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 .
Information Disclosure Statement
The information disclosure statements (IDS) submitted on Nov. 17, 2025 and Dec. 17, 2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Priority
This Application is a 371 of PCT/EP2021/082294, filed Nov. 19, 2020 and claims provisional benefit of U.S. Provisional Application nos. 63/115,749 and 63/211,809, filed Nov. 19, 2020 and June 17, 2021, and foreign priority to EP20209467.8, filed Nov. 24, 2020 with the EPO.
Claim Status
Claims 158-159 and 174-175 are currently pending and subject to examination.
Withdrawn Rejections – Overcome by Applicant’s Cancellation of the Claims
Claims 160-173 were cancelled, rendering the rejection of these claims moot.
Claim Objections – Necessitated by Amendment
Claim 175 objected to because of the following informalities: “arimoclmol” in line 1. Furthermore, the appropriate conjunction between the second to last and last elements in the Markush group is “and” not “or”. Appropriate correction is required.
Claim Rejections – 35 USC § 112(b) – New Grounds of Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(b):
“(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.”
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
“The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.”
Claims 174 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 174 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: chiral resolution of the compound of formula I.
Claim 174 recites: The process of claim 158, wherein the arimoclomol having formula I is present in a stereoisomeric quantity of greater than 98% N-{[(2R)-2-hydroxy-3-piperidin-1- ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide.
Claim 158 claims a process for preparing a compound of formula I:
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. This compound is racemic and is not enantiomerically pure without performing chiral separation steps as detailed in the specification. Claim 158 corresponds to step 1 on page 1 of the specification:
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Specification, p. 1.
Chiral separation begins in step 2:
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Specification, p. 2.
The specification explicitly states that the chiral purity is the result of step 2:
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Id.
Therefore, claim 174 omits the essential chiral purification steps necessary to obtain arimoclomol having formula I present in a stereoisomeric quantity of greater than 98% N-{[(2R)-2-hydroxy-3-piperidin-1- ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide and one of ordinary skill in the art would not know how arimoclomol having formula I is present in a stereoisomeric quantity of greater than 98% N-{[(2R)-2-hydroxy-3-piperidin-1- ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide.
Claim Rejections - 35 USC § 112(d) – New Grounds of Rejection Necessitated by Amendment
The following is a quotation of 35 U.S.C. 112(d):
“(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
“Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.”
Claims 175 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 175 fails to further limit the subject matter of claim 174 because it is merely directed towards an intended use of the product, which does not limit the process of making the product. The intended use in a pharmaceutical composition has no impact on the process of making the arimoclomol of formula I.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103 – Previously Presented
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, 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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The rejection of claim(s) 158-159 under 35 U.S.C. 103 as being unpatentable over Urogdi et al. (US 7,126,002 B2, Published Oct. 24, 2006) is maintained.
Response to Arguments
The Applicant argues that the instant invention differs from Urogdi in that ORZY-01A (the compound of formula V) is not isolated by the Applicant and Urogdi Example 5 synthesizes arimoclomol with high purity by starting with either the R or S isomer of the compound of formula V (Remarks, p. 8). These arguments were fully considered but are not persuasive. The Applicant uses a substantially identical process to Urogdi. Urogdi. Both the Applicant and Urogdi use racemic arimoclomol as starting material, react it with tartaric acid for chiral resolution and then react with citric acid to form the preferred citrate salt, as shown in the rejection below.
Reiterated Rejection
Claim(s) 158-159 is/are rejected under 35 U.S.C. 103 as being unpatentable over Urogdi et al. (US 7,126,002 B2, Published Oct. 24, 2006).
Claim 158 is directed towards a process for preparing
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comprising:
Mixing a compound of formula (I)
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with a compound of formula (II)
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in a polar protic solvent or a mixture of polar protic solvents and at a temperature between about 70°C to 100°C;
Wherein the intermediate formed during step 1 is then reacted with sodium nitrite in a solvent that is a chlorinated hydrocarbon, a mixture containing at least one chlorinated hydrocarbon or a combination thereof and at a temperature of about 0°C to 15°C.
Urogdi discloses a substantially identical process comprising similar steps 1 and 2:
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Urogdi, Figs. 1-5;
“FIG. 1 shows the compound of formula (I): N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboxamidine.
FIG. 2 shows the compound of formula (II): 3-cyano-pyridine-1-oxide.
FIG. 3 shows the compound of formula (III): 3-pyridine-amidoxim-1-oxide.
FIG. 4 shows the compound of formula (IV): 2-hydroxy-4-azoniaspiro[3,5]nonane chloride.
FIG. 5 shows the compound of formula (V): N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride.”
Urogdi, Specification, col. 1-2;
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Urogdi, Specification, col. 5;
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Urogdi, Specification, col. 5-6.
The above example 3 is substantially identical to step 1. Urogdi teaches that
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is reacted with
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in a mixture of polar protic solvents, water and ethanol, at reflux temperature which must be between 78°C and 100°C, which are the boiling points of ethanol and water respectively.
The above example 4 is substantially identical to step 2. Urogdi teaches that the intermediate prepared during step 1 is reacted with sodium nitrite in an aqueous solution alkalified with sodium hydroxide at a temperature -5°C to 0°C and less than 7°C and then extracted three times with dichloromethane.
The temperatures of -5°C to 0°C and less than 7°C overlaps with the range of 0°C to 15°C and therefore the claimed temperature range is prima facie obvious.
While Urogdi does not teach that the reaction is carried out in a mixed solvent of water and dichloromethane as in the instant application, one of ordinary skill in the art would have a reasonable expectation of success to carry out the reaction in a mixed solvent of water and dichloromethane because Urogdi teaches extraction with dichloromethane. Dichloromethane and water are immiscible and therefore products and reactants can be separated in different liquid layers.
Therefore, claim 158 was prima facie obvious at the time of filing.
Claim 159 is directed towards a process for preparing arimoclomol citrate:
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comprising the steps of: performing the process of claim 158 to provide
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, precipitating
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with dibenzoyl-L-tartaric acid to provide:
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reacting
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with at least one base to form the free base of
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and precipitating the free base of
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with citric acid to provide arimoclomol citrate.
One of ordinary skill in the art would have a reasonable expectation of success to perform the claimed process because Urogdi teaches a process which is substantially identical to the claimed process wherein the product from Urogdi example 4 is used as a substrate in example 5, reacted with dibenzoyl-L-tartaric acid to provide the dibenzoyl-L-tartrate salt of the compound, which is reacted with potassium carbonate to form the free base, which is reacted with citric acid to provide arimoclomol citrate :
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Urogdi, Specification, col. 6-7;
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Urogdi, Specification, col. 7.
Therefore, claim 159 was prima facie obvious at the time of filing.
Claim Rejections - 35 USC § 103 – New Grounds of Rejection Necessitated by Amendment
Claim(s) 158-159 and 174 is/are rejected under 35 U.S.C. 103 as being unpatentable over Urogdi et al. (US 7,126,002 B2, Published Oct. 24, 2006), as applied to claims 158-159 above, and further in view of Atkinson et al. (Organic & Biomolecular Chemistry, Vol. 15, 2017, p. 9794-9799) (of record).
The rejection of claims 158-159 are incorporated herein by reference.
Claim 174 recites: The process of claim 158, wherein the arimoclomol having formula I is present in a stereoisomeric quantity of greater than 98% N-{[(2R)-2-hydroxy-3-piperidin-1- ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide.
Urogdi teaches that N-{[(2R)-2-hydroxy-3-piperidin-1- ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide can be obtained with an optical purity of at least 96%:
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Urogdi, Specification, col. 9;
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Urogdi, Specification, col. 2.
An optical purity of at least 96% is so similar to at least 98% that one of ordinary skill in the art would have a reasonable expectation of success to obtain an optical purity of at least 98%.
For example, Atkinson uses the method of Urogdi and teaches N-{[(2R)-2-hydroxy-3-piperidin-1- ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide having an optical purity of at least 98%:
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Atkinson, p. 9794-9795.
Therefore, claim 174 was prima facie obvious at the time of filing.
Claim(s) 158-159 and 174-175 is/are rejected under 35 U.S.C. 103 as being unpatentable over Urogdi et al. (US 7,126,002 B2, Published Oct. 24, 2006), in view of Atkinson et al. (Organic & Biomolecular Chemistry, Vol. 15, 2017, p. 9794-9799) (of record), as applied to claims 158-159 and 174 above, in view of “Arimoclomol prospective double blind, randomised, placebo-controlled study in patients diagnosed with Niemann Pick disease type C” (sponsored by Orphazyme A/S, EudraCT Number: 2015-004438-93, EU Clinical Trials Register, Published March 11, 2016, p. 1-7) (herein “Orphazyme”) (of record, cited in the prior office action).
The rejection of claims 158-159 and 174 above is incorporated herein by reference.
Claim 175 recites: “The process of claim 174, wherein the arimoclmol having formula I is used to make a composition comprising an amount of arimoclomol citrate selected from the group consisting of 47 mg, 62 mg, 93 mg, or 124 mg.”
Urogdi teaches that the optically active enantiomers of arimoclomol are valuable active ingredients in pharmaceutical products (Urogdi, Specification, col. 1).
While Urogdi does not teach a pharmaceutical composition comprising 47 mg, 62 mg, 93 mg, or 124 mg of arimoclomol citrate, one of ordinary skill in the art would have a reasonable expectation of success to use the highly optically pure arimoclomol to make a composition comprising an amount of arimoclomol citrate selected from the group consisting of 47 mg, 62 mg, 93 mg, or 124 mg because similar compositions are commonly known in the art.
For example, Atkinson teaches a pharmaceutical composition comprising
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(Atkinson, Scheme 1, p. 9795), with an optical purity of at least 99%:
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Atkinson, col. 2, p. 9798.
Atkinson demonstrates in vivo pharmacokinetic data in mice for this composition:
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(Atkinson, Table 2, p. 9797).
For example, Orphazyme teaches unit dosage forms for use in humans comprising 50 mg or 100 mg of arimoclomol citrate, which are equivalent to 47 mg or 93 mg of the free base:
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Orphazyme, p. 3.
These amounts are so similar to the claimed amounts that a prima facie case of obviousness exists (In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists… Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. (MPEP 2144.05)).
Therefore, claim 175 was prima facie obvious at the time of filing.
Given the above teachings, the invention as a whole was prima facie obvious at the time of filing.
Conclusion
No claim is found to be allowable.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any extension fee pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HEATHER DAHLIN whose telephone number is (571)270-0436. The examiner can normally be reached 9-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Lundgren can be reached on (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/HEATHER DAHLIN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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