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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/23/2025 has been entered.
Applicants' arguments, filed 12/23/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1, 3-5, 8-11, and 13-22 are pending and under examination.
Claim Rejections - 35 USC § 112(b) or pre-AIA 2nd ¶
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 13 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 recites “water-soluble liquid selected from glycols, glycol ethers and mixtures thereof per liter of aqueous injectable composition,” and it is unclear if the glycols, glycol ethers and mixtures thereof are intended to be the water-soluble liquid selected from the group consisting of propylene glycol, glycol ethers of molecular weight of no more than 300, polyethylene glycol of molecular weight of no more than 300, dipropylene glycol monomethyl ether, and mixtures thereof, as recited in claim 1, or something else. For purposes of examination, the claim is interpreted as those recited in claim 1.
Claim Rejections - 35 USC § 103
Claims 1, 3-5, 8-11, 13, and 15-22 stand rejected under 35 U.S.C. 103 as being unpatentable over Smith (WO 2013/171538 A1), in view of Heep et al (US 2015/0328318 A1) and Cruz et al (US 20080039422 A1).
Smith teaches injectable trace element solutions comprising copper at 15 mg/ml, manganese at 10 mg/ml, zinc at 60 mg/ml, selenium at 5 mg/ml, vitamin B12 (cyanocobalamin) at 1.5 mg/ml, water, and other excipients (pg 6 lines 6-11, pg 7 line 9). The zinc may be at least 24 mg/ml. Vitamin B12 is at least 0.6 mg/ml, where some embodiments disclose at least 1.5 mg/ml (pg 4 lines 1-6, claim 4). The trace elements were dissolved in water and complexed with EDTA. Vitamin B12 is not very stable in solution and degradation is observed on storage; to remedy this, a stabilizer may be added, such as butaphosphan (pg 7 lines 10-12). The injection is administered subcutaneously between 1 ml per 50 kg of bodyweight and 1 ml per 100 kg of bodyweight, which can improve the trace mineral status of an animal (pg 14 lines 12-20). The trace element solution is predominantly to be used for cattle (pg 4 lines 19-20).
Smith does not teach an embodiment with the water-soluble liquid, their amounts, an embodiment with a pH of claim 17, nor the specific amount of water of claim 18.
Heep et al teach injectable preparations for livestock comprising vitamin B12 (abs, ¶ 40, ex. 1-8) where glycols may be present at 0.01 to 10% (equivalent to 0.1 to 100 g/L), such as fatty alkyl polyethylene glycol ethers (wetting agent) and propylene glycol (cosolvent) and the cosolvents improve solubility of certain ingredients of the formulation (¶ 28, claims 10, 11, 24). The pH of the solutions may be adjusted by adding acids or bases, and is typically 2-11, with working embodiments with a pH of 5.6 +- 0.2 (¶ 51, ex. 1-8, claims 8 and 9). In one embodiment, water constitutes over 75% m/V of the formulation, in other embodiments, water is added to achieve final injection volume (claims 15 and 16, ex. 1-8).
Cruz et al teach that propylene glycol was known to increase the stability of vitamin B12 (cyanocobalamin), over time (abs, ¶ 126, tables 3A, 4). Polyethylene glycol is also taught to be suitable, including PEG 200 or PEG 300 (abs, ¶¶ 79-80, claim 9). Specific embodiments from the tables show propylene glycol from 10-60% v/v (tables 3A, 4), which is calculated to be 103.6 g to 621.6 g per liter. However, it is taught that the glycols may be present from 5-95% v/v (¶13), which would expand the range further.
Regarding claim 1, it would have been obvious to include glycols, such as propylene glycol, PEG 200, PEG 300, etc., to the injectable solution of Smith, where it was known vitamin B12 is not very stable, and Heep et al teach that propylene glycol can improve the solubility of certain ingredients (e.g., vitamin B12) in solution, and therefore the stability. Additional motivation to include propylene glycol is provided by Cruz et al, where it was known that glycols improve the stability of vitamin B12, where Smith and Cruz et al are both directed to compositions for improving the stability of vitamin B12.
Regarding the amount of glycols, it would have been obvious to include known amounts of glycols for improving the stability of vitamin B12, such as from 103.6 to 621.6 g per liter, in the case of propylene glycol, as taught by Cruz et al. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 3, the injectable solution made obvious above comprise copper and zinc, thereby meeting the claimed limitation.
Regarding claims 4, 5, 8, 9, 15, and 22, the injectable solution made obvious above comprises copper at 15 mg/ml, manganese at 10 mg/ml, zinc at 60 mg/ml, selenium at 5 mg/ml, resulting in 90 g/L, falling within the claimed ranges.
Regarding claims 10 and 11, the injectable solution made obvious above comprises cyanocobalamin at 1.5 mg/ml (1.5 mg/ml = 1.5 g/l), falling within the claimed range.
Regarding claims 13, it would have been obvious to vary the amounts of glycols used to improve the solubility and stability of vitamin B12, within the ranges taught to be suitable by Cruz et al, such as from 103.6 to 621.6 g/L. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 16, it would have been obvious to vary the amount of glycols for the same reasons discussed above, within the ranges taught by Cruz et al above and for the same reasons. Further, it would have been obvious to adjust the amount of zinc and cyanocobalamin within the suitable ranges, such as at least 24 mg/ml and at least 0.6 mg/ml, respectively. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Regarding claim 17, it would have been obvious to select a pH from a range taught to be suitable for injectable vitamin B12 solutions, such as 5.6 +- 0.2 from the preferred embodiments, as taught by Heep et al, falling within the claimed range.
Regarding claim 18, both Smith and Heep et al teach the inclusion of water, with Heep et al teaching water at 75% in terms of m/v, where various embodiments teach the addition of water to desired injection volume; it would therefore be reasonably expected that a skilled artisan would adjust the amount of water to desired volume of injectable solution, such as those amounts instantly claimed.
Regarding claims 19 and 20, it would have been obvious to supplement the nutritional status of livestock by subcutaneously administering the injection made obvious above to livestock, including cattle, as taught by Smith above.
Regarding claim 21, where the trace element solutions of Smith are injected at a dosage of 1 ml per 50 kg of bodyweight and 1 ml per 100 kg of bodyweight, it would be expected that depending on the weight of the livestock, the dose would fall within the range of the instant claim. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I).
Response to Arguments
First, Applicants assert Smith, Heep, Cruz, and Laurie, alone or in any combination, fail to teach or suggest the claimed invention. Applicants assert that examples 1-4 are comparative examples, which are not representative of the currently claimed invention, and assert examples 1-4 show that other techniques for stabilizing vitamin B12 were ineffective.
Second, Applicants assert they do not agree that it is unclear what the critical feature that leads to the observed stability is and that the application provides an aqueous injectable nutritional supplement for livestock comprising vitamin B12 and EDTA chelated with trace elements in combination with glycol and/or glycol ethers, which is surprisingly and unexpectedly able to provide the nutrients at the high concentrations required, while also remaining stable over prolonged periods of time in storage. Applicants assert that the working examples provided in the specification and in the inventor declaration dated April 17, 2025 support this interpretation, which are summarized below.
Applicants assert examples 1-7 show compositions falling within the scope of the pending claims that are surprisingly stable over time, and asserts greatly improved stability. Applicants assert it has been surprisingly found that compositions containing vitamin B12 of high trace element complexes of EDTA can be stabilized for years at elevated temperatures solely by the use of a polyalkylene glycol. Applicants assert this effect is unexpected.
Applicants assert that it is clear from table 7 that adding propylene glycol into vitamin B12 aqueous solutions would keep vitamin B12 at a high level for a prolonged time up to 5 months at 40 deg C, in the presence of significant amounts of trace element complexes. Applicants assert that it can be seen in view of working examples 1-6 that combining propylene glycol, glycol ethers, and polyethylene glycol, and/or dipropylene glycol monomethyl ether, which has a specific molecular weight at a specific amount, that vitamin B12 is stable over long periods of time and provide the nutrients at the high concentrations required.
Third, Applicants assert the declaration shows the formulations are surprisingly stable over at least two years, where all three batches kept vitamin B12 level (lower limit 1.8 g/L) stable over 24 months at different storage conditions in the presence of significant amounts of trace element complexes.
Fourth, Applicants assert Heep et al relates to preparations comprising vitamin B12 and butanol, and discloses glycerol, propylene glycol, in a list for possible water-miscible solvents. Applicants assert none of the working examples of Heep et al disclose a water-miscible substance as a solvent. Based on the teaches of Heep et al, the skilled person would not be able to know whether butanol may work in the presence of significant amounts of trace element complexes or know that glycols or glycol ethers could act synergistically for stabilizing vitamin B12. Applicants assert the skilled person would not get any teaching from Heep et al to arrive at the presently claimed invention.
Fifth, Applicants assert Cruz et al does not mention the stability of vitamin B12 in the presence of significant amounts of trace element complexes, and it would require creative work to work out specific compositions that can work together to stabilize vitamin B12 with trace elements at the high concentrations require.
First, respectfully, this argument is not persuasive. The examiner recognizes that examples 1-4 are comparative examples, however, it appears that some of the comparative examples without the water-soluble liquid as instantly claimed were stable. For example, formulations 1-3 do not comprise a water-soluble liquid as instantly claimed and while some loss is observed initially, over time the amount of cyanocobalamin remains the same, while formulations 4-6 appear to be less stable. From this, it does not appear that in all cases, the inclusion of the water-soluble liquid as instantly claimed is required for stability of cyanocobalamin in the presence of trace element complexes.
Second, respectfully, this argument is not persuasive. The examiners position that the results are unclear is due in part to the fact that the results are not consistent across the tested comparative embodiments and the tested working embodiments. As noted above, some of the comparative embodiments appear to be stable and do not comprise the water-soluble liquid as instantly claimed. Likewise, when comparing the comparative embodiments to the working examples of table 7, formulations 11, 12, and 26 (23.4.18) all show some initial loss that then show some loss over time, which is similar to the comparative embodiments. Even comparing formulation 26 (23.4.18) and 26 (23.6.18), which appear to comprise the same components and amounts, one is more stable than the other, though both show loss of cyanocobalamin over time. Formulation 26 (21.9.18) in table 9 shows no loss over 4 months at 40 deg C, and appears to be the same composition as the two previously mentioned formulation 26 formulations, just with different batch numbers, and it is unclear why this formulation is stable yet the others are not. As previously recognized, it does appear that some formulations show improved stability over some of the comparative embodiments, but the results are not consistent, where even the same formulations with different batch numbers are not consistently stable. The inclusion of the water-soluble liquid in all embodiments does not result in stable formulations with no, or virtually no loss of cyanocobalamin. Applicants main argument appears to be one of stability, however, the examiner is not sure what is required for the compositions to be considered stable. For example, is no loss required to be stable? Is some initial loss and then virtually no loss stable? Is some loss over time stable, and if so, how much? The instant specification does not appear to provide the answer to the proposed questions.
In addition to the lack of consistency across the comparative and working embodiments, purely arguendo, even if some of the working embodiments that fall within the scope of the instant claims do appear to be more stable than the comparative and other working examples that also fall within the scope of the instant claims, the tested embodiments do not appear to be commensurate in scope with the full breadth of the instant claims. For example, the instant examples only test cyanocobalamin in specific amounts, and is not clear to the examiner if the results would be the same for any from of vitamin B12 and in any amount. The claims recite one or more trace elements are in an amount of 1-100 g/L wherein the one or more trace elements comprise zinc, copper, manganese, selenium, and chromium. From the tables, it appears that the total range of trace elements tested for the working embodiments range from 47-65 g/L. The specification provides no examples with concentrations of trace elements at the lower and upper ranges, and it is not clear if the compositions would be stable at those amounts. Likewise, embodiments comprising manganese and chromium are not tested, and their effects on vitamin B12 are unknown. Additionally, the claims recite a wide range of water-soluble liquids in a wide range of amounts. There appears to be no examples where dipropylene glycol monomethyl ether is explicitly disclosed in an amount of 20-300 g/L, where example 3 does not provide sufficient information to determine the concentration. Examples 1 and 2 teste propylene glycol in an amount of 100 g/L and 150 g/L, and the amounts are not sufficiently disclosed in example 3. Polyethylene glycol is only exemplified in example 5 at 127 g and the concentration used in example 6 is not disclosed. Therefore, there appears to be no evidence to suggest that the claimed invention would have suitable stability across the entire claimed range of 20-300 g/L. While Applicants do not have to test every concentration for every component, Applicants do have to provide proof of a trend in the exemplified data which would allow the skilled artisan to reasonably extend the probative data. See MPEP 716.02(d). The examiner is willing to consider functional limitations regarding stability parameters under certain conditions, in addition to limitations that place the claimed commensurate in scope with the examples.
Third, respectfully, this argument is not persuasive. The declaration appears to test three batches of the same product, where the batches are said to remain potent, sterile, with no changes to the product packaging, however, no explicit or objective data was provided. The results appear to be based on visual observations of the batches over time, but provides no actual data on the content of the cyanocobalamin in terms of its concentration in g/L over the 24 month period. Without explicit data of the change in concentration of cyanocobalamin over time, it is difficult to compare these results to embodiments that do not comprise the water-soluble liquid, in order to determine if there is an improvement to the stability of cyanocobalamin.
Fourth, respectfully, this argument is not persuasive. 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). Heep et al was cited for simply teaching that glycols and glycol ethers were known to be used in injectable solutions for livestock comprising vitamin B12, and were known to improve the solubility of certain ingredients in the formulation, such as vitamin B12. While Heep et al teach preparations comprising vitamin B12 and butanol, and butanol is used for other purposes, Examiner again notes that butanol is not a claimed component and was not included as a part of the previous rejection. Applicants again are focused on butanol, but it is important to note that Smith is modified by Heep et al, not the other way around. Here, Heep et al is not being modified to include trace element complexes, rather, Smith is modified to include a known component suitable to improve the solubility of certain ingredients, including vitamin B12. Therefore, the skilled artisan would have motivation to include propylene glycol, etc., to the formulation of Smith, in order to improve the solubility of vitamin B12.
Fifth, respectfully, this argument is not persuasive. 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). Cruz et al was cited for simply teaching that propylene glycol was a known stabilizer of vitamin B12 in parenteral formulations. As such, it is obvious to include known vitamin B12 stabilizers to other formulations comprising vitamin B12, such as the formulations made obvious above, where Smith teaches vitamin B12 was known to have poor stability. Where it would be generally expected by the skilled person that trace elements can affect the stability of vitamin B12, adding a known stabilizer for vitamin B12, which was already known to have poor stability, would have been obvious.
Claim 14 stands rejected under 35 U.S.C. 103 as being unpatentable over Smith (WO 2013/171538 A1), Heep et al (US 2015/0328318 A1), and Cruz et al (US 20080039422 A1), as applied to claims 1, 3-5, 8-11, 13, and 15-22 above, and further in view of Laurie et al (US 6638539 B2).
Smith, Heep et al, and Cruz et al are discussed above but do not teach an embodiment specifically disclosing disodium EDTA.
Laurie et al teaches it was known to use disodium EDTA in complexing with trace elements in injectable solutions for providing the trace elements to livestock (abs, col 2 lines 12 and 20-23).
It would have been obvious to select from disodium EDTA, where it is taught to be suitable for complexing with trace elements in injectable solutions. MPEP 2143(I)(B).
Response to Arguments
Applicants assert Laurie fails to cure the above mentioned deficiencies of Smith, Heep et al, and Cruz et al.
This argument is not persuasive. Examiner disagrees for the same reasons above and of record.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSHUA A ATKINSON whose telephone number is (571)270-0877. The examiner can normally be reached M-F: 9:00 AM - 5:00 PM + Flex.
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612