DETAILED ACTION
This Office Action details a final action on the merits for the above referenced application No. Claims 3, and 5-27 are pending in this application.
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 .
Status of Claims
Claims 1-2, and 4 are cancelled. Claims 8-26 are withdrawn. Claim 27 is new.
Response to Amendment
The amendments filed on 5 Aug. 2026 have been entered.
Response to Arguments
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
Claim(s) 3 and 5-6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chaumeil et al. (Nature Com.; published 2013), in view of McInnes et al. (Accounts Chem. Res.; published 1975) for the reasons cited in the Office action filed on 10 Apr. 2026.
Regarding claims 1-2, and 4, Chaumeil et al. disclose a [1-13C]α-ketoglutarate composition that comprises 1-13C-5-12C alpha ketoglutarate
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(see Fig. 1; pg. 9, Sigma-Aldrich, 99 atom% 13C). Regarding claims 5 and 6, Chaumeil et al. teach that [1-13C]α-ketoglutarate was dissolved in Tris-based isotonic buffer prior to intravenous injection (see pg. 9). Chaumeil et al. teach non-invasive assessment of IDH1 mutational status in glioma (see title). Chaumeil et al. teach that [1-13C]α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity and can inform on IDH1 status. Using 13C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of [1-13C]α-ketoglutarate is studied in isogenic glioblastoma cells that differ in the IDH1 status (see abstract). Chuameil et al. teach a resonance of hyperpolarized [5-13C]α-KG (184 ppm) originating from 1.1% natural abundance of 13C at the C5 position (see pg. 2). Chaumeil et al. teach a schematic of reaction catalyzed by wild type IDH1 and mutant IDH1 and associated [1-13C]α-KG metabolism and a stack plot of 13C MR spectra of hyperpolarized [1-13C]α-KG in solution and a structure of [5-13C]α-KG
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(see Fig. 1). Chaumeil et al. teach that given the ~1 ppm linewidth of the 184 ppm resonance in vivo and light of our findings in cell extracts showing that [5-13C]α-KG and [1-13C]2-HG are only 0.1 ppm apart, these two resonances could not be spectrally resolved (see pg. 3). Ester derivatives of α-KG including octyl- and benzyl-esters have been reported to permeate the cell membrane more effectively (see pg. 6). Chaumeil et al. teach that 2-HG can be detected in vivo in mutant IDH1 tumors following injection of hyperpolarized [1-13C]α-KG in tumor bearing U87IDHmut rate and in vivo dynamic 13C MR imaging (see Fig. 4). The approach will probably require further optimization to enhance [1-13C]2-HG detection (see pg. 8). Hyperpolarized [1-13C]α-KG presents a promising, non-radioactive and potentially clinically relevant agent for interrogation of IDH1 status in vivo (see pg. 9).
Chaumeil et al. do not teach an enriched composition of 1-13C-5-12C-alpha ketoglutarate, the composition having 1-13C-5-12C-alpha ketoglutarate such that the 12C at instant Ca and Cd is of about 90% to about 99.9% isotope abundance and 13C is of about 80% to about 99.9% isotope abundance.
McInnes et al. teach the use of carbon-13 magnetic resonance spectroscopy for biosynthetic investigations (se title). McInnis et al. teach (99.5% 12C) (pg. 320). Metabolites obtained by this 13C-depletion method should give resonances for only the 13C labeled positions. The ability to observed signals arising from selected sites in proteins, enzymes, or nucleic acids is particularly attractive and could facilitate studies on enzyme substrate or drug receptor interactions by spin-lattice relaxation techniques (see pg. 320).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the composition of Chaumeil et al. (composition comprising 1-13C-5-12C-alpha ketoglutarate) so that the composition only comprises 1-13C-5-12C-alpha ketoglutarate or so that the composition is substantially enriched with 1-13C-5-12C-alpha ketoglutarate such that the 12C is of about 90% to about 99.9% isotope abundance and the 13C is of about 80% to about 99.9% isotope abundance as taught by Chaumeil et al. and McInnes et al. because the enriched composition would have been expected to advantageously enable a composition capable of monitoring IDH1 mutation activity without any interfering [5-13C]α-KG whereby enhancing 1-13C-5-12C-2-hydroxyglutarate detection.
Claim(s) 3 and 5-7 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chaumeil et al. (Nature Com.; published 2013), in view of McInnes et al. (Accounts Chem. Res.; published 1975), in further view of Cabella et al. (US 2015/0273086 A1; published 1 Oct. 2015) for the reasons cited in the Office action filed on 10 Apr. 2026.
Chaumeil et al. teach as discussed above.
Chaumeil et al. do not further teach a pharmaceutical composition further comprising a pharmaceutical acceptable carrier and a regime of one or more additional chemotherapeutic agents comprising an antineoplastic drug.
McInnes et al. teach as discussed above.
Cabella et al. teach hyperpolarized 2-oxoglutarte as metabolic agent in MR (see title). Cabella et al. teach a hyperpolarized 1-13C-2-oxoglutarate (example 2) as contrast agent in 13C Magnetic Resonance diagnostic technique (13C-MRI) for use in the diagnosis of cancer and determining the aggressiveness of a tumor or the efficacy of an anti-tumor therapy (see abstract). Cabella et al. teach saline solution. Preferred therapy are those with highly efficient cell killing antineoplastic drugs such as antimetabolites ([0090]-[0092], [0079]). These therapies can be monitored by administration of hyperpolarized 1-13C-2-oxoglutarate ([0080]). The method is performed on a subject who is subjected to antitumor treatment and the reference value is the signal of 13C glutamate in the region of interest determined before, during and after the treatment ([0106]-[0108]). Cabella et al. teach co-administration of biological agent ([0084],[0116]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Chaumeil et al. so that the pharmaceutical composition further comprises a regime of one or more additional agents such as chemotherapeutic agents that are a antineoplastic drug or antimetabolite or other biological agent as taught by Cabella et al. because such a composition would have been expected to advantageously enable monitoring the efficacy of chemotherapy during treatment or enhancing the conversion of [1-13C]α-ketoglutarate to 2-hydroxyglutarate.
Applicants’ Arguments
Applicants assert that all the compound now recited in amended claim 1 are designed such that a 13C atom is included to amplify MRI signal and a 12C atom is included in the same molecule to decrease MRI signal. This combination of increasing and decreasing MRI signal allows for better resolution during imaging.
Chaumeil does not teach an enriched composition of 1-13C-5-12C-alpha ketoglutarate such that the 12C at instant Ca and Cd is of about 99% to about 99.9% isotope abundance and 13C is about 99% to about 99.9% isotope abundance. Chaumeil does not disclose or suggest incorporating into the same molecule a 13C atom to amplify MRI signal and a 12C atom to decrease MRI signal much less realize that such a combination could be used to improve imaging results.
Chaumeil and McInnes do not disclose or suggest a compound wherein the compound has the claimed formula and wherein Ca, Cb, and Cd are any isotopic form of carbon and wherein at least two of Ca, Cb, and Cd together are represented by a pair of 12C and 13C, where 12C is of about 99% and about 99.9% isotope abundance and 13C is of about 99% and 99.9% isotope abundance. Nowhere does McInnes disclose or suggest isotope abundance for each of 12C and 13C atoms at essentially 100%. McInnes does not disclose or suggest incorporating into the same molecule a 13C atom to amplify MRI signal and a 12C atom to decrease MRI signal, much less realize that such a combination could be used to improve imaging results. There is not disclosure in the prior art that teaches, discloses or motivates the compounds recited in the pending claims and particularly alpha ketoglutarate derivatives with essentially 100% 13C and 12C isotope abundance in order to avoid signal overlaps. McInnes is theoretical for 12C compound and does not disclose or suggest the particular compounds claimed in the pending claims. Cabella does not disclose or suggest an enriched composition of 1-13C-5-12C-alpha ketoglutarate such that the 12C at instant Ca and Cd is of about 99% to about 99.9% isotope abundance and 13C is about 99% to about 99.9% isotope abundance.
Applicants’ arguments filed 5 Aug. 2026 have been fully considered but they are not persuasive. Instant claim 3 is directed to a compound wherein the compound has the formula
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wherein the compound is from 1-13C-5-12C-alpha ketoglutarate and wherein at least two of Ca, Cb, and Cd together are represented by an isotope pair of 12C and 13C and 12C is of about 99% to about 99.9% isotope abundance and 13C is about 99% and 99.9% isotope abundance. At for example Fig. 1, Chaumeil discloses the 1-13C-5-12C-alpha ketoglutarate meeting the definition of a compound of the claimed formula wherein Ca and Cd are essentially 100% 12C and Cb is essentially 100% 13C and wherein the compound is 1-13C-5-12C-alpha ketoglutarate. Anticipation is the epitome of obviousness. See May, 574 F.2d at 1089, 197 USPQ at 607. To the extent instant claim 3 is directed to a composition rather than a compound, Chaumeil teaches that the 1-13C-5-12C-alpha ketoglutarate compound therein is contaminated by a [5-13C]-αKG originating from the 1.1% natural abundance 13C at the C5 position. The [5-13C]-αKG exhibits a δC5-aKG at 184 ppm. According to Chaumeil, given the ~1-ppm linewidth of the 184 ppm resonance in vivo and in light of our finding in cell extracts showing that [5-13C]α-KG and [1-13C]2-HG are only 0.1 pm apart, these two resonances could not resolved. Accordingly Chaumeil provides reason and motivation to modify the 1-13C-5-12C-alpha ketoglutarate composition therein by removing the [5-13C]α-KG contaminant compound in order to more accurately detect [1-13C]2-HG. McInnes is prior art for all that it teaches. McInnes teaches, suggests and motivates an advantageous 13C depletion method that replaces 13C with 12C. McInnes teaches that in principle this method should give 13C spectra containing resonances for only the 13C positions. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Chaumeil (1-13C-5-12C-alpha ketoglutarate) so that the compound is essentially pure and free from the contaminant [5-13C]α-KG to arrive at a compound of the claimed formula wherein each 12C is of about 99% to about 99.9% isotope abundance and each 13C is about 99% to about 99.9% abundance as taught by Chaumeil and McInnes because that compound would have been expected to advantageously enable enhanced detection of [1-13C]2-HG in mutant IDH1 tumors.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
Claim(s) 27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Chaumeil et al. (Nature Com.; published 2013), in view of McInnes et al. (Accounts Chem. Res.; published 1975).
Chaumeil et al. teach non-invasive assessment of IDH1 mutational status in glioma (see title). Chaumeil et al. teach that [1-13C]α-ketoglutarate can serve as a metabolic imaging agent for non-invasive, real-time, in vivo monitoring of mutant IDH1 activity and can inform on IDH1 status. Using 13C magnetic resonance spectroscopy in combination with dissolution dynamic nuclear polarization, the metabolic fate of [1-13C]α-ketoglutarate is studied in isogenic glioblastoma cells that differ in the IDH1 status (see abstract). Chuameil et al. teach a resonance of hyperpolarized [5-13C]α-KG (184 ppm) originating from 1.1% natural abundance of 13C at the C5 position (see pg. 2). Chaumeil et al. teach a schematic of reaction catalyzed by wild type IDH1 and mutant IDH1 and associated [1-13C]α-KG metabolism and a stack plot of 13C MR spectra of hyperpolarized [1-13C]α-KG in solution and a structure of [5-13C]α-KG
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(see Fig. 1). Chaumeil et al. teach that given the ~1 ppm linewidth of the 184 ppm resonance in vivo and light of our findings in cell extracts showing that [5-13C]α-KG and [1-13C]2-HG are only 0.1 ppm apart, these two resonances could not be spectrally resolved (see pg. 3). Ester derivatives of α-KG including octyl- and benzyl-esters have been reported to permeate the cell membrane more effectively (see pg. 6). Chaumeil et al. teach that 2-HG can be detected in vivo in mutant IDH1 tumors following injection of hyperpolarized [1-13C]α-KG in tumor bearing U87IDHmut rate and in vivo dynamic 13C MR imaging (see Fig. 4). The approach will probably require further optimization to enhance [1-13C]2-HG detection (see pg. 8). Hyperpolarized [1-13C]α-KG presents a promising, non-radioactive and potentially clinically relevant agent for interrogation of IDH1 status in vivo (see pg. 9).
While Chaumeil et al. teach 1-13C-5-12C-alpha ketoglutarate, Chaumeil et al. do not teach the claimed compound 1-13C-5-12C-alpha ketoglutarate such that the 12C at instant Ca and Cd is of about 90% to about 99.9% isotope abundance and 13C is of about 80% to about 99.9% isotope abundance.
McInnes et al. teach the use of carbon-13 magnetic resonance spectroscopy for biosynthetic investigations (se title). McInnis et al. teach (99.5% 12C) (pg. 320). Metabolites obtained by this 13C-depletion method should give resonances for only the 13C labeled positions. The ability to observed signals arising from selected sites in proteins, enzymes, or nucleic acids is particularly attractive and could facilitate studies on enzyme substrate or drug receptor interactions by spin-lattice relaxation techniques (see pg. 320).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the compound of Chaumeil et al. ( 1-13C-5-12C-alpha ketoglutarate that is mixed with 1-12C-5-13C-alpha ketoglutarate) so that the compound is substantially enriched with 1-13C-5-12C-alpha ketoglutarate such that the 12C is of about 90% to about 99.9% isotope abundance and the 13C is of about 80% to about 99.9% isotope abundance as taught by Chaumeil et al. and McInnes et al. because the enriched compound having reduced 5-13C-α-KG would have been expected to advantageously enable a composition capable of monitoring IDH1 mutation activity without any interfering [5-13C]α-KG whereby enhancing 1-13C-5-12C-2-hydroxyglutarate detection.
Conclusion
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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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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