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 .
Acknowledgement of Receipt
Applicant’s Response, filed 9/29/2025, in reply to the Office Action mailed 6/2/2025, is acknowledged and has been entered. Claims 1, 5, 7, 9-11 and 13-16 have been amended. Claims 1-18 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds of rejection are set forth, necessitated by claim amendment.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-4, 17 and 18 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Weitl et al. (J. Med. Chem., 1976, 19, p. 1359-62).
Weitl discloses studies in the design of x-ray contrast agents, including synthesis, hydrophobicity, and solubility of some Iodoresorcyl Bis(β-glucosides).
An exemplary compound is compound 6, shown below:
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130
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See Scheme 1 and Table 1. Synthetic methods including conjugation are set forth on page 1361.
Such a compound is within the scope of the instant claims such that R1 is an amide group and R2 and R3 are a group of Formula 2.
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, 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.
Claim(s) 1-12, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Smith (CA 1099262A).
Smith teaches preparation of a compound of the Formula
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, wherein
X and Y are each non-ionizing functions compatible with low toxicity and/or water solubility in the 2,4,6-triiodophenyl configuration selected from the group consisting of lower alkoxy, hydroxy-(lower alkoxy), lower alkoxy-(lower alkoxy), lower acylamino, lower acylamino-(lower alkyl), lower acylamino-(lower acyl amino), hydroxy-lower acylamino, N-(lower alkyl)- lower acylamino, lower alkylsulfonamido, N-(lower alkyl)-lower alkylsulfonamido, 3,3-bis-(lower alkyl)- ureido, lower perfluoroacylamino, carbamyl, N-(lower alkyl)carbamyl, N,N-di-(lower alkyl) carbamyl, lower alkoxy-(lower acylamino), lower alkoxyalkoxy-(lower acylamino), hydroxy and hydroxy-lower alkyl and Z is the monovalent residue of a polyol selected from the group consisting of linear and branched chain polyols (see page 3) and claims 1-14.
Preparation of 6-[2,4,6-triiodo-3-(N-methyl-
acetamido)-5-(N-methylcarbamyl)carbanilyl]-D-galactose (V) is shown on pages 25-27.
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Accordingly, compound V is within the scope of the instant claims such that at least R1 is an atomic group that binds to an asialoglycoprotein receptor – linker and R2 and R3 correspond to an amino group represented by -NRxRy wherein Rx and Ry each independently represent a hydrogen atom, a C1 to C6 hydrocarbon group optionally having a substituent, or a C2 to C7 acyl group optionally having a substituent; or an amide group represented by -C(=O)NRzRw wherein Rz and Rw each independently represent a hydrogen atom or a C1 to C6 hydrocarbon group optionally having a substituent.
While Smith does not specifically exemplify a compound according to condition iii of the conditions of the instant claims such that when one of R1-3 is Formula 2, two of R1-3 are the amino group.
It would have been obvious to one of ordinary skill in the art at the time of the invention to modify compound V as having two amino groups, rather than amino group and an amide group according to the instant claim language in view of the broader teaching of Smith. One would have been motivated to do so, with a reasonable expectation of success, because Smith teaches that variables X and Y may be selected from among lower acylamino, lower acylamino-(lower alkyl)… carbamyl, N-(lower alkyl)carbamyl, etc. Accordingly, one of ordinary skill would have found it obvious to select from among the limited number of substituents at the stated position as providing non-ionizing functions compatible with low toxicity and/or water solubility with a reasonable expectation of success in providing a contrast agent for x-ray imaging. See also MPEP 2144. A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. “An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties.” In rePayne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979). See In rePapesch, 315 F.2d 381, 137 USPQ 43 (CCPA 1963) (discussed in more detail below) and In reDillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
Claim(s) 1-11 and 13-18 are rejected under 35 U.S.C. 103 as being unpatentable over Na et al. (KR 2018/0135180A, English translation) in view of Zhang et al. (Chinese J. Chem., 2006, 24, p. 1058-1061), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that it would not have been obvious to modify the triiodobenzene contrast agents of Na et al. to be mono-, di-, or tri-galactosylated triiodobenzene contrast agents comprising the linker shown above to provide improved binding to an asialoglycoprotein receptor in view of the Zhang et al., as suggested by the Office, and traverse the obviousness rejection. Applicant asserts that it was unexpectedly discovered that the claimed compound of formula (1) or pharmaceutically acceptable salt thereof is well-suited for use as an iodine contrast agent. In that respect the present application states: The present inventors have conducted diligent studies to attain the object and consequently completed the present invention by finding a novel compound capable of serving as an iodine contrast agent.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to allegations of unexpected results, see MPEP 716.02b. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992). In the instant case, the compounds of Na are capable of use as x-ray contrast agents, which is encompassed by the statement that Applicants have unexpectedly discovered that the claimed compound of formula (1) or pharmaceutically acceptable salt thereof is well-suited for use as an iodine contrast agent.
Further, whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980), see MPEP 716.02d. In the instant case, the claims are directed to a very large number of potential variables corresponding to a large number of potential compounds.
Applicant further argues that Na et al. does not provide any teaching or motivation to modify the compound of formula (I) or the compound of formula (II) so as to arrive at the claimed compound of formula (1) or pharmaceutically acceptable salt thereof. Applicant asserts that Na et al. does not suggest that there is any necessity to modify the structure of the compound of formula (I) or the compound of formula (II) (e.g., to increase the number of sugar residues) or to improve receptor affinity. Applicant argues that Zhang does not cure the deficiencies of Na. Applicant notes that Zhang et al. merely discloses sugar clusters with enhanced binding affinity to ASGPR. While Zhang et al. discloses that trivalent galactosides exhibit higher affinity to ASGPR than their divalent counterparts, and that sugar clusters incorporating an aryl scaffold demonstrate stronger binding affinity to ASGPR than those incorporating an aliphatic scaffold, Zhang et al. does not teach or suggest any relationship between the sugar clusters and the development of iodinated compounds or their diagnostic applications. Indeed, Zhang et al. is completely silent as to the use of the sugar clusters as ligands in iodine-based contrast agents.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to Applicant’s argument that Na et al. does not suggest that there is any necessity to modify the structure of the compound, the reference does not need to recognize a deficiency in their own work in order for a person of ordinary skill to look for ways to improve upon that work, the desire of a person of ordinary skill is to improve on what is already known in the art.
Applicant further argues that with regard to requirement (i) of the claimed invention, the Office contends that it would have been obvious to modify the mono- and di-galactosylated triiodobenzene contrast agents of Na et al. to provide tri-galactosylated triiodobenzene derivatives because Zhang et al. discloses that trivalent galactosylated aryl ligands exhibited increased affinity for ASGPR than divalent ligands. Applicant asserts that such a modification would be contrary to the teachings of Na et al. In that respect, Na et al. discloses that "[t]he contrast agent has a monomolecular size of less than 1500 Da and has a biliary specific property" (Na et al. at Abstract). Applicant contends the the di-galactosylated triiodobenzene contrast agent of formula (II) of Na et al. has a molecular weight of 1439 Da. In other words, if the compound of formula (II) of Na et al. were modified to be a tri-galactosylated triiodobenzene derivative, as suggested by the Office, the molecular weight would increase to more than 1700 Da, which is contrary to the teachings of Na et al.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that it is acknowledged that the monomolecular compound of Na is shown to have a size of less than 1500 Da, the reference does not discredit that a slightly larger compound would render the mononuclear compound unsuitable for the stated purpose. Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g.,In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988). See MPEP 2144. Further, in the instant case, Zhang teaches the benefit that a trivalent galactosylated aryl ligand proved to perform better than divalent one as binding ligands for ASGPR.
Conclusion
No claims are allowed at this time.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618