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 .
Election/Restrictions
Applicant’s election of Group (i) in the reply filed on 11/18/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of
(i) L-cysteine as the elected antioxidant species;
(ii) Polysorbate 80 as the elected surfactant species, and
(iii) propylene glycol, water, and a combination of sodium acetate and glacial acetic acid as the elected pharmaceutically acceptable excipients, in the reply filed on 11/18/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 8, 13, and 14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention/species, there being no allowable generic or linking claim.
Expansion of Election of Species Requirement
A reasonable and comprehensive search conducted by the Examiner determined that the prior art at the time of the present invention was such that it did anticipate or render obvious the elected species. In light of this discovery, the search is expanded to BHT as the expanded antioxidant and tartaric acid and water as the expanded excipients. However, the search has not been expanded to the full scope of antioxidant and pharmaceutically acceptable excipients.
Priority
This application is a filing under 35 U.S.C. § 371 of International Application No. PCT/IN2021/050771, filed August 11, 2021, which claims priority to Indian Patent Application No. 202021034467, filed August 11, 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/28/2023, 02/12/2026, and 02/24/2026 has been considered by the examiner.
Claim Status
Claims 1-14 are pending. Claims 8 and 13-14 are withdrawn. Claims 1-7 and 9-12 are examined in accordance to the elected species and the expanded species.
Claim Objections
Claim 9 is objected to because of the following informalities: the article “the” is missing in from of formulation. Appropriate correction is required.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-3, 5-7, and 12 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sakaguchi et al (JPH11236331A). The translated English version is cited and a copy is provided. However, the original copy is cited in the IDS filed on 03/28/2023.
Sakaguchi teaches a storage stable vitamin A solubilization preparation containing vitamins A having vitamin A activity, a surfactant for solubilizing the vitamins A in an aqueous solution, and a stabilizer for stably presenting the vitamins A in the aqueous solution, wherein the average particle diameter of the vitamins A in the aqueous solution is 50 nm or less. (See claim 1.) Moreover, Sakaguchi teaches a preferred vitamin A solubilized preparation was prepared by mixing aqueous and oil phases containing the following components:
Aqueous phase: Tartaric acid (a stabilizer): 1 g, Purified water 1500 g (a specific concept of "pharmaceutically acceptable excipients");
Oil phase: Vitamin A palmitate: 1 g, Polysorbate 80 (a surfactant): 161.15 g, BHT (an antioxidant): 0.24 g, Cholecalciferol (a vitamin D agent): 0.01 g, Tocopherol acetate (a vitamin E agent): 36 g, phytonadione (a vitamin K agent): 1.6 g.
First, each constituent material of the oil phase was placed in a glass beaker having a capacity of 500 ml and stirred using a magnetic stirrer Additionally, tartaric acid and water for injection were added to a 3L stainless steel beaker to dissolve it completely. Next, while stirring the tartaric acid solution, the previously prepared oil phase was gradually added to obtain a transparent mixed solution. Further, water for injection was added to the mixed solution to bring the total volume to 2L, thereby preparing a vitamin A solubilized preparation. These results indicate that the vitamin A solubilized preparations of Examples 1 to 4 hardly damage the vitamin A compounds even in aqueous solution and maintains their activity Furthermore, since almost no change in average particle size was observed over time, it can be concluded that the solubilized state is maintained stably over a long period of time. (See Example 2.)
The amount of phytonadione is 1.6 g in the 2 L total volume. Since the total final volume is 2 L, the amount of phytonadione is (1.6 g X 1000 mg) / (2L X 1000 ml) = 0.8 mg/ml of the total preparation.
The amount of phytonadione is 0.8 mg/ml of the total preparation.
The amount of BHT (antioxidant) is 0.24 g in the 2 L total volume. Since the total final volume is 2 L, the amount of BHT is (0.24 g X 1000 mg) / (2 L X 1000 ml) = 0.12 mg/ml of the preparation.
The amount of BHT (antioxidant) is 0.12 mg/ml of the preparation.
The amount of polysorbate 80 (surfactant) is 161.15 g in the 2 L total volume. Since the total final volume is 2 L, the amount of polysorbate 80 is (161.15 g X 1000 mg) / (2 L X 1000 ml) = 80.58 mg/ml of the preparation.
The amount of polysorbate 80 (surfactant) is 80.58 mg/ml of the preparation.
Accordingly, Sakaguchi does not specifically teach the stability of the formulation when stored for six months in a sealed and sterile vial at 25°C/ 60% RH and 40°C/ 75% RH contains no more than 1.0% of individual oxidative degradation products and no more than 3.0% of total degradation products as measured by HPLC as recited in claim 12. However, said limitation is the characteristic or the property of the preparation. Since the structure recited in Sakaguchi is substantially identical to that of the claims, the claimed properties are presumed to be inherent. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed method is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
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. 1-7 and 9-12
Claims 1, 2, 3, 5, 6, 7, 10, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Sakaguchi et al (JPH11236331A) as applied to claims 1-3, 5-7, and 12 as set forth in the 10-rejection above.
The teaching of Sakaguchi has been discussed supra.
Sakaguchi does not teach a mixture of propylene glycol and water as recited in claim 10. However, Sakaguchi teaches a Soluble Preparation of vitamin A where each aqueous phase having the following composition and an oil phase were mixed to prepare a vitamin A solubilized preparation.
Aqueous phase Propylene glycol: 400 g Sodium metaphosphate (stabilizer): 5 g Purified water: 395 g. Oil phase Vitamin A acetate: 50 g Polyoxyethylene hydrogenated castor oil 60 (surfactant): 150g. First, propylene glycol and an aqueous solution of sodium metaphosphate dissolved in purified water were mixed in a stainless-steel beaker having a capacity of 2 L to prepare an aqueous phase. (See Example 1.)
It would have been prima facie obvious to one of ordinary skill at the time the invention was filed in the art to have substituted the aqueous phase of Example 2 comprising tartaric acid and water with the aqueous phase of example 1 comprising propylene glycol and water to give Applicant’s claimed invention. One would have been moativated to do so, because Sakaguchi teaches both phases are functionally equivalent or interchangeable as in all examples 1-4 90% of vitamin A is maintained or obtained. (See Table 4.) As such, one would reasonably expect the substitution to be functionally equivalent.
Claims 1, 2, 3, 4, 5, 6, 7, 9, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Sakaguchi et al (JPH11236331A) as applied to claims 1-3, 5-7, and 12 as set forth in the 10-rejection above in view of Savarese et al (US9,220,700B2) and Koneru et al (US10,028,921B1)
The teaching of Sakaguchi has been discussed in the 102-rejection set forth above
Sakaguchi does not teach the antioxidant is L-cysteine and pH from about 3.5 to 7. Moreover, Sakaguchi does not teach a buffering agent comprising sodium acetate and glacial acetic acid in the amount of 0.05 mg to 1 mg/ml of the formulation. However, Sakaguchi teaches as a conventional technique for stabilizing vitamin A, a method using an antioxidant is known. For example, a method of adding a fat-soluble antioxidant such as dibutyl hydroxytoluene (BHT) and butyl hydroxyanisole (BHA) and a water-soluble antioxidant such as ascorbic acid, hydroquinone and cysteine. (See paragraph [0004].) Sakaguchi also teaches the preparation may use an electrolyte component as additive, a pH adjuster, and various buffer solu8tions. (See last paragraph of page 5.)
Savarese teaches a method of making and using physiological cysteine solutions useful for reversing a neuromuscular blockade caused by a cysteine-reversible neuromuscular blockade agent, that overcomes problems of cysteine precipitation and dimerization. (See Abstract.) Moreover, Savarese teaches the term "cysteine' includes both L-cysteine and D-cysteine, or any mixture thereof, e.g., a racemate, unless other specified. As described below, use of the L- or D-isomer of cysteine can be beneficial in certain situations. For example, L-cysteine is typically cheaper and more readily available. However, when administering large amounts of cysteine, the D-isomer of cysteine may be preferred because it is also active and tends to minimize side effects (e.g., adverse cardiovascular effects).
Koneru teaches phytonadione Injectable Emulsion, USP, is a yellow, sterile, aqueous colloidal solution of vitamin K1, with a pH of 3.5 to 7.0. It is available for injection by the intravenous, intramuscular, and subcutaneous route. Each 0.5 mL contains 1 mg phytonadione (Vitamin K1), 10 mg polysorbate 80, 10.4 mg propylene glycol, 0.17 mg sodium acetate anhydrous, and 0.00002 mL glacial acetic acid. Additional glacial acetic acid or sodium acetate anhydrous may have been added to adjust pH to meet USP limits of 3.5 to 7.0. (See lines 50-60 of column 1.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to have substituted the BHT taught by Sakaguchi with the L-cysteine taught by Savarese as the antioxidant and further included the glacial acetic acid or sodium acetate buffer taught by Koneru to adjust pH to give a pH of 3.5 to 7.0 to give Applicant’s claimed invention. One would have been motivated to do so, because Sakaguchi teaches cysteine and BHT are interchangeable antioxidant and because Savarese teaches L-cysteine is typically cheaper and more readily available and is used in small amount when administered, and also because Koneru teaches a buffer solution comprising 0.17 mg sodium acetate and 0.00002 mL glacial acetic acid that be used to adjust the pH of phytonadione to 3.5 to 7.0. One would reasonably expect the substitution and the inclusion of the buffer solution to give an injectable preparation of phytonadione with a long-term storage stability.
With respect to the claimed sodium acetate and glacial acetic acid being present in amount from about 0.05 mg to 1 mg per ml of the formulation. The 0.17 sodium acetate anhydrous, and 0.00002 mL glacial acetic give a buffer solution in an amount of 850 mg/ml. However, for a volume of 2 L or 2000 ml, the 850 mg/ml in a 2 L volume would give 0.43 mg/ml of the buffer solution, meeting the limitation of claim 9.
Conclusion
Claims 1-7 and 9-12 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628