DETAILED ACTION
The present application is a national stage entry of PCT/US2021/054619, filed 12 October 2021, which claims priority to US Provisional Application No. 63/093,084, filed 16 October 2020.
The preliminary amendment filed 16 December 2025 is acknowledged. Claims 1-25 are pending in the current application. Claims 3 and 7-18 are withdrawn as being drawn to species, see below. Claims 1, 2, 4, 6 and 19-25 are examined on the merits herein.
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 .
Election/Restrictions
Applicant’s election without traverse of child as a First species of human subject age; retinal degeneration as a Second species of disease associated/caused by cblC deficiency; and cblC disorder as a Third species of genetic disorder in the reply filed on 16 December 2025 is acknowledged.
Claims 3 and 7-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 16 December 2025.
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.
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) 1, 2, 4, 6 and 19-25 are rejected under 35 U.S.C. 103 as being unpatentable over Carrillo-Carrasco et al. (J. Inherit. Metab. Dis., 2009, vol. 32, pp. 728-731, cited in PTO-892) in view of Chang et al. (US Patent Application Publication No. 2015/0238527, cited in PTO-892) and Sloan et al. (Human Molecular Genetics, March 2020, vol. 29, no. 13, pp. 2109-2123, cited in IDS submitted 14 April 2023).
Carrillo-Carrasco et al. teach treating a 13-year-old (a child) with elevated levels of methylmalonic acid (MMA) and total homocysteine (tHcy) (p.729, Case Report and methods). At 13 years of age, the patient had pigmentary retinopathy with severely constricted visual fields. Metabolic measurements obtained after an overnight fast showed tHCy 112 µmol/L, plasma MMA 25 µmol/L, propionyl carnitine 3.92 µmol/L, methionine 17 µmol/L and a plasma vitamin B12 level of 58-680 pg/mL. To determine the dose of OHCbl required for an optimal response, step-wise dose escalation was performed at 1-month intervals using the following dosing regimen: 10 mg IM three times weekly, 10 mg IM daily and 20 mg IM daily. OHCbl was formulated t either 10 mg/mL or 20 mg/mL. The regimen also included betaine 8 g (140 mg/kg), carnitine 500 mg (9mg/kg), folic acid 1 mg daily and modest whole-protein restriction (1.2 g/kg per day). Carrillo-Carrasco et al. observed a dose-dependent response with an 80% reduction of plasma MMA, a 55% reduction of tHCy and a greater than twofold increase in methionine. Carrillo-Carrasco et al. teach “this suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients” (p.728, right col., first para). Carrillo-Carrasco et al. teach treatment goals in patients with cblC should include normalizing biochemical parameters.
While Carrillo-Carrasco et al. teach administering a high-dose of OHCbl to a child with a cblC deficiency, and retinal degeneration, Carrillo-Carrasco et al. do not expressly disclose administering a high-dose of MeCbl (present claim 1).
Chang et al. teach the use of a vitamin supplement composition formulated for treating vitamin deficiency (abstract; claim 1). Vitamin B is included in the supplement, and can be formulated as cyanocobalamin or methylcobalamin (para [0012]; [0034]; claim 8), and administered at a dosage of about 1500 to about 6250 µg (equivalent to about 1.5 to about 6.25 mg; para [0010]; claim 1).
Sloan et al. teach evaluating the effects of OHCbl, MeCbl, CNCbl, methionine and betaine on cblC deficient zebrafish, specifically having a mutation in MMACHC, the gene responsible for processing and trafficking of vitamin B12 (abstract; p.2117-2118, Response to established and potential small molecule therapies). Sloan et al. found that while OHCbl decreased MMA concentrations, it did not improve HAA as well as other treatments aimed at the reduction of homocysteine and the improvement of methionine deficiency (MeCbl, betaine and methionine). They found MeCbl was the most effective treatment to improve growth parameters in the cblC zebrafish despite having no effect on the metabolites measured (p.2118). Sloan et al. teach “This suggests that the further exploration of MeCbl treatment in patients could be considered but combination with OHCbl would likely be necessary as MeCbl alone showed only a small decrease in [MMA] in the cblC zebrafish. The zebrafish exhibited symptoms of retinal degeneration known to occur in patients with cblC deficiency (abstract).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a high-dose of MeCbl, and in combination with OHCbl to treat a child with a cblC deficiency and suffering from retinal degeneration.
According to MPEP 2144.06: “It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art.” In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Combining known therapies into a single therapy is a commonly applied method for identifying improved therapeutic outcomes with minimal adverse effect for the patient because each monotherapy is already known to be effective. Here, MeCbl was observed to have a positive effect on the growth of zebrafish in a cblC deficient/MMACHC mutant model, while OHCbl was observed to reduce/improve concentrations of MMA. Thus, the skilled artisan would have been motivated to combine the two drugs wherein they each produce different effects for the treatment of patients with cblC deficiency and suffering from retinal degeneration. Additionally, Sloan et al. expressly teach “MeCbl treatment in patients could be considered but combination with OHCbl would likely be necessary as MeCbl alone showed only a small decrease in [MMA] in the cblC zebrafish”.
With respect to administering a high-dose of MeCbl, the amount of MeCbl taught by Chang et al. for the treatment of vitamin deficiency overlaps with the range recited in present claims 1 and 21. One having ordinary skill in the art would have been motivated to optimize the concentration further, in view of the teachings by Carrillo-Carrasco et al., because a daily high dose of an alternative cobalamin derivative, OHCbl at 20 mg/day was dose-dependently effective in improving MMA plasma concentrations and tHcy levels. Carrillo-Carrasco et al. teach “this suggests that higher OHCbl doses might be required to achieve an optimal biochemical response in cblC patients” (p.728, right col., first para). Carrillo-Carrasco et al. teach treatment goals in patients with cblC should include normalizing biochemical parameters.
When Carrillo-Carrasco et al. is considered in view of the teachings of Chang et al. and Sloan et al., wherein Sloan et al. concluded both OHCbl and MeCbl may be needed to treat patients with cblC deficiency and retinal degeneration, the ordinary artisan would have been motivated to optimize and increase the daily dosage of MeCbl as done by Carrillo-Carrasco et al.
See MPEP 2144.05(II), “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.”.
The recitation “wherein retinal function is improved in the human subject following the administering” in present claim 6 necessarily occurs upon performing the positively recited steps.
The limitation “further comprising performing an assay on a biological sample from the subject” in claim 23 is met where Carrillo-Carrasco et al. and Sloan et al. teach measuring MMA and tHcy levels.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699