DETAILED ACTION
Status of the Application
Receipt is acknowledged of Applicants’ claimed invention filed on 12/27/2022 in the matter of Application N° 18/146,499. Said documents are entered on the record. The Examiner further acknowledges the following:
The present application, filed on or after December 27, 2022, is being examined under the first inventor to file provisions of the AIA .
Thus, claims 1-25 represent all claims currently under consideration.
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.
Claims 1-25 are rejected under 35 U.S.C. 103 as being unpatentable over Dusci (US10966990B2).
Regarding claims 1, 5, 6, 7, 16, 20, and 21, Dusci teaches a flexible plastic bag that contains a terminally sterilized, preservative-free aqueous midazolam solution that contains 0.25 to 1.5 mg/ml of midazolam and has a pH between 2.5 and 3.5 (See Abstract, claim 1, and claim 7). Dusci teaches flexible plastic containers (bags) that are sold commercially, like Excel, are made of three layers of ethylene-polypropylene with an outer layer of polyester elastomer (See pg. 5, column 4, lines 13-16). Dusci teaches polypropylene, polyethylene, and ethylene/propylene copolymers are the main polymeric materials that can be utilized (See pg. 5, column 3, lines 48-51).
Regarding claims 2 and 3, Dusci teaches the preferred tonicity agent is sodium chloride. The formulation should contain about 9 mg/ml of the midazolam if sodium chloride is the tonicity adjusting agent and the midazolam concentration is around 1.0 mg/ml (See pg. 4, column 2, lines 51-56, table 1, and claim 3).
Regarding claim 4, Dusci teaches when the pH approaches around 3.2, midazolam at a dosage of 2 mg/mL dissolves in a solution of 0.9% NaCl (See pg. 5, column 3, lines 3-6).
It would have been obvious to one of ordinary skill in the art prior to the instant effective filing date to use the teachings of Dusci wherein the terminally sterilized, preservative-free aqueous midazolam solution, which has a pH of 2.5 to 3.5 and contains 0.25 to 1.5 mg/ml of midazolam, is contained in a flexible plastic bag.
Regarding claim 8, Dusci teaches the ready to-use aqueous midazolam solution, which contains about 0.5 mg/ml of midazolam and is terminally sterilized and preservative-free (See claim 5).
Regarding claim 9, Dusci teaches aqueous midazolam solution that is terminally sterilized and free of preservatives, containing 0.25 to 1.5 mg/ml of midazolam (See Abstract).
Regarding claim 10, Dusci teaches there are roughly 450 mg of sodium chloride in a 50 ml solution with a midazolam concentration of 1 mg/ml and 100 ml solution with a midazolam concentration of 1 mg/ml (See pg. 4, column 2, lines 55-59).
Regarding claims 11, 15, 17, 23, 24, and 25, Dusci teaches the current invention’s formulations will range in concentration from roughly 0.5 mg/ml to 1.25 mg/ml. The ideal concentration range for the formulation is between 0.5 and 1.0 mg/ml. The amount of sodium chloride to be included in the formulation is about 9 mg/ml of the midazolam solution, where in the pH is 2.5 to 3.5. The primary polymeric materials which may be used include, polypropylene, polyethylene, ethylene/propylene copolymers etc. Dusci teaches as part of anesthesia or when a patient is receiving treatment in a critical care unit, midazolam is used intramuscularly or intravenously for preoperative sedation anxiolysis, and amnesia (See pg. 4, column 2, lines 34-40, lines 55-56, claim 7, and pg. 5, column 4, lines 43-46 and See pg. 4, column 1, lines 22-23 and lines 37-40 and claims 4 and 5).
Regarding claim 12, Dusci teaches, the ready to use midazolam solution, which is terminally sterilized and free of preservatives, contains about 9 mg/ml of sodium chloride solution (See claim 12).
Regarding claim 13, Dusci teaches, the ideal concentration range for the formulation is between 0.5 and 1.0 mg/ml and midazolam at a dosage of 2 mg/mL dissolves in a solution of 0.9% NaCl (See pg. 4, column 2, lines 34-40 and pg. 5, column 3, lines 3-6 and claim 5).
Regarding claim 14, Dusci teaches, the ideal concentration range for the formulation is between 0.5 and 1.0 mg/ml and midazolam at a dosage of 2 mg/mL dissolves in a solution of 0.9% NaCl. If sodium chloride is the tonicity adjusting agent and the midazolam concentration is about 1.0 mg/ml, the amount of sodium chloride to be included in the formulation is about 9 mg/ml of the midazolam solution (See pg. 4, column 2, lines 34-40, and lines 53-56, and pg. 5, column 3, lines 3-6 and claims 1 and 6).
Regarding claim 18, Dusci teaches, stability studies were conducted to confirm that the formulation was stable. A graphical illustration of the premix formulation midazolam injections chemical stability after six months of storage under accelerated settings can be found in FIG. 1-4. The pH and color of the liquids inside Nexcel bags did not change after six months of stability at 40 degrees Celsius. There was no apparent reduction in the Midazolam assay after six months at 40 degrees Celsius in comparison to T=0 sterilized. The formulations total impurities in the Nexcel bag are still equivalent to the outcomes at T=0 (See pg. 6, column 6, lines 26-36).
Regarding claim 19, Dusci teaches the amount of premixed formula determines the bag’s volume. Based on current midazolam dosage, the volume of the premixed formula can range from 10 ml to 1000 ml, with 50 ml and 100 ml being preferred (See pg. 5, column 3, lines 32-35).
Regarding claim 22, Dusci teaches for preoperative sedation, anxiolysis, and amnesia, midazolam is administered intramuscularly or intravenously. It can also be continuously infused into the veins to sedate patients who are intubated and on mechanical ventilation as part of anesthesia or while they are receiving treatment in a critical care unit (See pg. 4, column 1, lines 22-23 and lines 37-40).
Response to Arguments
Applicant's arguments filed August 27, 2025 have been fully considered but they are not persuasive. Dusci discloses terminally sterilized, preservative free aqueous midazolam solutions having concentrations of 0.25-1.5 mg/mL and a pH of 2.5-3.5, contained in flexible plastic bags used for storage and administration. Dusci also expressly teaches the use of polymeric packaging materials such as polypropylene, polyethylene, and ethylene/propylene copolymers as suitable materials of construction for the flexible container. Thus, Dusci provides both (i) the same type of midazolam aqueous formulation at essentially overlapping concentrations with those presently claimed and (ii) flexible polymeric containers that encompass the polymers recited in the instant claims.
Applicant argues that Dusci does not specifically disclose or test the long-term stability of midazolam when stored in a flexible container fabricated from a multilayer sheeting comprising polypropylene, polyamide, or polyethylene. Applicant further argues that Dusci’s working example utilizes a Nexcel® bag having an ethylene-vinyl acetate (EVA) inner layer, and therefore one of ordinary skill would not reasonably expect stable storage of midazolam in the claimed multilayer container.
These arguments are not persuasive. As set forth in MPEP 2144, a reference need not explicitly teach long-term stability for a particular polymer combination in order for the selection of one known, suitable polymeric container material over another to be considered an obvious design choice. Dusci expressly teaches that polypropylene, polyethylene, and ethylene/propylene copolymers are suitable polymeric materials for fabricating flexible bags for the same use, storage and delivery of aqueous midazolam solutions. The polymeric container materials recited in the present claims (polypropylene, polyamide, polyethylene) are all well-known pharmaceutical packaging polymers with established compatibility for aqueous parenteral solutions, and selection among them represents no more than the predictable substitution of one known container material for another, pursuant to KSR v. Teleflex. Applicant’s focus on the EVA-lined Nexcel bag described in one example of Dusci does not overcome the fact that Dusci broadly teaches multiple alternative polymeric materials. The example does not limit the broader teachings. See MPEP 2124 (“Examples do not limit the disclosure”). In view of Dusci’s express identification of polypropylene and polyethylene as suitable materials for constructing the flexible container, one of ordinary skill in the art would have had a reasonable expectation of success in using such materials for housing a midazolam premix solution, especially because the formulation disclosed in Dusci (preservative-free aqueous midazolam at overlapping concentration ranges and acidic pH) is substantially similar to the formulation recited in the present claims.
Applicant’s argument regarding stability testing also does not established nonobviousness. A reference is not required to demonstrate the same duration or temperature stability testing as claimed. It must only provide sufficient teachings to render the claimed selection of materials and formulation obvious to try with a reasonable expectation of success. Dusci provides such teachings by identifying the same formulation type and identifying the same formulation type and identifying the same class of suitable container polymers. Routine optimization of packaging material based on known suitable substitutes is considered obvious where, as here, the art provides motivation and recognizes equivalent container materials. See MPEP 2143, and 2144.
Accordingly, Applicant has not shown error in the underlying factual findings, nor has applicant identified any teaching in Dusci that would have dissuaded the skilled artisan from employing the claimed polypropylene, polyamide, or polyethylene, containing multilayer containers. The argument presented do not overcome the prima facie case of obviousness. The rejection is therefore maintained, and the application is made final.
Conclusion
No claim is allowed.
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Robert A. Wax, can be reached at telephone number (571) 272-0623. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KIMBERLY BARBER/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615