DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application is a national stage application under 35 U.S.C. § 371 of
International Application No. PCT/EP2021/076980, filed 09/30/2021, which claims the priority benefit of European Patent Application No. EP20306141.1, filed 10/01/2020.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on dates 03/09/2023, 03/15/2023, 05/16/2023, 11/08/2023, 02/15/2024, 07/26/2024, 09/05/2024, 01/13/2025, and 06/03/2025 were filed in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Applicant has submitted jumbo information disclosure statements without specifically pointing out where relevant material can be found in each of the references. As a result, the examiner has considered said information disclosure statements to the extent permitted by the allotted time for such consideration and consistent with the MPEP.
Status of the Application
Claims 1-8 and 10-18 are pending. Claims 1-8 and 10-14 are currently amended. Claims 15-18 are new. Claim 9 has been cancelled. Claims 1-8, and 10-18 are examined herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (page 42). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claims 3-6 and 17-18 are objected to because of the following informalities: x is defined as being 1.4, 1.5, 1.6, 2.9, and 3.1 without clearly defining whether those values are ratios, equivalents or mg or some other value as the claims are currently written. See MPEP 2111.01(II) Appropriate correction is required.
Claims 12-14 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 10 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating a neurodegenerative disease wherein a dysfunction of the Tau protein phosphorylation is observed, does not reasonably provide enablement for preventing any or every neurodegenerative disease wherein a dysfunction of the Tau protein phosphorylation is observed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), the factors to be considered in determining whether a disclosure meets the enablement requirement are as follows:
1. The nature of the invention
2. The state of the prior art
3. The predictability or lack thereof in the art
4. The amount of direction or guidance present
5. The presence or absence of working examples
6. The breadth of the claims
7. The quantity of experimentation needed, and
8. The level of skill in the art
The Nature of the Invention and Breadth of the Claims
Claim 10 is drawn to a method for treating a neurodegenerative diseases wherein a dysfunction of the Tau protein phosphorylation is observed, comprising administering an effective amount of the succinate salt of N-(3-(4-(3-(diisobutylamino)propyl) piperazin-1-yl)propyl)-1 H-benzo[d]imidazol-2-amine, to a patient in need thereof.
The State of the Prior Art and the Predictability or lack thereof in the art
“Succinate salts of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-lH-benzo[d]imidazol-2-amine provide stable powders, which polymorphs have a high degree of crystallinity, are very stable, non-hygroscopic and obtainable in a good yield in a one-pot salt formation/ direct crystallization from the free base. The succinate salts satisfy to the demanding criteria set forth above and are especially suitable for use as an API in solid formulations like capsules.” (Specification pg. 4, lines 28-33) “succinate salts of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-IH-benzo[d]imidazol-2-amine and pharmaceutically acceptable solvates thereof are useful in rectifying the metabolism of the Tau protein in particular by inhibiting pathological Tau protein phosphorylation. Tau protein (a.k.a. Microtubule Associated Protein Tau - MAPT) interacts with tubulin to stabilize microtubules and promote tubulin assembly into microtubules, microtubule stability being controlled by isoforms and phosphorylation.” (specification pg. 11, lines 4-10).
However, none of the prior art compounds are reported to completely prevent the onset of any or every preventing neurodegenerative diseases and all diseases wherein a dysfunction of the Tau protein phosphorylation is observed by administering a succinate salt of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-IH-benzo[d]imidazol-2-amine.
It is noted that pharmacological activity in general is a very unpredictable area. In cases involving physiological activity, such as the instant case, “the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.” See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Guidance Present and Presence/Absence of Working Examples
The only guidance disclosed by the specification regarding prevention of a neurodegenerative disease with a dysfunction of the Tau protein phosphorylation, by administering an effective amount of the succinate salt of N-(3-(4-(3-(diisobutylamino)propyl) piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine is found on pages 13-16 and 18.
“Therefore, due to their abilities to rectify the metabolism of the Tau protein, to increase levels of PGRN neurotrophic factor and to reduce neuroinflammation as described above, the succinate salts of the invention and solvates thereof are useful as a medicament, in particular for treating or preventing neurodegenerative diseases, including tauopathies and Parkinson's disease. The succinate salts of the invention are thus useful as a medicament, in particular for treating or preventing neurodegenerative diseases and all diseases wherein a dysfunction of the Tau protein phosphorylation is observed, including but not limited to tauopathies.
In one embodiment, the invention concerns a succinate salt of the invention for use in treating or preventing of a disease selected from neurodegenerative diseases and diseases wherein a dysfunction of the Tau protein phosphorylation is observed, including but not limited to tauopathies”
The specification does not provide any guidance for determining which particular patient population would be susceptible to developing neurodegenerative diseases. Also lacking are data showing that the compounds are capable of treating all or every neurodegenerative diseases. The
results of effects of N-(3-(4-(3-(diisobutylarnino)propyl)piperazin-1-yl)propyl)-lH-benzo[d] imidazol-2-arnine sesqui-succinate salt Form 1 showing survival (A), the neurite network (B) and on Tau phosphorylation (ATl00) (C) in figure 25 and activation of microglial cells (A) and PGRN release (B) in cortical neurons in figure 26 indicates solely that the compounds can treat the claimed diseases/disorders dependent on Tau phosphorylation, not prevent them.
The quantity of experimentation needed, and level of skill in the art
In order to treat every or all neurodegenerative diseases wherein a dysfunction of the Tau protein phosphorylation is observed one would need to precisely identify those subjects with the disease or disorder who are likely to respond to treatment, administer the claimed invention, and demonstrate that administration directly resulted in the subject overcoming the disease or disorder. One skilled in the art would conclude that the guidance in the specification would not have taught one skilled in the art how to treat every or all neurodegenerative disease with a dysfunction of the Tau protein phosphorylation using the compounds of formula (I), because there is no guidance for how to select a patient population and no evidence that the claimed compounds can broadly treat every neurodegenerative disease with a dysfunction of the Tau protein phosphorylation. Given the lack of guidance in the specification and the lack of success in the prior art, one skilled in the art would find that preventing the claimed diseases or disorders would require experimentation that is unduly burdensome. This rejection may be overcome by cancelling claim 10, or amending the limitations of the claim.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sergeant (U.S. PAT. 9,044,478 B2) in view of Hamblin (U.S. PAT. 8,993,576 B2).
The instant claims are directed to a succinate salt of N-(3-(4-(3-(diisobutylamino)propyl) piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine CAS RN 615539-20-3.
Sergeant et al. teach the oxalate salt form synthesis of formula II as N-(3-(4-(3-(Diisobutylamino) propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine CAS RN 615539-20-3 which is equivalent to the structural limitations of the compound of formula II of the instant claims (col. 22, line 33). Sergeant discloses “The use of derivatives of formula (I) is more particularly intended for the treatment of neurodegenerative diseases or related neurodegenerative diseases” (col. 3, lines 16-18). Sergeant teaches suitable addition salts may be formed with organic and inorganic acids and that the compounds of formula (I) and or salts thereof may form solvates (e.g. hydrates) and the invention includes all such solvates (col. 4, lines 1-5). Sergeant also discloses a pharmaceutical composition comprising a compound of formula II and an excipient (col. 51, lines 35-44).
However, Sergeant et al. provides scope for a succinate salt form of the compound of N-(3-(4-(3-(Diisobutylamino) propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine but does not explicitly disclose a succinate salt version of the compound of formula II in an example.
Hamblin et al. teach a succinate salt version of a compound of formula II (compound A) (col. 9, lines 65-67). Hamblin also discloses the polymorphs and salts of the invention may be useful in the treatment of disorders wherein the underlying pathology is (at least in part) attributable to inappropriate PB-kinase activity, such as neurodegenerative diseases. Hamblin also discloses “In a further embodiment, the hemi succinate salt of Compound A may have stability, for example in formulations containing excipients such as lactose, and solubility properties which make it particularly suitable for administration by inhalation.”(col. 9, lines 24-29).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to use a succinate salt version of N-(3-(4-(3-(Diisobutylamino) propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine (applicants formula II) in a pharmaceutical composition with an excipient because Sergeant disclosed all solvate forms of formula II. A skilled artisan would have selected a succinate salt version of the compound of formula II because Hamblin disclosed a succinic salt version of compound A was singled out for stability in formulations containing excipients. Given the disclosures of Sergeant regarding the different salt versions compound of formula II in the treatment of neurological diseases, a person of ordinary skill would have looked towards identifying which salts provide desirable properties in a pharmaceutical composition which is also used in treating neurological diseases and arrived at Hamblin’s use of a succinate salt in a composition which can be used to treat neurodegenerative diseases. See MPEP 2144.05 (II).
A person of ordinary skill in the art would have been motivated to combine the teachings of the salt versions of N-(3-(4-(3-(Diisobutylamino) propyl)piperazin-1-yl)propyl)-1H-benzo [d]imidazol-2-amine from Sergeant with the disclosures of a succinate salt form providing stability to pharmaceutical compositions containing an excipient by Hamblin because a skilled artisan would have sought to improve the stability of pharmaceutical compositions using salt forms known in the art to induce favorable characteristics in a pharmaceutical composition. See MPEP 2143(I)(B). Therefore a skilled artisan would have had a reasonable expectation of success in combining Sergeant and Hamblin to provide a pharmaceutical composition of a succinate salt of N-(3-(4-(3-(Diisobutylamino) propyl)piperazin-1-yl)propyl)-1H-benzo[d] imidazole-2-amine.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Burlet (WO 2014/102339 Al), and further in view of Mirmehrabi (US 2008/0262008 Al).
The instant claims are directed to a process for making a crystalline forms form of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine sesquisuccinate salt comprising the steps of:
step 1: dissolving N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine in an organic solvent;
step 2: heating the reaction medium to temperature B, wherein temperature B is defined as a temperature comprised between 30 and 50 °C;
step 3: adding a substantially equimolar amount of succinic acid;
step 4: stirring the reaction medium at temperature B for 0.25 to 4 hours;
step 5: temperature cycling the reaction medium between temperature A and temperature B in 2 to 4-hour cycles for 10 to 30 hours wherein temperature A is defined as a temperature comprised between 0 and 10°C;
step 6: cooling down the reaction medium to temperature A;
step 7: filtering the reaction medium at temperature A;
step 8: washing the filter cake with said organic solvent at temperature A;
step 9: drying the filter cake at a temperature between 30 and 50°C.
Burlet et al. teach in addition to the disclosures above, the unexpected findings that sulphate salts of N-(3-( 4-(3-( diisobutylamino)propyl)piperazin-1-yl)propyl)- 1H-benzo[d] imidazol-2-amine provide stable free flowing crystalline powders which are not hygroscopic (page 3, lines 17-20). Burlet teaches synthesis of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)lH-benzo[d]imidazol-2-amine, 1 eq sulphate salt in example 3 wherein ethanol is used to dissolve N-(3-(4-(3-( diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d] imidazol-2-amine by heating up to 70 °C and equimolar quantity of a 0.5 M aqueous solution of sulphuric acid was added to fully dissolve the compound before drying re-dissolving and cooling to room temperature (example 3, page 24). Burlet also teaches in example 4 wherein crystallization was observed within a solution of ethanol and N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d]imidazol-2-amine upon the first drying before subsequently stirring in methanol and IPA for a combined total of 45 minutes and allowed to cool to room temperature (page 24, lines 17-33). Burlet also discloses table 4 wherein the free base and chloride, bromide, acetate , fumarate, tartrate, malate, oxalate and sulphate salt physical forms of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d]imidazol-2-amine are disclosed (table 4, page 25).
However, Burlet et al. fail to disclose a method of forming a succinate salt crystallized form of a compound of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d] imidazol-2-amine.
Mirmehrabi et al. teaches form I of a hemi-succinate salt of compound 3 prepared by mixing 2 molar equivalents of the free base 3 in an acetone: water solvent (5:2 by volume) and one molar equivalent of succinic acid and heating the mixture to 50-55° [0074]. Mirmehrabi also discloses “The present invention provides methods for preparing and manufacturing forms and polymorphs of crystalline salts of compounds of formulas I or II that have acceptable water solubility, which also improves corresponding bioavailability when ingested by a mammalian patient. As one example, the water solubility of the succinate salts of compound 3 is 1.1 mg/mL.” [0083] Mirmehrabi also teaches the X-ray crystal diffraction form of Mono-Succinate Salt of N-(3-(dimethylamino) propyl)-4-( 4-(3-fluoro-4-methoxypheny l)pyrimidin-2-ylamino)benzene sulfonamide in example 1 wherein “[t]he slurry of compound 3 was heated to ~50-55° C. Succinic acid (382 mg) was added. The mixture was stirred for 10 minutes and 2.5 mL acetone was added. The mixture was cooled to room temperature and 12 mL acetone was added and the mixture stirred for 30 minutes, then filtered and dried at 50° C” [0119].
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the instant application, to form a crystalline, succinate salt version of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d] imidazol-2-amine by dissolving the compound in an organic solvent, applying heat to the mixture up to 70 °C by adding an equimolar amount of succinic acid while stirring the mixture and cycling through heating and cooling periods before lastly filtering and washing the remaining filter cake as taught by Burlet and Mirmehrabi. A skilled artisan would have applied the knowledge disclosed by Burlet in regards to the free base, chloride, bromide, acetate, fumarate tartrate, malate, oxalate and sulfate salt forms of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d] imidazol-2-amine and combined it with the disclosures of forming crystalline succinate salt forms by Mirmehrabi because of his disclosures of improved bioavailability when ingested by a mammalian patient.
It is noted that a temperature range of 30-50°C is encompassed by heating to 70°C. See MPEP 2144.05(I).
A person of ordinary skill in the art would have been motivated to combine Burlet’s teachings of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d] imidazol-2-amine salt forms and crystallization methods with Mirmehrabi’s disclosures of improved bioavailability of compounds when administered as a crystallized succinic salt form because of the reasonable expectation of success in forming an improved crystalline form of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl)-lH-benzo[d] imidazol-2-amine as a succinic salt form because of Burlets teachings of N-(3-(4-(3-(diisobutylamino) propyl)piperazin-1-yl)propyl) -lH-benzo[d] imidazol-2-amine to have multiple salt forms and would have therefore been prima facie obvious toa skilled artisan to try to form a crystalline succinic salt form especially when combined with Mirmehrabi’s teachings that multiple succinate salt forms are possible of the same compound by substituting succinic acid for another acid during synthesis. See MPEP 2143 and 2144.05.
Claims 10-16 are rejected under 35 U.S.C. 103 as being unpatentable over Sergeant (U.S. PAT. 9,044,478 B2) in view of Hamblin (U.S. PAT. 8,993,576 B2) and further in view of Burlet (WO 2014/102339 Al).
The instant claims are directed to a method for treating a disease selected from neurodegenerative diseases and diseases wherein a dysfunction of the Tau protein phosphorylation is observed, comprising administering an effective amount of the succinate salt according to claim 1 or of a pharmaceutically acceptable solvate thereof, to a patient in need thereof.
The succinate salt form of N-(3-(4-(3-(Diisobutylamino) propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine in claims 1-7 is discussed above by Sergeant and Hamblin.
Sergeant et al. teach “The use of derivatives of formula (I) is more particularly intended for the treatment of neurodegenerative diseases or related neurodegenerative diseases where APP and its catabolic products are a cause or a risk factor for the development of the pathology. The derivatives of formula (I) can be used for treatment or prevention. Among neurodegenerative diseases Alzheimer’s disease, Down syndrome, amyloid angiopathies, dementia with Lewy bodies and Parkinson’s disease may be cited.” (col. 3, lines 16-24). Sergeant also discloses correcting the metabolic cleavage of the C-terminal part of APP (amyloid precursor protein) and/or APP-like proteins and how APP concerns pathologies including tauopathies (col. 3, lines 42-50).
However, Sergeant et al. fail to disclose an explicit example in which a compound of formula II is used to treat a neurodegenerative disease including Parkinson’s, or a tauopathy.
Burlet et al. teach the compound of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-l-yl)propyl)-lH-benzo[d]imidazol-2-amine (formula I) and its usefulness for the treatment of neurodegenerative diseases.( page 1, lines 12-23). Burlet teaches a compound of formula I and pharmaceutically acceptable solvates useful for altering the pathological Tau protein phosphorylation (page 6, line 29 through page 7, line 6). Burlet also discloses a sulphate salt of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine for use in treating neurodegenerative diseases including Alzheimer's disease, dementia with Lewy bodies (DLB), amyotrophic lateral sclerosis (ALS) with frontotemporal dementia, inclusion body myopathy with Paget's disease of bone and/or frontotemporal dementia (IBMPFD), frontotemporal lobar degeneration, and Parkinson's disease, amyloidopathies including amyloid angiopathies, tauopathies including frontotemporal dementia with Parkinsonism linked to chromosome 17 (page 8, lines 18-26).
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art, prior to the effective filing date of the claimed invention, to administer the succinate salt form of N-(3-(4-(3-(diisobutylamino)propyl)piperazin-1-yl)propyl)-1H-benzo[d]imidazol-2-amine (applicants formula II) to a patient with a neurodegenerative disease including Parkinson’s or a tauopathy to a patient in need thereof because Sergeant, Hamblin and Burlet all disclose the compound of formula II of the instant claims is a compound for treatment of neurodegenerative diseases. Additionally, a skilled artisan would have been inclined to select a succinate salt form of formula II given Hamblin’s disclosure of a succinate salt to provide stability in a pharmaceutical composition.
A person of ordinary skill in the art would have been motivated to use the disclosures of Sergeant, Hamblin and Burlet’s teachings of treating a neurodegenerative disease to form a pharmaceutical composition of the succinate salt form of formula II for administration to a patient with a neurodegenerative disease. A person of ordinary skill would have had a reasonable expectation of success in treating a tauopathy, Parkinson’s or other degenerative disease in a patient in need thereof with the succinate salt form of compound of formula II given the strong evidence provided by the prior art to that effect. See MPEP 2144.05 (II).
Conclusion
Claims 1-8, and 10-16 are rejected. Claims 17 and 18 are objected to.
Correspondence
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/E.V./Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623