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 10/14/2025, in reply to the Office Action mailed 7/11/2025, is acknowledged and has been entered. Claim 2 has been amended. Claims 1-20 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. The Examiner’s response to Applicant’s arguments is incorporated below.
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) 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Rojas-Quijano et al. (Chem. Eur. J., 2012, 18, p. 9669-9676 and Supporting Information) in view of Lexa et al. (WO 96/10359), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that Rojas-Quijano does not teach each and every element of claims 1-20 because Rojas-Quijano does not teach or suggest any macrocycle-free chelating agents, let alone the use of any macrocycle-free chelating agents in hypoxia imaging. Instead, Rojas-Quijano specifically discloses chelating agents that are DOTA derivates only. Applicant asserts that Lexa does not cure the deficiencies of Rojas-Quijano because Lexa does not disclose any hypoxia imaging, let alone any hypoxia-targeting chelating agents.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the argument that Rojas-Quijano does not teach macrocycle-free chelating agents and that Lexa does not teach hypoxia-targeting chelating agents, see MPEP 2145, directed to arguing against references individually. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Where an applicant’s reply establishes that each of the applied references fails to teach a limitation and addresses the combined teachings and/or suggestions of the applied prior art, the reply as a whole does not attack the references individually as the phrase is used in Keller and reliance on Keller would not be appropriate. This is because “[T]he test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA].” In re Mouttet, 686 F.3d 1322, 1333, 103 USPQ2d 1219, 1226 (Fed. Cir. 2012). In the instant case, the combined teaching of the references addresses conjugation of additional chelating agents to a carrier/targeting molecule.
Applicants argues that, based on the teaching of Rojas-Quijano, the Examiner's proposed modification of Rojas-Quijano would render the chelating agents of Rojas- Quijano unsuitable for its intended purpose. Applicant asserts that Rojas-Quijano explicitly teaches that the presence of a binding macrocycle, such as DOTA, is essential for the stability of the MRI agent. For example, Rojas-Quijano states that "Gd" complexes with DOTA-like ligands have high thermodynamic stability, are kinetically inert and have favorable relaxation properties." Applicant asserts that based on the teaching of Rojas-Quijano, replacing the binding macrocycle-containing chelating agent of Rojas-Quijano with a linear chelating agent (i.e., a chelating agent that does not comprise a binding macrocycle) would compromise the stability of the MRI agents and render the result completely unsuitable for the intended use of Rojas-Quijano. Therefore, Rojas-Quijano provides no motivation or suggestion to modify the macrocycle-containing chelating agents of Rojas-Quijano with linear compounds having the structure of Formula (I).
Applicant’s arguments have been fully considered. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, Lexa teaches that chelating agents for conjugation with a carrier molecule, and complexing with a paramagnetic atom can be selected from the non-toxic group of chelating agents of polyaminopolycarboxylic acids, particularly DOTA and DTPA, but examples of other suitable alternative chelating agents include EDTA, DTPA-BMA, BOPTA, TTHA, NOTA, D03A, HP-D03A, TETA, HAM, DPDP, Acetate, TPPS4, EHPG, HBED, and Desferrioxamine B. Accordingly, it is known from Lexa to provide alternative chelating molecules for conjugation to a carrier/targeting ligand and for complexing with a paramagnetic ion. As such it is considered that substitution of DFO for DOTA/DO3A would not render the chelating agents of Rojas- Quijano unsuitable for its intended purpose.
Applicant further argues that Rojas-Quijano explicitly teaches and provides stability data to indicate that the presence of amides in the chelating agents resulted in less stable MRI agents. Applicant asserts that Rojas-Quijano states that "these complexes are about four orders of magnitude less stable than the corresponding Ln(DOTA) complexes due to the substitution of a carboxylate in DOTA for the weaker amide donor atom". Rojas- Quijano also explicitly states "Further substitution of acetate arms for amides resulted in even lower stabilities". Thus, based on the teaching of Rojas-Quijano, the presence of each amide group in chelating agents further lowers the stability of the resulting MRI agents. As such, based on the teaching of Rojas-Quijano, replacing the chelating agent of Rojas-Quijano with amide-containing chelating agents would further compromise the stability of the MRI agents and render the result completely unsuitable for the intended use of Rojas-Quijano. Therefore, Rojas-Quijano provides no motivation or suggestion to modify the carboxylate-containing chelating agents of Rojas-Quijano with amide-containing chelating agents having the structure of Formula (1) that comprise three amides.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that deferoxamine is not limited to amide-containing chelating agents, but rather features three hydroxamic functional groups. Accordingly, the arguments are not commensurate in scope with the structures set forth in Rojas-Quijano. As set forth above, it is known from Lexa to provide alternative chelating molecules for conjugation to a carrier/targeting ligand and for complexing with a paramagnetic ion. As such it is considered that substitution of DFO for DOTA/DO3A would not render the chelating agents of Rojas- Quijano unsuitable for its intended purpose.
Applicant argues that lastly, Rojas-Quijano teaches that the large lanthanides are essential for the stability of the MRI agent. For example, Rojas-Quijano indicates that the stabilities of the LnIII complexes increased as the size of the lanthanide increased, following the CeIII< GdIII < LuIII order (Table 2 of Rojas-Quijano). Applicant asserts that based on the teaching of Rojas-Quijano, replacing the large lanthanide-containing metal chelate of Rojas-Quijano with a much smaller iron-containing metal chelate would even further compromise the stability of the MRI agents and render the result completely unsuitable for the intended use of Rojas-Quijano.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the instant claims are not limited to any particular metal, accordingly the claims are not commensurate in scope with the argument that the stabilities of the LnIII complexes increased as the size of the lanthanide increased. It is further noted that Lexa teaches lanthanide or transition metal ions as suitable paramagnetic ions for use in MRI. Applicant’s arguments have been fully considered but the rejection is maintained.
Conclusion
No claims are allowed at this time.
THIS ACTION IS MADE FINAL. 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