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 .
Claim Status
Claims 1, 2, 4, 5, 8-10, 12, and 15 were amended, claim 3 was canceled, and claims 19-21 were newly added in the response filed 1/23/2026. Claims 1, 2, and 4-21 are pending, claims 14 and 16-18 stand withdrawn, and claims 1, 2, 4-13, 15, and 19-21 are under examination.
Election/Restrictions
On p. 10 of the response filed 1/23/2026, the Applicant refers to rejoinder of the withdrawn claims under MPEP 821.04. In response, the Examiner notes that the Applicant has elected process claims, and not product claims. Should the process under examination for making a compound be indicated as being allowable, the withdrawn claims will not be rejoined. Claims 14 and 16 are product-by-process claims and claims 17-18 are directed toward a method of using a product produced by the reaction under examination. Also see MPEP 2113.
Withdrawn Objections
The amendments and response filed on 1/23/2026 are persuasive to overcome the objections of record on p. 2-3 of the OA dated 7/25/2025. Therefore, all objections are withdrawn.
Modified Claim Rejections - 35 USC § 112(b)-Necessitated by Amendment
The amendments filed on 1/23/2026 are persuasive to overcome the rejection of record on p. 4-5 of the OA dated 7/25/2025. Therefore, the rejections are withdrawn. However, the amendments have introduced new issues into the claims which are addressed below.
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 1, 4, 7, 9, 10, and 20 are 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 1, step (i), was amended to recite “contacting 2-acetyloxypropanoyl chloride (APC) with a mixture comprising a compound of Formula (I) in a solvent system comprising pyridine, wherein the amidation and subsequent hydrolysis are carried out in one vessel without isolation of the amidation product to generate a compound of Formula (II),”.
The underlined limitation above was newly introduced into the independent claim on 1/23/2026. This limitation is indefinite because it is not clear if a hydrolysis step is required in step (i) or not. The claim reads as if a hydrolysis step is required, however, the product formed from the reaction, the following formula (II):
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teaches that variable R can be a protecting group. The specification as filed only contemplates one hydrolysis step which produces a compound of instant formula (III), wherein all R are H. Also see claim 2. Therefore, it is unclear if the “subsequent hydrolysis” is a required or optional step in claim 1.
Claims 4, 7, 9, 10, and 20 are rejected for depending from claim 1 and failing to cure the deficiency.
Claim Rejections - 35 USC § 112(a)-Necessitated by Amendment
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 20 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Newly introduced claim 20 recites “the process of claim 4, wherein the solvent system consists essentially of pyridine and acetonitrile, with a pyridine : acetonitrile volume ratio between 1:1 and 3:1”. At the top of p. 10 of the response filed 1/23/2026, the Applicant indicates that “support for the amendments made can be found throughout the specification as filed”. The disclosure as filed does not recite any “volume ratio”. The pyridine : acetonitrile solvent system is present in examples 1-4, however, only masses (g) of each are specified. The Applicant additionally provides the concentration of the pyridine in mmol. However, the volumes are not provided. Therefore, it is unclear where the Applicant has support for the newly introduced volume ratio between 1:1 and 3:1, and the limitation appears to constitute new matter.
New Claim Rejections - 35 USC § 112(d)-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.
Claim 11 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 11 does not further limit claim 2, which depends from newly amended claim 1, containing the limitation “…are carried out in one vessel without isolation”. 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.
Withdrawn Claim Rejections - 35 USC § 102
The Applicant limited the product of the process of independent claim 15 to one wherein R is
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Therefore, the 35 USC 102 rejections of claim 15 as being anticipated by Barge (WO 2018/104228), De Santis (US 6262303), and Savac (GB1472050A) on p. 5-8 of the OA dated 7/25/2025 are withdrawn. Barge and De Santis only teach compounds wherein R is H and Savac does not explicitly teach compounds of Formula (II) wherein all R are the claimed protecting group.
Modified Claim Rejections - 35 USC § 103-Necessitated by Amendment
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action. See p. 9-15 of the OA dated 7/25/2025 regarding the rejection of record.
Due to the 35 USC 112(b) issues above, it is not clear if the hydrolysis step is required in claim 1, and if so, what the product is. Therefore, in the interests of compact prosecution, for the purposes of applying prior art, the hydrolysis step is interpreted as being optional in claim 1.
Claim(s) 1, 4, 7, 9, and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Savac (GB1472050A, published on 4/27/1977, of record in the IDS filed on 12/28/2022) in view of Speck (US 4364921, published on 12/21/1982, of record).
Applicant Claims
A process for the preparation of a compound of Formula (II):
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comprising contacting 2-acetyloxypropanoyl chloride (APC) with a mixture comprising a compound of Formula (I):
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and pyridine, wherein the amidation and subsequent hydrolysis are carried out in one vessel without isolation of the amidation product to generate a compound of Formula (II).
Determining the Scope and Content of the Prior Art (MPEP §2141.01)
The teachings of Savac were discussed in the preceding rejection and are incorporated by reference herein.
Regarding the amidation step, the Savac compound that is reacted with L-2-acetoxypropionyl/propanoyl chloride, referred to as “5-amino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide)”, corresponds to the compound of instant formula (I) and the product of that reaction, before being contacted with NaOH, corresponds to the compound of instant formula (II), wherein each R is one of the claimed options. See step B) of example 7. Savac further teaches that the reaction is carried out in the presence of dimethylacetamide (DMA) as a solvent. Savac teaches that preferred solvents include aprotic solvents, which encompasses all of those recited in claim 4. See p. 9, lines 4-9. Savac teaches that the reaction is carried out by adding the acid chloride (APC) to a mixture of the compound of instant formula (I) and solvent at a temperature of about 0 to 5°C and then warming the reaction to room temperature (about 20-25°C) to stand overnight. Both of these temperatures overlap with or fall within the range of claims 7 and 10. See Step B) of example 7 and MPEP 2144.05.
Speck teaches novel triiodinated isophthalic acid diamides of the following formula:
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. See abstract. These compounds are analogous to those of Savac. Speck teaches that the compounds are obtained by one of three methods.
In method a), the process comprises reacting a compound of Formula (IIA):
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with a base of formula (III):
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, and then a base of formula (IV):
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.
In method b), a compound of Formula (IIB) is N-acylated, preferably with an acid chloride:
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.
In method c), a compound of formual IIC is O-acylated:
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with a base of formula (IV). See col. 2, line 56-col. 4, line 15.
Speck teaches that when method b) is employed, that the reaction is carried out in an inert solvent, including pyridine, dimehtylacetamide (DMA), or dimethylformamide (DMF) and similar compounds. See col. 5, lines 39-51. Speck teaches that these bases can also be used as proton acceptors for neutralizing HCl produced from the amidation reactions. See Speck also teaches that acceptable amidation solvents include water, dioxane, tetrahydrofuran (THF), DMF, DMA, hexametapol, and similar compounds and mixtures thereof. See col. 4, line 39-col. 5, line 2.
Ascertainment of the Difference Between Scope of the Prior Art and the Claims (MPEP §2141.02-03)
Regarding claims 1 and 4, Savac does not explicitly teach that the amidation reaction is carried out in the presence of pyridine or in one of the claimed solvents.
Additionally, as indicated above, the “subsequent hydrolysis” limitation in claim 1 is interpreted as being optional.
Finding of Prima Facie Obviousness Rationale and Motivation (MPEP §2142-2143)
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Savac and Speck to arrive at the instantly claimed process with a reasonable expectation of success before the effective filing date of the claimed invention. A person of ordinary skill would have been motivated to replace or combine the DMA solvent of Savac with pyridine because Speck explicitly teaches that pyridine and DMA are equivalents in the reaction. Therefore, replacing one with another will predictably lead to the claimed process for producing compounds of formula (II) and (III). A person of ordinary skill would have been further motivated to include one of the solvents of claim 4 in the process of Savac because Speck teaches that the claimed solvents can be used to carry out analogous amidation reactions. Speck explicitly teaches that at least dioxane and tetrahydrofuran (THF) can be substituted or combined with DMF and/or DMA in amidation reactions. Also see MPEP 2143(A) and (B) and MPEP 2144.07.
Further regarding claim 9, Savac teaches that the APC is added to a mixture of the DMA and compound of instant formula (I) dropwise. See example 7. Savac does not explicitly teach the time over which the dropwise addition takes place, however, the rest of the example 7 indicates that the time of addition is not critical to the outcome of the reaction so long as the APC is added dropwise. Further, as Savac explicitly teaches when the reactions are run for long periods of time, the addition is assumed to fall within the scope of less than 1 hour. See MPEP 2144.05.
Claim(s) 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Savac (GB1472050A, published on 4/27/1977, of record in the IDS filed on 12/28/2022) in view of Speck (US 4364921, published on 12/21/1982, of record), as applied to claims 1, 4, 7, 9, and 10 above, and further in view of Sovak (US 5698739, published on 12/16/1997).
Applicant claims the process of claim 4, wherein the solvent system consists essentially of pyridine and acetonitrile with a pyridine: acetonitrile volume ratio between 1:1 and 3:1.
Savac teaches that preferred solvents include aprotic solvents, which encompasses all of those recited in claim 4. See p. 9, lines 4-9. Neither Savac nor Speck teach a solvent system of acetonitrile and pyridine in the ratio claimed.
Sovak is directed toward triiodo 5-aminoisophthaldiamides for use as non-ionic contrast agents. See abstract and title. Sovak teaches an analogous amidation process to that of the combined process of Savac and Speck, wherein an acid chloride is reacted with an amine (anhydrous ammonia) in an organic solvent (acetonitrile). See examples 24, 30, and 48.
It would have been prima facie obvious to one of ordinary skill in the art to combine the teachings of Savac, Speck, and Sovak to arrive at the instantly claimed process with a reasonable expectation of success before the effective filing date of the claimed invention. A person of ordinary skill would have been motivated to employ a co-solvent in the amidation reaction of the combined process of Savac and Speck, in particular acetonitrile, because Sovak teaches analogous amidation reactions of similar compounds which can be carried out in acetonitrile. Further, Savac explicitly teaches that aprotic solvents, which includes acetonitrile, can be included in the amidation reaction. Therefore, including acetonitrile in the amidation step would predictably produce the same product with a reasonable expectation of success. Also see MPEP 2143(I)(B) and MPEP 2144.07. Further regarding the claimed volume ratio, it is prima facie obvious for the skilled artisan to modify the concentration of reactants, among other reaction variables, using routine optimization with a reasonable expectation of success. Further, the claimed volume ratio does not appear to impart criticality to the claimed invention. Also see MPEP 2144.05.
Applicant Arguments on p. 12-14 of the response dated 1/23/2026
In the response, Applicant limited the process of independent claim 1 to that wherein the solvent system comprises pyridine and the amidation and subsequent hydrolysis are carried out in one vessel without isolation of the amidation product to generate a compound of Formula (II). Applicant further limited the process of claim 2 to require hydrolysis within the pH range of about 12.0 to about 14.0. The Applicant argues that the claimed process, wherein pyridine is included during an amidation and high-pH (12-14) hydrolysis step without isolation of the amidation product, produces unexpectedly high purity results. This argument is persuasive in view of the examples in the specification.
However, independent claim 1 is not commensurate in scope with the advantageous results in the examples. It is not even clear if the hydrolysis step is required in claim 1, as discussed in the 35 USC 112(b) rejection above. Claim 2, which includes pyridine; an amidation and pH 12-14 hydrolysis reaction; and a one-pot process without isolation, is commensurate in scope with the examples. Therefore, the rejection over claims 2, 5, 6, 8, and 11-13 is withdrawn. The rejection over claims 1, 4, 7, 9, and 10 is maintained and extended to cover newly introduced claim 20. Also see MPEP 2145.
Allowable Subject Matter
Claim 15 is allowable. The following is a statement of reasons for the indication of allowable subject matter: the closest prior art to the claimed process is the art of record. The art does not teach or suggest the use of a compound of instant formula (II), wherein the secondary oxygen group is selectively deprotected vs. the four primary alcohol groups (R is the claimed group) to produce a compound of instant formula (III). The prior art teaches that all of the -OH groups are protected, all of the OH groups are unprotected, or that the primary alcohol groups are deprotected and the secondary amino group remains protected. Nor does there appear to be motivation to modify the prior art processes to arrive at that claimed.
Conclusion
Claims 1, 4, 7, 9-11, and 20 are rejected.
Claim 15 is allowed.
Claims 2, 5, 6, 8, 12, 13, 19, and 21 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.
Claims 14 and 16-18 stand withdrawn and are not eligible for rejoinder.
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 nonprovisional extension fee (37 CFR 1.17(a)) 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY C BONAPARTE whose telephone number is (571)272-7307. The examiner can normally be reached 11-7.
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/AMY C BONAPARTE/ Primary Examiner, Art Unit 1692