Amend fd: 11-13-2019
`
`Reply to 06-25—2019 OA
`
`Remarks
`
`Status of the Claims
`
`— 10 -
`
`Murase et a].
`
`Appl. No. 16/075,828
`
`Claims are 1-21 are pending. Claims 1-11, 13-15, 17—19 and 21 are withdrawn.
`
`Claims 12, 16 and 20 are active.
`
`The Amendments
`
`Support for the amendment to claim 12 is found, inter alia, at specification page
`
`22 (first and last paragraphs) and page 23 (first paragraph).
`
`Support for amending withdrawn claims 1-4 and 8 to refer to a “pharmaceutically
`
`acceptable carrier” is found, inter alia, in specification 1] [0042] on page 20.
`
`Support for amending active claim 12 and withdrawn claims 1-4, 10, 11 and 13 to
`
`refer to an effective amount is found, inter alia, in specification fl [0051] on page 28.
`
`No new matter has been added by any of the amendments.
`
`The Rejections
`
`Reconsideration of the application is respectfully requested.
`
`The Indefiniteness Rejections
`
`At Office action pages 4-7, claims 12, 16 and 20 are rejected as being indefinite.
`
`Applicant respectfully traverses these rejections.
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`
`Reply to 06—25—2019 OA
`
`“In need thereof”
`
`- 11 -
`
`Murase et a].
`
`Appl. No. 16/075,828
`
`The pending claims refer to a “subject in need thereof.” At Office action paragraph
`
`14, Examiner states that any person qualifies as a “subject in need thereof.”
`
`In the interests of advancing prosecution, claim 12 has been amended to recite that
`
`the subject desires to darken the subject’s skin or hair color at the site at which the
`
`compound(s) is applied. Support for this amendment is found, inter alia, on specification
`
`page 22, last paragraph, where the specification refers to the subject as being preferably a
`
`human who desires to produce the recited effect, for example, darkening the skin.
`
`“Ingesting”
`
`At Office action paragraph 22, Examiner states that “ingesting” is considered to
`
`encompass intravenous administration, topical administration and subcutaneous
`
`administration. In the interests of advancing prosecution, the claims have been amended to
`
`refer to “externally” applying or to an external preparation. Therefore, this rejection is
`
`believed to be moot.
`
`Claim 20
`
`Claim 20 is rejected for insufficient antecedent basis in reciting “when applied as an
`
`external preparation .
`
`.
`
`. .” Examiner notes that claim 20 depends from claim 12 and claim
`
`12 refers to “ingesting” the compound in an effective amount. In the interests of advancing
`
`prosecution, claim 12 (from which claim 20 depends) has been amended to refer to
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`
`Reply to 06-25-2019 OA
`
`— 12 -
`
`Murase et al.
`
`Appl. No. 16/075,828
`
`“externally applying” instead of “ingesting.” The phrase “as an external preparation” in
`
`claim 20 has been canceled because it is believed to be moot in View of the amendment to
`
`claim 12. Therefore, this rejection is believed to be moot.
`
`The First Novelty Rejection
`
`At Office action page 8, claims 12 and 16 are rejected as being anticipated by
`
`Reactions 1499: 8. This is an abstract of an article published in full as Amelot, A. er al.,
`
`”Phototoxic reaction associated with Malarone (atovaquone/proguanil) antimalarial
`
`prophylaxis.” J. Derm. 41 :346-348 (April 2014). Applicant respectfully traverses this
`
`rejection.
`
`Independent claim 12 has been amended to refer to “externally applying.” As noted
`
`in the “Reactions” abstract,
`
`the route by which the Malarone drug was taken was not stated
`
`in the article. According, the “Reactions” abstract does not detract from the novelty of the
`
`invention.
`
`The Second Novelty Rejection
`
`At Office action page 9, claim 12 is rejected as being anticipated by Browne et al.,
`
`Brit. Med. Journal 5225 : 5 50-5 51 (1961). Applicant respectfully traverses this rejection.
`
`As reported by Browne, the patient discussed in Case 1 took aspirin, mepacrine and
`
`proguanil (page 551, col. 1, “Previous History”). The route of administration is not stated.
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11—13—2019
`Reply to 06-25-2019 OA
`
`- 13 -
`
`Murase et a1.
`Appl. No. 16/075,828
`
`In trying to find the causative agent for the patient’s epidermal necrolysis, a “patch
`
`test” was performed with “all of the drugs” the patient had taken (page 551, col. 1,
`
`“Subsequent History”). The results of the patch tests for aspirin, mepacrine and proguanil
`
`were negative.
`
`In the interests of advancing prosecution, independent claim 12 has been amended to
`
`recite “darkening the subject’s skin or hair color at [the application] site as a result of the
`
`applying.” Browne does not disclose the claim element that recites “darkening that the skin
`
`or hair color as a result of the applying” because the patch test for proguanil in Browne was
`
`negative. Also, Browne does not disclose that the subject desires to darken the subject’s skin
`
`or hair color at the application site. Accordingly, Browne does not detract from the novelty
`
`of the claimed invention and this rejection can be withdrawn.
`
`The Obviousness Rejection
`
`At Office action page 10, claims 12, 16 and 20 are rejected as being unpatentable
`
`over the combination of Van Neste er a1 (Micron 35:193-200 (2004), Hue et al., (FR
`
`2901133 A1; published November 23, 2007) and Chulay (US 6,413,993; published July 2,
`
`2002). Applicant respectfully traverses this rejection.
`
`Preliminarily, Examiner is respectfully asked to note that, as shown on the cover
`
`page of the document, the first named inventor of FR 2901133 A1 is “Breton,” not Hue.
`
`“Hue” is the last named inventor of FR 2901133 A1. To avoid confusion though, in the
`
`discussion below, FR 2901133 A1 is referred to as “Hue” as in the Office action.
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`Reply to 06—25-2019 0A
`
`— 14 -
`
`Murase et a].
`App]. No. 16/075,828
`
`Van Neste is focused on hair follicle melanogenesis. Examiner relies on Van Neste,
`
`inter alia, as evidence that the loss of skin color and hair graying occurs with age, and that
`
`people who are aging represent subjects in need of darkening skin and hair. Proguanil is not
`
`mentioned.
`
`Hue is relied on as teaching treating aging skin and hair, and promoting keratinocyte
`
`proliferation, by administering a glycolysis inducer (proguanil) to “control differentiation”
`
`of epidermal cells and to increase proliferation of young keratinocyte cells.
`
`Hue discloses that inducing glycolysis in epidermal cells limits the ability of
`
`epidermal cells to differentiate, and specifically, limits the differentiation of keratinocytes.
`
`As a result, by inducing glycolysis, a basal pool of “young,” proliferating keratinocytes can
`
`be maintained in the skin. At translation page 3, first paragraph, Hue states:
`
`By limiting and / or delaying the passage of the cells in the
`differentiation phase, the pool of young cells is maintained. It
`is therefore important to preserve this pool of proliferative
`cells, avoiding or delaying their differentiation, in order to
`help delay the appearance of signs of aging.
`
`Hue does not suggest that Hue’s method darkens skin or hair or that it has any effect
`
`on skin or hair darkening. Instead, the compositions are said to be intended to prevent or
`
`reduce wrinkles, fine lines, thinning of the skin, “against soft,” faded skin, hair loss
`
`“promoting the hair follicle” alopecia, etc. (translation page 9). Hue mentions melanocytes
`
`only once, in the background of the invention. Melanocytes are listed as being one of three
`
`types of epidermis cells: keratinocytes, melanocytes and Langerhans cells. Hue does not
`
`suggest that melanosomes have any effect on keratinocytes.
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`
`Reply to 06-25-2019 OA
`
`- 15 -
`
`Murase et a].
`
`Appl. No. 16/075,828
`
`Chulay discloses the use of a composition that comprises proguanil and other active
`
`agents for the treatment of malaria. The composition can be taken internally or applied to the
`
`skin. Chulay is relied on as evidence that the disclosed doses of proguanil are known to be
`
`safe and effective.
`
`In Office action 1i 47, Examiner concludes that it would have been primafacie
`
`obvious to administer proguanil to aging patients who are in need of treating aging skin and
`
`hair in View of Van Neste and Hue in order to arrive at the instantly claimed methodology.
`
`Examiner states that motivation to administer proguanil flows logically from the fact that
`
`proguanil was recognized in the art to effectively treat chronobiologically aging skin and
`
`hair, dry skin and the promotion of keratinocyte proliferation and promoting the levels of
`
`hair follicles. Examiner views the property such as darkening the hair or skin as a
`
`characteristic feature of the claimed process of administering proguanil.
`
`Reconsideration is respectfully requested. Claim 12 has been amended to recite that
`
`the compound(s), such as proguanil, is applied externally to a site on the skin where the
`
`subject desires to darken the skin or hair at that site. As shown below,
`
`the property such as
`
`darkening skin or hair cannot be considered to be a characteristic feature of the process of
`
`administering proguanil that was known or suggested in the art.
`
`Examiner’s attention is respectfiilly to an article by Choi et al., ”Melanosome uptake
`
`is associated with the proliferation and differentiation of keratinocytes,” Arch Dermatol Res
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`
`Reply to 06-25-2019 OA
`
`— 16 -
`
`Murase et al.
`
`Appl. No. 16/075,828
`
`2014, 306:59-66. (A copy of Choi is submitted as document NPL9 in the accompanying
`
`IDS.)
`
`It should be recalled that melanocytes produce melanosomes. The melanosomes are
`
`transferred from melanocytes to neighboring keratinocytes, thus pigmenting those
`
`keratinocytes. Therefore, conditions that promote the transfer of melanosomes into
`
`keratinocytes are desired if one wants to darken skin or hair keratinocytes.
`
`Choi examined melanosome uptake in differentiating and in proliferating
`
`keratinocytes. In the abstract, Choi summarizes the results stating:
`
`o
`
`“melanosome uptake was higher in differentiating keratinocfles compared to
`
`non-differentiating keratinocytes”; and
`
`o melanosomes inhibit keratinocyte proliferation.
`
`These effects of melanosomes are the opposite of the effects of proguanil as reported
`
`by Hue. The combination of the cited art does not suggest or lead to the conclusion that
`
`darkening skin or hair is a natural result or characteristic feature that flows from
`
`administering proguanil. In fact, Hue’s teachings are inconsistent with an expectation of
`
`darkening skin or hair because Hue teaches proguanil will “limit and/or delay” the passage
`
`of keratinocyte cells into the differentiation phase and maintain them in the proliferative
`
`stage — thus opposing the effects that melanosomes would be inducing in the keratinocyte
`
`population.
`
`The results of two competing mechanisms on the keratinocytes population,
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`Reply to 06-25—2019 OA
`
`- l7 -
`
`Murase et a1.
`Appl. No. 16/075,828
`
`that is, the presence of both a glycolysis inducer such as pro guanil and the presence of
`
`melanosomes could not have been predicted.
`
`The discussion above shows that the artisan did not have a reasonable expectation of
`
`success in reaching an invention in which the skin or hair is darkened by administration of
`
`proguanil based on the teachings of Hue, Van Neste and Chulay. The rational underpinning
`
`of the articulated reasoning presented by Examiner does not support the legal conclusion of
`
`obviousness. The evidence of record, and above, establishes that the invention, even if
`
`characterized as a combination of familiar elements, yields more than predictable results.
`
`Primafacie obvious is not established, or, if it has been established, it has been
`
`overcome. Accordingly, this rejection can be Withdrawn.
`
`Conclusion
`
`It is respectfially believed this application is now in condition for allowance.
`
`Early notice to this effect is earnestly solicited.
`
`It is not believed that extensions of time
`
`or additional fees are required, beyond those that may otherwise be provided for in
`
`accompanying documents. Any required fees are hereby authorized to be charged to our
`
`Deposit Account No. 19-0036. If additional extensions of time are necessary to prevent
`
`abandonment of this application, then such extensions of time are hereby petitioned under
`
`37 C.F.R. § 1.136(a).
`
`2537.1600002/MAC
`
`

`

`Amend fd: 11-13-2019
`Reply to 06-25-2019 OA
`
`- 18 -
`
`Murase et al.
`Appl. No. 16/075,828
`
`Respectfully submitted,
`
`STERNE, KESSLER, GOLDSTEIN & Fox P.L.L.C.
`
`Michele A. Cimbala
`
`’“" L“
`
`Attorney for Applicant
`Registration No. 33,851
`
`Date: Warm/W 23% § 11»; 2.23 g a
`1100 New York Avenue, NW.
`Washington, DC. 20005—3934
`(202) 371-2600
`
`l36ll701.1
`
`2537‘1600002/MAC
`
`

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