“Burg”).
3 Jeffrey W.H. Watthey, US 4,515,792, issued May 7, 1985 (“Watthey”).
4 Philip L. Gould, Salt selection for basic drugs, 33 Intem’l J. Pharmaceutics
201-217 (1986)(“Gould”).
5 Joanna Moody et al., Biotransformation of Mirtazapine by Cunninshamella
Elesans. 30 Drug Metabolism and Disposition 1274—79 (2002)
(“Moody”).
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Application 11/547,152
fjazepine, a.k.a. mirtazapine. Burg 20:5—35. The structure of the
compound of example 19 is provided below:
2-methyl-1,23,4,10, 14b~hexahydro-benzo[c jpyrazmol 1,2-aJpyrido[3,24]azepine
See Burg 20:5—35.
FF2. Burg teaches the acid addition of salts of compounds. See Burg 20,
By salts of the compounds according to the
invention are understood: the pharmaceutically
acceptable acid addition salts and quaternary ammonium
compounds I.
The acid addition salts are obtained by reaction of
the free base I with a suitable inorganic or organic acid,
such as hydrochloric acid, sulphuric acid, phosphoric
acid, acetic acid, maleic acid, fumaric acid, citric acid,
ascorbic acid etc.
Burg 6:60-68.
FF3. Burg teaches acid addition salts of mirtazapine. Treatment of the
“free base with an alcoholic HC1 [(hydrochloric acid)]solution gives
the HC1 salt of 2-methyl l,2,3,4,10,14b-hexahydro-benzo[c]
pyrazino-[l,2-a]-pyrido[3,2-f]azepine.” Burg 11:28—31.
claim 1.
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FF4. Example 17 of Burg teaches the acid addition of maleic acid to a
structurally related compound to mirtazapine. Burg 19:44-47. The
structure of the compound in Example 17 is as follows:
1,2 <3,4? 10* 1,4b-hexahydro-benzo[e]pyrazmo[ 1,2-a]pyrido-[3,2-f]azepme
“The purified oil [containing 1,2,3,4, 10, 14b-hexahydro-
benzo[c]pyrazino[l,2- a]pyrido-[3,2-f]azepine] is then treated with a
solution of 1.78 g maleic acid in 100 ml acetone, resulting in
crystallization of the maleate-salt of the title compound. After
recrystallization from ethanol, 3.6 g of the maleate salt is obtained.”
Burg 19:44-47.
FF5. Gould teaches:
Salt formation provides a means of altering the
physicochemical and resultant biological characteristics
of a drug without modifying its chemical structure. The
importance of choosing the ‘correct’ salt form of a drug
is well outlined in a published review (Berge et al., 1977)
but, although salt form can have a dramatic influence on
the overall properties of a drug, the selection of the salt
form that exhibits the desired combination of properties
remains a difficult semi-empirical choice.
Gould 201.
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FF6. Gould teaches that “[s]alt formation is frequently employed to raise
the melting point (and crystallinity) of the drug species being
processed.” Gould 206. “In general, an increase in melting point,
usually by maximizing or encouraging crystal symmetry, leads to
reduced solubility in all solvents but generally improved stability,
particularly if salt formation results in a crystalline solid, and easier
formulation processing.” Gould 207.
FF7. Moody teaches Cunninghamella elegans is a suitable microbial
model of mammalian metabolism.
Incubation of C. elegans with optically pure R(-) and
lS,(+)-mirtazapine showed that all seven metabolites were
formed from the lS'(+)-enantiomer, with mirtazapine N-
oxide as the major metabolite .... The R(-) enantiomer
formed N-desmethyl-8- hydroxymirtazapine, mirtazapine
A-oxide, A-desmethylmirtazapine, and 8-
hydroxymirtazapine. 8-Hydroxymirtazapine was the
major metabolite.
Moody 8. “The lS,(+)-enantiomer was converted to the same
metabolites as the racemic mixture, whereas the /?(-)-enantiomer
formed neither 12- nor 13-substituted metabolites.” Moody 9.
FF8. The Specification defines non-subliming as:
a salt of S- or R-mirtazapine, from which less than 1 % of
the mirtazapine is sublimating from the sample,
calculated on the basis of the amount of the base, when a
sample of approximately 10 mg (for example an amount
between 8-12 mg) is placed for the duration of 72 hours
under standard conditions of 150 mBar pressure and
60°C temperature.
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Spec. 2. Examples of non-subliming salts of mirtazapine, include
salts of: maleic acid, hydrochloric acid, hydrobromic acid, fumaric
acid, and methanesulfonic acid. Spec. 1.
Principle of Law
“If the claim extends to what is obvious, it is invalid under § 103.”
KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007).
Analysis
The Examiner finds that Burg teaches the method of producing
mirtazapine, as well as optical resolution of mirtazapine, as well as
producing acid addition salts of mirtazapine. Final Act. 4—5; Ans. 3^4. The
Examiner, however, finds that “Burg does not teach a solid-salt form” of a
maleic acid addition salt of mirtazapine. Final Act. 6; Ans. 4. The
Examiner looks to Watthey for the production of “therapeutically acceptable
salts.” Final Act. 6; Ans. 4. The Examiner looks to Gould for an
explanation “why a salt such as maleic acid inter alia (claim 5) would be
most preferred.” Final Act. 8. The Examiner relies on Moody to establish a
“reason[] as to why the S-enantiomer may be preferred over its counter
enantiomer.” Final Act. 8; Ans. 5.
The Examiner relies on the combination of references to provide a
“motivation to prepare a maleate salt form of S-mirtazapine. This salt would
be non-sublimating, as instantly claimed. Whether recognized as non­
sublimating or not, this is a property of the maleate salt of mirtazapine,
which is suggested by the instantly cited prior art.” Ans. 8.
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Claim 1
Appellants contend that there is no motivation to combine the
references. Appeal Br. 5—9, 14. Appellants also contend that Gould teaches
that the preparation of salt forms of a compound are unpredictable. Appeal
Br. 15—17. Appellants also contend that the rejection relies on hindsight.
Appeal Br. 17—18.
We are not persuaded by Appellants’ contentions. Based on the
combination of Burg, Gould, and Moody, we agree with the Examiner’s
conclusion that it would have been obvious to formulate an enantiomerically
pure form of mirtazapine as a salt form, as suggested by Burg. FF1—FF2.
To summarize, Burg teaches the optical resolution of mirtazapine. FF1.
Burg teaches the production of pharmaceutically acceptable acid addition
salts of mirtazapine, as well as related compounds. FF1—FF3. The
pharmaceutical formulation teaching of Burg implies that the salts are
intended for use in patients. As recognized by the Examiner, “Burg does not
teach a solid-salt form” of a maleic acid addition salt of mirtazapine. Ans. 4.
However, Burg does teach the production of a maleic acid addition salt with
a structurally related compound of mirtazapine. FF4.
Gould teaches that the benefits of creating a salt form of drugs is to
alter the “physicochemical and resultant biological characteristics of a drug
without modifying its chemical structure.” FF5. Gould teaches that the salt
form of a pharmaceutical is easier to process into formulations for
administration to patients. FF6; see Gould 204 (“high melting point
crystalline salts are potentially easier to process”), 205 (“small highly
hydrogen bonding acids such as malonic and maleic gave higher melting
salts”). Moody teaches pure enantiomer forms of mirtazapine and that the
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S-enantiomer of mirtazapine results in the same metabolites as the racemic
mixture, suggesting that the use of the S-enantiomer will have the same
beneficial properties as the racemic mixture. FF7.
Claim 1 is directed to a product, wherein the product is an
enantiomerically purified solid salt of mirtazapine. The claims further
describe the salt as having the property of being a non-sublimating solid salt
of mirtazapine. We understand that sublimation is the transformation of a
solid to a gaseous phase without forming a liquid state in between. The
Specification defines “non-sublimating salt” as a salt of S- or R-mirtazapine,
from which less than 1 % of the mirtazapine is sublimating from the sample
in the specific parameters recited. FF8. The Specification provides
examples of non-sublimating and solid salts of S-mirtazapine as well as R-
mirtazapine. See Spec. 1. The Specification further indicates that suitable
salts that meet the non-sublimating requirements include salts of mirtazapine
that are made using the following acids: maleic acid, hydrochloric acid,
hydrobromic acid, fumaric acid, and methanesulfonic. See Spec. 1. Thus, a
mirtazapine salt form made with any of the listed acids is expected to have
the non-sublimating property because a chemical and its properties
inseparable. “From the standpoint of patent law, a compound and all of its
properties are inseparable; they are one and the same thing.” In re Papesch,
315 F.2d 381, 391 (CCPA 1963). “Products of identical chemical
composition can not have mutually exclusive properties.” In re Spada, 911
F.2d705, 709 (Fed. Cir. 1990).
Burg teaches the production of an HCl-mirtazapine salt. FF3. Burg
also suggests using optically pure forms of mirtazapine, as well as making a
salt of the optically pure form. See FF1, FF2. Both Burg and Moody teach
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that mirtazapine has two enantiomeric forms. See FF1, FF7. Moody teaches
that the S(+) form of mirtazapine produces the same metabolites as the
racemic mixture, therefore, suggesting that the use of the S(+) form of
mirtazapine would have the same beneficial effects. FF7. Based on these
combined teachings in Burg and Moody, we agree with the Examiner’s
conclusion that the combination of references would have rendered obvious
a solid salt form of mirtazapine, including using an optically pure form of
mirtazapine for the production of salts with acids that include acids such as
hydrochloric acid and maleic acid. FF2. Here, the totality of the evidence
provided suggests the production of the claimed salts, which are expected to
have the requisite non-subliming properties because those are properties
associated with the structure of the compound.
We are not persuaded by Appellants’ contention that there is no
motivation to combine the references. Appeal Br. 4. Here, Burg specifically
suggests the production of pharmaceutical salts made with hydrochloric and
maleic acid compounds that include mirtazapine. FF1—FF4. Acid addition
salts are recognized as beneficial for the production and formulation of
pharmaceuticals, especially if they result in crystalline solids because that
eases formulation processing. FF6. Burg teaches that a closely related
compound to mirtazapine is able to form a crystalline salt with the use of
maleic acid. FF4. Based on the close structural similarity between this
compound combined with the suggestion in Burg to make salts of
mirtazapine, as well as optically purified mirtazapine, we find there is ample
motivation to combine the references. See FF1-FF3. Burg suggest making
acid addition of salt of compounds including mirtazapine and the other
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references relied on by the Examiner support the position that there is a
reasonable expectation of success when making the claimed products.
Appellants contend that “[t]he specification and Gould teach that
preparation of a salt form of a compound is unpredictable.” Appeal Br. 4.
Appellants contend that “there is an assumption by the Examiner that there
is a relationship between melting point of a compound or salt thereof and
sublimation of the compound and salt thereof. . . . However, there is no
teaching anywhere in Gould that sublimation is related to melting point.”
Appeal Br. 8.
We are not persuaded. Even though Gould teaches that the selection
of the salt form that exhibits the desired combination of properties” requires
experimental verification (FF5), the rejection is not solely based on the
teachings of Gould but is combined with the teachings of Burg that teaches a
crystalline salt of a structurally related compound to mirtazapine, differing
only by the presence of a single methyl substituent on the piperazine ring
(FF4). “Obviousness does not require absolute predictability of success ...
all that is required is a reasonable expectation of success.” In re Droge, 695
F.3d 1334, 1338 (Fed. Cir. 2012) (quoting In re Kubin, 561 F.3d 1351, 1360
(Fed. Cir. 2009) (citingIn re O’Farrell, 853 F.2d 894, 903-04
(Fed.Cir.1988)). Here, Burg produces a maleic acid addition salt of a
closely related compound to mirtazapine. Compare FF1 and FF4. This salt
forms a crystal structure. See FF4 (“The purified oil [containing 1,2,3,4, 10,
14b-hexahydro-benzo[c]pyrazino[l,2- a]pyrido-[3,2-f]azepine] is then
treated with a solution of 1.78 g maleic acid in 100 ml acetone, resulting in
crystallization of the maleate-salt of the title compound”). Burg suggests
making acid addition salts of compounds including mirtazapine. FF1—FF3.
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Burg also suggests optically purified forms of mirtazapine. FF1. Gould is
relied on for teaching that salt forms are beneficial for the ease of making
pharmaceutical formulations. See FF6. Based on the combined teachings
we find no error with the Examiner’s conclusion that the solid salt form of
an enantiomeric mirtazapine compound is obvious.
Appellants contend that there is no “relation between melting point
and sublimation.” Appeal Br. 14.
The Examiner is not relying on the relationship between melting point
and sublimation in arriving at the conclusion that the product is obvious.
Appellants argue that Examiner had made an inadvertent
relationship between sublimation and melting point and hereby
withdraw any explanation drawn to same. This inadvertent
disclosure will no longer be submitted as objective evidence.
The Moores references Appellant refers to is not relied upon in
the pending rejection.
Ans. 8.
As discussed above, the combination of Burg, Gould, and Moody
renders obvious the production acid addition salts of compounds including
optically purified structures that include mirtazapine. We note that we may
affirm a multiple reference rejection under 35 U.S.C. § 103 relying on fewer
than all of the references relied on by the Examiner and without designating
it as a new ground of rejection. In re Bush, 296 F.2d 491, 496 (CCPA
1961).
“From the standpoint of patent law, a compound and all of its
properties are inseparable; they are one and the same thing.” In re Papesch,
315 F.2d at 391. “Products of identical chemical composition can not have
mutually exclusive properties.” In re Spada, 911 F.2d at 708. In other
words, the combination of references suggests the production of acid
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addition of salts of an enantiomerically pure mirtazapine, even though the
references do not recognize that sublimation is an issue with these solid
forms of mirtazapine. FF6. Because there is another reason for making the
claimed salts, namely for the ease of making pharmaceutical formulations,
we find no error with the Examiner’s conclusion that production of an
enantiomerically pure mirtazapine salt is obvious.
Appellants contend the rejection is based on hindsight. Appeal Br. 4,
17-18.
While we are fully aware that hindsight bias often plagues
determinations of obviousness, Graham v. John Deere Co., 383 U.S. 1, 36
(1966), we are also mindful that the Supreme Court has clearly stated that
the “combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results.” KSR,
550 U.S. at 416.
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level
of ordinary skill at the time the claimed invention was made
and does not include knowledge gleaned only from applicant’s
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971).
Here, the Examiner is relying on Burg to teach the production of
pharmaceutical acid addition salt of compounds including mirtazapine. See
FF1—FF4. Acid addition of salts are recognized as beneficial for the
production and formulation of pharmaceuticals. FF6. Burg teaches that a
closely related compound to mirtazapine, is able to form a crystalline salt
with the use of maleic acid. FF4. The Examiner explains that “Burg
adequately addresses the limitations of claim 1. Burg does teach maleic acid
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which is a salt formulation which would make the mirtazapine species of
claim 5 obvious because of the further teachings of. . . Gould.” Ans. 7. We
agree with the Examiner’s position that Burg teaches optically pure forms of
mirtazapine, and suggests the formulation of compounds encompassing
mirtazapine as acid addition of salt for the purpose of formulating
pharmaceuticals, and Burg even discloses a list of acids that are suitable for
the purpose of making such salts. See FF1—FF4. Based on these teachings
in Burg alone, one or ordinary skill in the art would have found an acid
addition salt of mirtazapine obvious, because Burg already teaches an HC1-
mirtazapine salt. FF2. We agree with the Examiner’s conclusion that the
teachings of Burg combined with the additional teachings in Gould, and
Moody render an enantiomerically purified salt of mirtazapine obvious.
Accordingly, we affirm the obviousness rejection of claim 1.
Appellants do not separately argue dependent claims 2-4. Therefore, these
claims fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv).
Claim 5
Appellants contend that the cited references “failed to recognize that
there was a sublimation problem with enantiomers of mirtazapine in base
form and with enantiomers of mirtazapine HC1.” Appeal Br. 4.
We recognize, but are not persuaded by, Appellants’ contention that
none of the references recognize that sublimation is a problem. We note that
this argument contradicts the teaching in the Specification that “non­
subliming salts of mirtazapine, include salts of: maleic acid, hydrochloric
acid, hydrobromic acid, fumaric acid, and methanesulfonic acid.” FF8. The
references also do not have to recognize the problem of sublimation with
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mirtazapine salts because they provide a different reason to make salt forms
of mirtazapine to ease pharmaceutical formulation processing. The law does
not require that the teachings of the reference be combined for the reason or
advantage contemplated by the inventor, as long as some suggestion to
combine the elements is provided by the prior art as a whole. In re Beattie,
974 F.2d 1309, 1312 (Fed. Cir. 1992); In re Kronig, 539 F.2d 1300, 1304
(CCPA 1976). As explained above, Burg already suggests the production of
acid addition salts of compounds that include mirtazapine. See FF1—FF4.
Gould teaches that acid addition of salts are beneficial for the production and
formulation of pharmaceuticals, especially if they result in crystalline solids
because this eases formulation processing. FF6. Burg teaches that a closely
related compound to mirtazapine, is able to form crystalline salt with the use
of maleic acid. FF4. The Examiner recognizes that “Burg does teach maleic
acid which is a salt formulation which would make the mirtazapine species
of claim 5 obvious because of the further teachings of. . . Gould.” Ans. 7.
Here, the Examiner relies on the teachings of Burg that acid addition salts
are useful for the formulation of pharmaceutical compositions and Gould
supports this position that such salts are useful for formulating
pharmaceuticals. See FF2, FF6.
We find no error with the Examiner rationale for combining the
teachings of the references to arrive at the conclusion that the claims are
obvious. Accordingly, we affirm the rejection of claim 5 under 35 U.S.C.
§ 103(a). Appellants do not separately argue dependent claims 6—9.
Therefore, these claims fall with claim 5. 37 C.F.R. § 41.37(c)(l)(iv).
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SUMMARY
We affirm the rejection of claims 1 and 5 under 35 U.S.C. § 103(a)
over Burg in view of Gould and Moody. Claims 2-4 and 6—9 were not
separately argued and fall with claims 1 and 5.
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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