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 2/5/2026, in reply to the Office Action mailed 11/6/2025, is acknowledged and has been entered. Claim 1 has been amended. Claims 1, 3-9, 12 and 13 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 Any rejection not reiterated herein has been withdrawn. 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, 5-9, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Milani et al. (Rev. Sci. Instruments, 2017, 88, 015109) in view Ardenkjaer-Larsen (US 6466814), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that Milani's disclosure is limited to spectroscopic characterization of a urea species, ¹⁵N-enriched urea (ND2COND2). Applicant asserts that Figure 5 of Milani, referred to by the Examiner, is confined to the identity, preparation, and solution-state NMR characterization of this specific hyperpolarized, N-deuterated urea species following dissolution. Applicant contends that while Milani notes, in general terms, that ¹⁵N hyperpolarization may be of interest for metabolic imaging, Milani does not teach or suggest a rationale or motivation for administering to a subject the ¹⁵N-deuterated urea as recited in claim 1, nor does it teach or suggest in vivo monitoring of such compounds. Rather, Milani's disclosure is directed to demonstrating the technical feasibility of hyperpolarization and subsequent spectroscopic detection, and does not address considerations relevant to use in a living subject.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the Milani reference teaches DNP in the context of metabolic imaging and further is combined with Ardenkjaer-Larsen, which teaches hyperpolarized urea to be a suitable high T1 agent for magnetic resonance investigation of a human or non-human animal body comprising the step of ex vivo polarization of a high T1 agent.
Applicant further argues that Ardenkjaer-Larsen provides a general framework of polarization of high T1 agents, including agents enriched with a range of nuclei including ¹⁵N. Applicant asserts that while Ardenkjaer-Larsen includes "(5) ureas:" in its list of compound types, this generic mention of "ureas" within a broad list of preferred compounds does not disclose or suggest selecting urea selectively labeled with ¹⁵N-deuterated, as required by claim 1, for in vivo diagnostic imaging. Applicant contends that Ardenkjaer-Larsen's discussion of deuterium labeling is explicitly tied to ¹³C-enriched compounds stating, "Preferably the ¹³C enriched compound should be deuterium labelled, especially adjacent the ¹³C nucleus" (column 6 lines 32-35). Ardenkjaer-Larsen does not provide any teaching or motivation for selecting urea specifically labeled with ¹⁵N and deuterated, for administration to a subject. Accordingly, the selection of urea as a substrate, labeled with ¹⁵N and deuterated for use in diagnostic imaging is neither taught nor suggested by Milani, Ardenkjaer-Larsen, or their combination. Applicant argue that generalized statements do not overcome the absence of any teaching or suggestion in the cited art to administer the specifically recited compounds to a subject and to monitor those compounds in vivo, as required by claim 1. Even accepting Ardenkjaer-Larsen's generic reference to "ureas," this does not supply the specific isotopic and deuteration limitations recited in the claims.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the argument that Ardenkjaer-Larsen does not disclose or suggest selecting urea selectively labeled with ¹⁵N-deuterated, as required by claim 1, for in vivo diagnostic imaging, it is respectfully submitted that the partly or wholly deuterated or 14 F analogues of any of the compounds are particularly preferred (column 13). Further, Milani teaches that deuterium nuclei which exchange with the solvent, since the molecule is completely deuterated after dissolution with D2O as in Figure 5. Further it is known from Milani that in small molecules where 15N is bound to protons, T1(15N) is typically on the order of 60 s; but when 15N is not directly bound to any protons, very long relaxation times 200 < T1(15N) < 800 s have been observed near 300 K. This makes d-DNP particularly attractive for nitrogen-15 (015109-1).
Claim(s) 1, 3-9, 12 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Milani et al. (Rev. Sci. Instruments, 2017, 88, 015109) in view Ardenkjaer-Larsen (US 6466814), in further view of Cho et al. (US 2020/0260983), for reasons set forth in the previous Office Action.
Response to arguments
Applicant further argues that the US 62/557,696 provisional application (filed September 12, 2017) is the only Cho provisional that predates Applicant's priority date. Applicant asserts that this 2017 provisional application does not disclose hyperpolarized urea, deuterium-exchanged probes, or in vivo imaging of urea. Its title is "HYPERPOLARIZED 13C, 15N LABELED ARGININE AND XANTHINE PROBES" and its abstract and detailed description are limited to xanthine and arginine compounds. Applicant contends that the teachings from Cho et al. are not effective prior art against the present claims.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that Applicant’s provisional Application 62/622,296 does not contain the specifically claimed subject matter of instant claim 1, accordingly the claims are not afforded the 1/26/2018 priority date. For example, urea is generically mentioned at paragraph [0049] of the ‘296 provisional Application. “Although non-protonated positions of ¹⁵N show advantages for ¹⁵N hyperpolarization we have devised a strategy for improving the lifetime/visibility of protonated ¹⁵N positions as described above, and validated it here for ammonium, urea, arginine, and succinimide. This strategy may prove useful for shorter term contrast such as that injected on vascular and interventional radiology or for short-term imaging such as myocardial first-pass perfusion imaging.” Accordingly, the effective filing date for the subject matter of the instant claims is the filing of PCT/IL2019/050102, or 01/24/2019; which is later than Cho’s filing of Application Serial No. 16/646549, or 9/10/2018. As such it is considered that Applicant’s arguments have been fully considered but the rejections are 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
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