Ex Parte Dey et al

Patent Trial and Appeal Board

Oct 16, 2018

14152000 (P.T.A.B. Oct. 16, 2018)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE
14/152,000 01/10/2014
144695 7590 10/16/2018
Ewers & Hasselmann PLLC
1101 Connecticut Avenue NW, Suite 450
Washington, DC 20036
FIRST NAMED INVENTOR
Michael Dey
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.
2115-1002-N 7065
EXAMINER
BROWN-PETTIGREW, ANGELA C
ART UNIT PAPER NUMBER
1621
MAIL DATE DELIVERY MODE
10/16/2018 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 MICHAEL DEY, JOEL RICHARD, MARIE-MADELEINE
BARONNET, NATHALIE MONDOLY, LAURENT BERTOCCHI,
and JEREMIAH HARNETT
Appeal2017-004020
Application 14/152,000
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREY N. FRED MAN, and
DEBORAH KATZ, Administrative Patent Judges.
KATZ, Administrative Patent Judge.
DECISION ON APPEAL
Appeal2017-004020
Application 14/152,000
Appellants 1 seek our review, under 35 U.S.C. § I34(a), of the
Examiner's decision to reject claims 1-3, 5-7, 11-14, and 17. (Appeal Brief
("App. Br.") 1.) We have jurisdiction under 35 U.S.C. § 6(b). We affirm.
The Examiner rejected claims 1-3, 5-7, 11-14, and 17 as being
obvious under 35 U.S.C. I03(a) over Quay2 and Burczynski. 3 (See Final
Office Action issued December 17, 2015 ("Final Act.") 3-6; Examiner's
Answer issued November 14, 2016 ("Ans.") 2-5.)
Appellants' specification is directed to a formulation of apomorphine,
a drug previously known to be used for treating patients with advanced
Parkinson's disease, when formulated in a solution suitable for subcutaneous
infusion and injection. (See Specification ("Spec.") 1: 14--20.) Appellants
report that these routes of administration can cause injection site reactions
when the apomorphine precipitates and chemically degrades under
physiological conditions and pH. (See Spec. 1:21-26.) To address these
concerns, Appellants report that their formulation has a pH "close to the
physiological pH," which stabilizes increased concentrations of the drug and
makes them suitable for parenteral4 subcutaneous administration. (Spec.
1:32-2:2.)
1 Appellants report that the real party in interest is Britannia Pharmaceuticals
Ltd. (App. Br. 2.)
2 Quay, U.S. Patent Application Publication 2005/0090518 Al, published
April 28, 2015.
3 Burczynski and Cote, U.S. Patent Application Publication 2008/0171072
Al, published July 17, 2008.
4 We understand parenteral administration to be administration by a route
other than the gastrointestinal tract.
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Application 14/152,000
Claim 1, Appellants' only independent claim, recites:
A pharmaceutical composition for parenteral
administration having an active substance and being provided
in the form of a solution, the pharmaceutical composition
compnsmg:
i) apomorphine as the active substance;
ii) a water miscible co-solvent;
iii) an antioxidant; and
iv) water;
wherein a pH of the composition is greater than 4.
(App. Br. 18, Claims App'x.)
Findings of Fact
Based on the Examiner's rejection, we make the following findings of
fact, which are supported by a preponderance of the evidence.
1. Quay is directed to formulations of apomorphine, along with an
apomorphine prodrug, for the treatment of Parkinson's disease. (See Quay
abstract.)
2. Quay teaches a formulation for nasal administration that
comprises apomorphine, propylene glycol, ascorbic acid, and water. (See
Quay ,r 27 and accompanying table; Final Act. 3.)
3. Appellants' Specification includes propylene glycol as a water-
miscible co-solvent within the scope of the invention. (See Spec. 3: 19-20.)
4. Appellants' Specification includes ascorbic acid as an anti-
oxidant within the scope of the invention. (See Spec. 4:4--5.)
5. Quay does not teach that the apomorphine formulation has a pH
greater than 4. (See Final Act. 4.)
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Application 14/152,000
6. Burczynski is directed to formulations of apomorphine as
ocular inserts that can be used to induce vomiting in dogs. (See Burczynski
,r,r 3 and 4.)
7. Burczynski provides a comparative example in which
apomorphine was administered intravenously to patients in a solution
buffered to pH 5.5 using a phosphate buffer in water for injection.
(Burczynski ,r 56; see Final Act. 4.)
8. Burczynski teaches that apomorphine can be protected from
oxidative degradation by formulating it with antioxidants, such as ascorbic
acid, at "an acidic pH." (Burczynski ,r 38; see Final Act. 4.)
Analysis
Appellants claim a composition that comprises four elements:
apomorphine, a water miscible co-solvent, an antioxidant, and water. Quay
teaches a composition that comprises apomorphine, a water miscible co-
solvent (propylene glycol), an antioxidant (ascorbic acid), and water. (See
Quay ,r 27; Findings of Fact 1--4.) Quay does not disclose the pH of this
composition. (See Finding of Fact 5.)
Burczynski teaches a composition of apomorphine for intravenous
delivery that uses a phosphate buffer to maintain a pH of 5.5. (See
Burczynski ,r 38.)
The Examiner determined that
[ t ]he person of ordinary skill in the art would have been
motivated to [ modify the composition of Quay with the pH
taught in Burczynski] in order to achieve a pharmaceutical
composition comprising apomorphine wherein the apomorphine
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Application 14/152,000
did not degradate[5]. One of ordinary skill in the art would
achieve the predictable result of combating degradation with an
acidic pH level and addition of antioxidants. Therefore, the
invention as a whole would be obvious to the person of
ordinary skill in the art.
(Final Act. 4.)
Appellants argue that the Examiner's reason to modify the
composition of Quay by increasing the pH to 5.5 to combat degradation is an
error. (See App. Br. 11-12.) Appellants argue that the "less acidic pH of an
apomorphine solution ... increases the risk of degradation of the
apomorphine, unless the apomorphine solution for parenteral administration
can be stabilized." (Reply Brief ("Reply Br.") 5; see App. Br. 11-12.)
Similarly, Appellants argue that "[ s ]imply dissolving apomorphine in water
buffered to a pH of 5.5 ... does not result in a pharmaceutical composition
for parenteral administration, but, at best, in a control solution in which
apomorphine immediately starts to decompose." (Reply Br. 9.)
We are not persuaded by these arguments because Appellants fail to
cite evidence in a timely manner showing that a higher pH, which is still
acidic, would increase the risk of degradation. 6 Appellants do not direct us
5 Appellants discuss the word "degradate" in their Reply Brief. (See Reply
Br. 4.) It is assumed that the word is a typographical error and is understood
to mean "degrade" because of the use of the word "degradation" in the next
sentence.
6 In their Reply Brief, Appellants present a picture that reportedly shows
"aqueous apomorphine solutions at pH values of 3, 4, 5, 6, and 6.5,
respectively, after storage." (See Reply Br. 14.) Appellants assert that "[a]
discoloration ( darkening) over time is an indication of destabilization,
wherein the darkening becomes more pronounced with increasing pH
values." (Id.) We do not consider this evidence because it was presented to
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Application 14/152,000
to evidence in support of their assertion that a range of 3 to 4 is more
suitable than other acidic pH levels.
Appellants' Specification states that
parenteral subcutaneous injection of an active pharmaceutical
ingredient (API) formulated in acidic conditions may lead to in
situ precipitation and chemical degradation under physiological
conditions and pH. Low pH value of the formulation, as well
as potential precipitation and degradation of the drug under
physiological conditions, may induce local subcutaneous site
reactions as redness, etching, local indurations and nodules
which are sore and troublesome. This is typically the case of
apomorphine when administered in a subcutaneous (SC)
infusion.
(Spec. 1 :24--30.) The Specification discusses "low pH" and "physiological
... pH," but does not define either term or indicate that either excludes the
pH of 5. 5 taught in Burczynski. Appellants argue that Quay teaches an
"acidic solution," but the pH taught in Burczynski is also acidic. 7 (See App.
us for the first time in the Reply Brief and we therefore lack the benefit of
the Examiner's review. See 37 C.F.R. § 4I.41(b )(1) ("A reply brief shall not
include any new or non-admitted amendment, or any new or non-admitted
affidavit or other Evidence."). In addition, we note that none of Appellants'
claims include a limitation regarding time or storage. Accordingly, even if
we considered this evidence, it would not be persuasive to show that the
claimed composition would not have been obvious.
7 The Examiner finds that "[a] pH of 1-7 is an acidic pH level." (Ans. 7.)
Appellants argue that this statement is factually incorrect because a pH of 7
is not acidic. (See Reply Br. 8.) Nevertheless, all of the pH values at issue
in regard to the prior art and the pH values encompassed by Appellants'
claims up to pH 7 are in the acidic range. (See, e.g., Reply Br. 8 ("It is
undisputed that a pH of, for example, 4.5 is an acidic pH.").) We disagree
with Appellants' statement that "claim 1 does not recite an acidic pH, but a
pH of greater than 4." (Reply Br. 15.)
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Application 14/152,000
Br. 11 ("However, this is merely a description of what is suggested in Quay,
which is the preparation of an acidic solution."); see also App. Br. 12
("Quay is completely silent about stability issues of apomorphine solutions
and simply accepts that acidic pH values must be chosen.").) Thus, we are
not persuaded by Appellants' argument that the Examiner's reasoning is
flawed. Instead, in light of the evidence properly presented to us, the
Examiner's position is reasonable that it would have been obvious to use the
pH of 5.5 taught in Burczynski with the ingredients taught in Quay to avoid
degradation.
Appellants raise a similar argument against the Examiner's reliance
on Burczynski. According to Appellants, Burczynski teaches away from the
claimed invention because it teaches that apomorphine is subject to
oxidative degradation that can be prevented by acidic pH in a formulation.
(See App. Br. 13, citing Burczynski ,r 38.) As noted above, a pH of greater
than 4 can be an acidic pH. Thus, paragraph 3 8 of Burczynski does not
teach away from the claimed composition.
Appellants also argue that the recitation in the preamble of claim 1 of
"parenteral administration" is not merely an intended use of the ingredients
and pH recited in the claim, but instead indicates limitations of stability and
storage. Specifically, Appellants argue that
[a] skilled artisan understands that a pharmaceutical
composition for parenteral administration must at least be stable
enough to be shipped to the patient and stored for a few days
prior to being administered. The in-situ preparation of the
comparison solution in Burczynski et al would not be
considered by a skilled artisan to correspond to a
pharmaceutical composition for parenteral administration
because the comparison solution is not suitable for being
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Application 14/152,000
shipped or stored. As such, the apomorphine in the comparison
solution is subject to degradation at the high pH level of the
comparison solution. This is not a problem in Burczynski et al
because the comparison solution therein is only needed to
confirm that the ocular inserts are functioning as intended.
(App. Br. 10-11.) Similarly, Appellants assert that "it is the combination of
all recited components that provides for the required shelf-life and the
resulting ability of the pharmaceutical composition for parenteral
administration to be injected into a patient suffering from Parkinson's
disease." (App. Br. 11.)
We are not persuaded by this argument because Appellants' claim 1
does not recite any limitations on stability or the ability to be shipped and
stored. (See Ans. 8.) Although Appellants argue that their Specification
discusses increased stability of the claimed composition (see Reply Br. 13),
these features are not recited in the claims and, thus, do not limit the claims.
See E-Pass Techs., Inc. v. 3Com Corp., 343 F.3d 1364, 1369 (Fed. Cir.
2003) ( claims must be interpreted in view of the specification without
importing limitations from the specification into the claims unnecessarily).
Appellants fail to direct us to evidence in support of their assertion that one
of ordinary skill in the art would have understood a specific degree of
stability is necessarily required for parenteral administration. Appellants'
claim 1 is not limited to a particular shelf-life. Instead, nothing in
Appellants' claims precludes the formulation and immediate parenteral
administration of the claimed compound.
Appellants raise several arguments that refer to only one of the
references cited by the Examiner. We are not persuaded by these arguments
because the Examiner's rejection is based on the combination of Quay and
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Application 14/152,000
Burczynski under 35 U.S.C. § 103, not on an anticipation of the claimed
inventions by either reference. "Non-obviousness cannot be established by
attacking references individually where the rejection is based upon the
teachings of a combination of references." In re Merck & Co., 800 F.2d
1091, 1097 (Fed. Cir. 1986).
For example, Appellants argue that the solution described in
paragraph 27 of Quay would have a pH of approximately 3.6. (See App. Br.
8.) Appellants argue further that the compositions of samples 1 and 2 of
paragraphs 31 and 32 of Quay would also be acidic because of the large
amount of lactic acid added. (See App. Br. 8.) Neither of these arguments
are persuasive because the Examiner's rejection is not that the claimed
invention is anticipated by Quay.
Similarly, Appellants argue that Burczynski teaches a removable
ocular insert from a formulation that does not contain a co-solvent or
propylene glycol. (See App. Br. 10 and 13.) Quay teaches a composition of
apomorphine and the ingredients recited in claim 1, including the co-solvent
propylene glycol. Thus, these arguments do not address the Examiner's
rejection.
Appellants also argue that Quay teaches a nasal formulation, not a
formulation for subcutaneous or intravenous administration. (See App. Br.
9.) According to Appellants, the physical properties of the nasal formulation
are different from those for parenteral administration and "ingredients
provided to allow for a delivery via a nasal delivery system may not interfere
with the other ingredients." (App. Br. 9.) Again, this argument refers only
to the teachings of Quay and does not address the Examiner's rejection that
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the claimed composition would have been obvious over a combination of the
teachings of Quay and Burczynski.
Appellants argue further that the formulation taught in Quay is not
suitable for parenteral administration because it includes what Appellants
report to be a "the highly toxic excipient benzalkonium chloride, which is an
antiseptic substance suitable for topical administration only." (App. Br. 9--
10.) In addition to being unsupported attorney argument, 8 even if Quay
teaches that other components are present in the formulations, it nevertheless
teaches the components recited in Appellants' claim 1. Appellants do not
argue or present persuasive evidence showing that those of ordinary skill in
the art would have considered Quay to teach that benzalkonium chloride is a
necessary ingredient when formulating a composition of apomorphine.
Appellants have not provided us with a reason to believe that removing the
8 The Examiner cites evidence showing that benzalkonium chloride was
known to be used in parenteral formulations, refuting Appellants' assertion
that benzalkonium chloride is too toxic. (See Ans. 10, citing Mehmood and
Fahooq, OPEN SCIENCE JOURNAL OF PHARMACY AND PHARMACOLOGY 3: 19--
27 (2015) at 24--25 ("Mehmood").) Appellants reply that although
Mehmood teaches using benzalkonium chloride for parenteral suspensions,
it also states that "[b ]enzalkonium chloride is used in ophthalmic dosage
forms & not in injectable dosage forms." (See Reply Br. 18, quoting
Mehmood 25.) We are not persuaded by Appellants' argument because
claim 1 is not limited to administration by injection, but encompasses all
routes of parenteral administration. Furthermore, Appellants' argument that
Mehmood was not available when the application was filed is unpersuasive
because Mehmood was not cited as prior art, but instead to rebut Appellants'
assertion that one of ordinary skill in the art would have dismissed Quay
because it teaches using benzalkonium chloride. (See Reply Br. 18.)
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benzalkonimn chloride from the formulation of Quay would affect any of the
other components recited in paragraph 27.
Appellants also argue that Quay is directed to treating a dopamine
deficiency with apomorphine in conjunction with apomorphine prodrug, but
that paragraph 27 of Quay is directed to a formulation of only apomorphine.
(See App. Br. 9; see also App. Br. 12.) According to Appellants, the portion
of Quay cited by the Examiner is not directed to the desired product
providing the benefits sought by Quay. (See App. Br. 9.) This argument is
not persuasive because Appellants' claim 1 is not directed to a specific effect
of administering the claimed composition or a method of using it.
Appellants' claim 1 is merely directed to the recited composition, which
includes the ingredients taught in Quay. Furthermore, the recitation of other
ingredients in Quay does not negate the teaching of the claimed ingredients
because Appellants' claim 1 recites the transitional phrase "comprising,"
which allows for other elements. ( Contra Reply Br. 10 ("It is unclear how
Appellant's choice of the transitional phrase 'comprising' has a bearing on
what Quay can include in the nasal formulations suggested therein.")).
Appellants argue that paragraph 25 of Quay teaches away from
parenteral administration because it suggests that subcutaneous and
continuous infusion require injections that risk infection, discomfort, and
other adverse effects. (See App. Br. 13, citing Quay ,r 25.) Paragraph 25
does not mention parenteral administration. Accordingly, we disagree with
Appellants that one of ordinary skill in the art would have been discouraged
from using parenteral administration after reading Quay. See In re Gurley,
27 F.3d 551, 553 (Fed. Cir. 1994) ("A reference may be said to teach away
when a person of ordinary skill, upon reading the reference, would be
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discouraged from following the path set out in the reference, or would be led
in a direction divergent from the path that was taken by the applicant.").
Appellants argue for the first time in their Reply Brief that there was a
long-felt need in the art for a pharmaceutical composition that causes fewer
or no side effects. (See Reply Br. 9.) Appellants do not explain why the
argument could not have been presented earlier and do not show why there
is good cause that it should be considered, given its belated filing.
Accordingly, we do not consider the argument. See 3 7 C.F .R. § 41.41 (b )(2)
("Any argument raised in the reply brief which was not raised in the appeal
brief, or is not responsive to an argument raised in the Examiner's answer,
including any designated new ground of rejection, will not be considered by
the Board for purposes of the present appeal, unless good cause is shown.").
Appellants have not persuaded us that the Examiner erred in rejecting
claim 1 as being obvious over Quay and Burczynski.
Claim 2
Claim 2 recites: "The composition of claim 1, wherein an amount of
the active substance is between about 10 to 70 mg/ml." (App. Br. 18,
Claims App'x.) The Examiner cites to paragraph 52 of Burczynski for the
teaching of a dose for parenteral administration of 0.08 mg/kg. (See Final
Act. 4.) The Examiner determines that it is not inventive to discover dosing
regimens by routine experimentation when general conditions of a claim are
disclosed in the prior art. (See Final Act. 5.) The Examiner also finds that
the medical arts recognize that drug therapy may be optimized by designing
regimens that account for the concentration of a drug by considering factors
such as weight, age, gender, renal and hepatic status. (See Final Act. 5.)
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We agree with Appellants that the concentration range recited in claim
2 is not a dosage regime. (See App. Br. 14; Reply Br. 6-7.) But we are not
persuaded by Appellants' argument that the claimed concentration allows for
a dosage regime wherein the active substance can be administered over a
shorter period of time due to a smaller injection volume. (See App. Br. 14.)
Appellants argue: "A skilled artisan would not arrive at such a shorter period
of time through routine experimentation because the compositions of Quay
or Burczynski et al are not stable at high concentrations." (App. Br. 14--15.)
Because claim 2 does not recite limitations regarding a period of time for
administration, the ability to ship the composition, or an injectable volume,
we are not persuaded by this argument.
Claim 2 recites only an amount between about 10 to 70 mg/ml.
Appellants do not argue or cite to evidence showing that it would not have
been routine for those of ordinary skill in the art to have optimized the
concentration of apomorphine in a composition for parenteral administration
to the recited amount. 9 "[I]t is to be expected that a change in temperature,
9 Appellants include a sheet titled "Product Information" in an appendix to
their Reply Brief and request that it be considered as showing the solubility
of apomorphine for the purposes of rebutting the Examiner's findings
regarding adding more drug to a formation. (See Reply Br. 3, citing Ans. 9.)
Although Appellants argue that this particular sheet was not available until
after the Appeal Brief was filed (see Reply Br. 3), apomorphine has been
known since at least 1970. (See Quay ,r 23 ("Apomorphine, as a dopamine
agonist, has been proposed as a therapy for Parkinson's disease since at least
1970 and as a therapy for 'on-off fluctuations since at least 1987.").) Thus,
we are not persuaded that Appellants were not aware of its solubility until
after they had filed their Appeal Brief. Because Appellants do not present
an argument based on the relative solubility of apomorphine in their Appeal
Brief, and the Examiner had previously rejected claim 2 based on the
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or in concentration, or in both, would be an unpatentable modification." In
re Aller, 220 F.2d 454, 456 (CCPA 1955). Appellants do not direct us to
evidence that the claimed concentration would have been critical, that is
unexpected or different in kind and not merely in degree from the results of
the prior art. Nor do Appellants direct us to evidence that obtaining the
claimed concentration would not have been within the capabilities of one
skilled in the art. See id.
Accordingly, we are not persuaded that the Examiner erred in
rejecting claim 2 as being obvious over Quay and Burczynski.
Other Dependent Claims
Appellants argue that the claims dependent on claim 1 include
separately patentable subject matter, but fail to discuss any specific elements
of the claims. (See App. Br. 16.) We are not persuaded that the Examiner
erred in rejecting any of Appellants' dependent claims because of the lack of
specific argument against the rejections. See 37 C.F.R. § 4I.37(c)(l)(iv) ("A
statement which merely points out what a claim recites will not be
considered an argument for separate patentability of the claim.").
Conclusion
Upon consideration of the record and for the reasons given, the
rejection of claims 1-3, 5-7, 11-14, and 17 under 35 U.S.C. § 103(a) over
Quay and Burczynski is sustained.
Therefore, we affirm the decision of the Examiner.
knowledge in the art to optimize drug concentration (see Final Act. 5), this
evidence was presented too late for consideration. See 37 C.F.R.
§ 41.41 (b )(1 ).
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No time period for taking any subsequent action in connection with
this appeal may be extended under 37 C.F.R. § 1.136.
AFFIRMED
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