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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114 was filed in this application after a decision by the Patent Trial and Appeal Board, but before the filing of a Notice of Appeal to the Court of Appeals for the Federal Circuit or the commencement of a civil action. 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examination under 37 CFR 1.114 and the fee set forth in 37 CFR 1.17(e) has been timely paid, the appeal has been withdrawn pursuant to 37 CFR 1.114 and prosecution in this application has been reopened pursuant to 37 CFR 1.114. Applicant’s submission filed on 02/13/2026 has been entered.
Status of the Claims
Per Applicant’s amendment to the claims, submitted on 02/13/2026, claim 21 is newly added. Currently, claims 1 and 3-21 are pending in the instant application.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/20/2026 and 03/04/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103 - Maintained
Claim(s) 1 and 3-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan (previously referenced) in view of Butler (previously referenced).
Response to Applicant Remarks:
Applicant has not currently provided further arguments for the traversal of the currently rejected claims. Accordingly, the rejections are hereby maintained. Applicant has conveyed in Remarks the intent to collect further information to demonstrate unexpected effects and non-obviousness of the instant claims in alignment with the Board Decision (cited in Remarks pages 6-7). As said information has yet to be presented, and therefore cannot be presently considered, the outstanding rejections will be otherwise maintained.
The outstanding rejections will be reiterated below for the purpose of reference.
Reiterated Rejections:
Claim 1 recites a method of making a pharmaceutical composition in a pre-filled syringe comprising:
Preparing a batch solution, wherein preparing the batch solution comprises:
Providing a solvent having an initial dissolved oxygen content
Sparging the solvent with a first inert gas until the solvent has a reduced dissolved oxygen content that is lower than the initial dissolved oxygen content, wherein the reduced dissolved oxygen content is less than about 0.5 ppm
Combining the solvent with an active agent and an antioxidant, wherein the solvent is continuously sparged with the first inert gas during combination with the active agent and the antioxidant
Introducing at least a portion of the of the batch solution of (a) into a syringe to provide the pharmaceutical composition in the pre-filled syringe,
wherein the batch solution of (a) is sparged with a second inert gas when provided in the pre-filled syringe
wherein the second inert gas is the same as or different from the first inert gas
wherein the pharmaceutical composition in the pre-filled syringe has a concentration of total impurities of the active agent of no more than about 5.5% (w/v) after 3 months of storage in accelerated storage conditions
Kannan teaches pharmaceutical compositions comprising epinephrine, an antioxidant, a solvent, and methods of making said compositions. Among the compositions taught by Kannan is the following example 17 (specification column 27):
PNG
media_image1.png
263
410
media_image1.png
Greyscale
The example above containing an active (epinephrine), an antioxidant (sodium metabisulfite), and a solvent (water). Kannan additionally provides the following method for preparing a bulk solution of their compositions (specification column 23, lines 28-51)1:
Water for injection with an acceptable dissolved oxygen content may be added to a manufacturing tank kept under nitrogen pressure
A tonicity regulating agent may be added and mixed
A pH raising agent may be added and mixed
A metal complexing agent may be added and mixed
An antioxidant may be added and mixed
In a separate container a pH lowering agent may be mixed with an active, then added to the manufacturing tank and mixed
The separate container is rinsed with water for injection and added to the manufacturing tank. Rinsing may be repeated up to 3 times
The solution may then mix before the final net weight of the solution is adjusted using water for injection
Kannan further teaches that the composition may be contained in an auto-injector and administered by subcutaneous, intracameral, intravenous, and intramuscular injection (specification column 23, lines 26-27 and 65-67)2. In summary, Kannan teaches a pharmaceutical mixture comprising epinephrine, an antioxidant, and a solvent, the use of an autoinjector to contain said mixture, and a method of making the aforementioned. Kannan, however, does not teach sparging of the solvent or the batch mixture with nitrogen in order to decrease oxygen levels in solution. Though Kannan does not teach the sparging steps of the instant claim, they do teach that ESA formation is influenced by an oxygen-dependent mechanism, and that reducing the availability of oxygen in composition may reduce ESA formation (specification, column 15, lines 33-43). Given the disclosure by Kannan, it would be obvious for a person of ordinary skill in the art to seek out a method of reducing oxygen in pharmaceutical epinephrine compositions in order to prevent the formation of degradants such as ESA. One such method is taught by Butler, as discussed below.
Butler teaches a method of reducing dissolved oxygen content in water whereby an inert gas such as nitrogen is bubbled through water, a process materially identical to gas sparging. Butler specifically bubbles nitrogen through one liter of DI water for 5, 20, 40, and 60 minutes at room temperature (page 211)3. Using this method, Butler found they were able to decrease dissolved oxygen content in water from about 0.5 ppm to about 0.2 ppm per the following Table 2 (page 212):
PNG
media_image2.png
191
285
media_image2.png
Greyscale
Provided the above disclosures, a person of ordinary skill in the art would have found it prima facie obvious at the time of filing to be able to apply the nitrogen sparging method of Butler to the formulation method of Kannan with the reasonable expectation of reducing levels of dissolved oxygen in the solvent and the batch solution, subsequent reduction of ESA degradant formulation during long term storage, and a potential of increasing shelf life.
Claim 2 further limits the method of claim 1 wherein the active agent comprises epinephrine.
As discussed above in the claim 1 rejection, Kannan teaches compositions comprising epinephrine. Accordingly, claim 2 is rejected for the same obviousness reasons as claim 1.
Claim 3 further limits the method of claim 2 wherein the antioxidant comprises sodium metabisulfite and the pharmaceutical composition in the prefilled syringe has a concentration of epinephrine from about 0.01 to about 2 mg/ml.
As discussed above in the claim 1 rejection, Kannan teaches a composition comprising sodium metabisulfite, and wherein epinephrine concentration is 1-10 mg/ml. Per MPEP 2144.05(I):
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.").
Accordingly, claim 3 is rejected for the same obviousness reasons as claim 2.
Claim 4 further limits the method of claim 2 wherein the pharmaceutical composition in the prefilled syringe has a concentration of from about 0.01 to about 2 mg/ml.
As discussed above in the claim 1 rejection, Kannan teaches a composition comprising sodium metabisulfite, and wherein epinephrine concentration is 1-10 mg/ml. Per MPEP 2144.05(I), a case of obviousness exists on the basis of overlapping ranges (see MPEP citation in claim 3 rejection above). Accordingly, claim 4 is rejected for the same obviousness reasons as claim 2.
Claim 5 further limits the method of claim 1 wherein the first inert gas comprises nitrogen.
As discussed previously in the claim 1 rejection above, Butler teaches a method of reducing dissolved oxygen levels in solution by sparging with nitrogen gas. Accordingly, claim 5 is rejected for the same obviousness reasons as claim 1 above.
Claim(s) 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Kannan in view of Butler, and further in view of Belgaid (J. Chem. Pharm. Res., 2014).
Claim 6 further limits the method of claim 1, wherein the solution of (a) is passed through a filter prior to being provided in the pre-filled syringe such that the pharmaceutical composition in the pre-filled syringe is sterile.
While neither Kannan nor Butler explicitly teach the use of a filter, a person of ordinary skill in the art would recognize that filter sterilization is a technique commonly used in order to remove potentially harmful microorganisms in pharmaceutical compositions. For instance, Belgaid teaches the common use of 0.2 um and 0.22 um filters in sterile filtration for pharmaceutical products as defined by the USDA and USP (page 760)4. Accordingly, a person of ordinary skill would find it prima facie obvious at the time of filing to apply sterile filtration to the mixture of Kannan, as Kannan suggests the use of their mixture as an injectable,.
Claim 7 further limits the method of claim 6 wherein the filter comprises pores with an average pore size of about 0.22 um.
As discussed in the claim 6 rejection above, Belgaid teaches the common use of 0.22 um filters for the purpose of sterile filtration. Accordingly, claim 7 is rejected for the same obviousness reasons as claim 6 above.
Claim 8 further limits the method of claim 1 wherein preparing the solution of (a) further comprises combining the solvent with one or more of a tonicity adjusting agent, a buffer system, a chelating agent, and a pH adjusting agent.
The composition taught by Kannan contains sodium chloride as a tonicity agent as well as both sodium hydroxide and hydrochloric acid as pH adjusting agents. Accordingly, claim 8 is rejected for the same obviousness reasons as claim 1.
Claim 9 further limits the method of claim 8 wherein the tonicity adjusting agent comprises sodium chloride, the buffer system comprises tartaric acid and sodium hydroxide, the chelating agent comprises EDTA, and the pH adjusting agent comprises hydrochloric acid.
As previously discussed in claim 8, the composition taught by Kannan comprises sodium chloride, sodium hydroxide, and hydrochloric acid. The composition also comprises disodium edetate dihydrate, also known as EDTA dihydrate. While the composition of Example 17 does not include tartaric acid, Kannan reasonably suggests its inclusion in the composition as a pH lowering agent or a pH raising agent (specification column 5 lines 4-13, column 8 lines 37-45)5. Accordingly, claim 9 is rejected for the same obviousness reasons as claim 8 above.
Claim 10 further limits the method of claim 1 wherein the solvent comprises water for injection (WFI).
As discussed previously in the claim 1 rejection, Kannan teaches a method of making their composition which comprises the use of WFI as the solvent. Accordingly, claim 10 is rejected for the same obviousness reasons as claim 1.
Claim 11 further limits the method of claim 1 wherein preparing the solution of (a) further comprises combining the solvent with additional solvent after combination with the active agent and/or the antioxidant, and wherein the solution of (a) has a final dissolved oxygen content of no more than about 0.9 ppm.
As discussed previously in the claim 1 rejection above, the method taught by Kannan provides step (viii), wherein a final addition of WFI is added to solution to adjust the final net weight; this step occurs after the solvent has been combined with the active agent and antioxidant. With regards to the final dissolved oxygen content, Butler was able to achieve a final dissolved oxygen content in water of about 0.2 ppm after 40 minutes of sparging with nitrogen. Without evidence of the contrary, it would remain obvious to a person of ordinary skill in the art that a similar result may be obtained by sparging the formulation taught by Kannan with nitrogen. Accordingly, claim 11 is rejected for the same obviousness reasons as claim 1.
Claim 16 recites a pharmaceutical composition provided in a pre-filled syringe prepared by a method comprising:
Preparing a batch solution, wherein preparing the batch solution comprises:
Providing a solvent having an initial dissolved oxygen content
Sparging the solvent with a first inert gas until the solvent has a reduced dissolved oxygen content that is lower than the initial dissolved oxygen content, wherein the reduced dissolved oxygen content is less than about 0.5 ppm
Combining the solvent with an active agent and an antioxidant, wherein the solvent is continuously sparged with the first inert gas during combination with the active agent and the antioxidant
Introducing at least a portion of the of the batch solution of (a) into a syringe to provide the pharmaceutical composition in the pre-filled syringe,
wherein the batch solution of (a) is sparged with a second inert gas when provided in the pre-filled syringe
wherein the second inert gas is the same as or different from the first inert gas
wherein the pharmaceutical composition in the pre-filled syringe has a concentration of total impurities of the active agent of no more than about 5.5% (w/v) after 3 months of storage in accelerated storage conditions
Claim 16 recites a pharmaceutical composition that is prepared by a method which is essentially the same as the method of claim 1 above. Accordingly, claim 16 is rejected as being unpatentable over Kannan in view of Butler for the same obviousness reasons as stated in the claim 1 rejection above.
Claim Rejections - 35 USC § 103 – New Grounds of Rejection
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.
Claim(s) 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan in view of Butler and Belgaid, and further in view of Vijay (US 20180200202 A1).
Claim 21 further limits the method of claim 6 wherein the filter comprises regenerated cellulose, polyethersulfone, polyvinylidene fluoride, polytetrafluoroethylene, or a combination thereof.
As iterated in the outstanding rejection of claim 6, the teachings of Kannan, Butler, and Belgaid obviate a method of claim 6 wherein the solution of the instant composition is sterile filtered. None of Kannan, Butler, or Belgaid explicitly teach the use of a filter comprising regenerated cellulose, polyethersulfone, polyvinylidene fluoride, polytetrafluoroethylene, or a combination thereof. However, it would be obvious to use such filters because Vijay teaches the use of such filters and provides a reasonable expectation of success in sterilizing epinephrine formulations.
Vijay teaches pharmaceutical compositions comprising epinephrine which are housed in pre-filled syringes or auto-injector devices. Vijay further teaches a method of manufacture of said compositions wherein: (i) excipients are dissolved in water, (ii) API (i.e., epinephrine) is added to the excipient solution, (iii) HCl is added to the resulting composition, (iv) pH of the composition is adjusted to target, (v) the composition is then sterile filtered into a container or syringe body (specification [0110])6. Of relevance to the instant claim is the sterile filtrations step. According to Vijay, the sterile filtration is conducted using sterile 0.22um PVDF (polyvinylidene fluoride) filters (specification [0107])7.
Given that the teachings of Vijay are directed towards the manufacture of an injectable epinephrine composition, it would have been prima facie obvious for a person of ordinary skill int the art to be able to modify the combined teachings of Kannan, Butler, and Belgaid to utilize at least a PVDF filter, because there would have been a reasonable expectation of success that the method would result in a sterile and stable epinephrine composition.
Conclusion
Claims 1 and 3-21 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC TRAN whose telephone number is (571)272-7854. The examiner can normally be reached Mon-Fri 8:00-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ERIC TRAN/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 “The present invention also provides for methods of making pharmaceutical compositions of the present invention. In some embodiments of carrying out a method of making the present composition, a bulk solution may be produced as follows: water for injections, whose dissolved oxygen content is in an acceptable range as measured by a WFI USP/EP O.sub.2 probe, may be added to a manufacturing tank kept under nitrogen pressure. Then, a tonicity regulating agent may be added and mixed. Then, a pH raising agent may be added to the solution while mixing. Then, a metal complexing agent may then be added to the solution while mixing. An antioxidant may then be added while mixing. In another container equipped with a stir bar, a pH lowering agent may be combined with an active agent. The pH lowering agent and the active agent together may then be stirred using the stir bar in the separate container before the mixture is added to the manufacturing tank under nitrogen. Then, the separate container may be rinsed with water for injections, whose dissolved oxygen content is in an acceptable range as measured by a WFI USP/EP 0.sub.2 probe, using a pipet and added to the manufacturing tank. This rinsing step may be repeated 1 to 3 more times. The solution may then mix before the final net weight of the solution is adjusted using water for injections.”
2 “In some embodiments, the composition may be contained in an autoinjector… Examples of methods of administration comprise subcutaneous, intracameral, intravenous, and intramuscular injection, infusion, intra-arterial administration, intracardiac injection, endotracheal administration, intraosseous administration, oral inhalation, topical administration, and as ophthalmic irrigation.”
3 “One litre of deionized water was placed in a PTFE stoppered Pyrex reaction kettle. A glass bubbler was fitted and the water was bubbled with prepurified grade nitrogen for 5,20,40 and 60 min at room temperature.”
4 “When looking at filtration as an overall technique which ensures quality for pharmaceuticals products, there is only one clearly defined and accepted level of rating: the sterile filtration [2]. According to the Food and Drug Administration (FDA, USA) and the United States Pharmacopoeia (USP), sterile filtration is defined as a nominal rating of 0.2 µm and 0.22 µm respectively to produce sterile effluent [3-7]. Thus, the obvious objective of a sterile filtration step is the removal of any viable microorganism that may be present in the bulk product.”
5 “Preferably, pH raising agents comprise the acids or salt forms of one or more of lactate, tartarate, glutamate, malate, citrate, gluconate, benzoate, succinate, acetate, glycine, and aspartate, as well as lithium hydroxide, sodium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, calcium hydroxide, strontium hydroxide, and barium hydroxide. Preferably, the pH raising agent comprises at least one of tartaric acid and sodium hydroxide, and more preferably both of these compounds.”
“Preferably, the pH lowering agent comprises one or more of acetic acid, adipic acid, ascorbic acid, citric acid, hydrochloric acid, lactic acid, malic acid, monopotassium phosphate, monosodium phosphate, phosphoric acid, pyrophosphoric acid, succinic acid, sulfuric acid, and or tartaric acid. Preferably, the pH lowering agent comprises hydrochloric acid. In certain embodiments, the pH lowering agent may be a portion of the buffer system in conjugation with a pH raising agent.”
6 “In other words, the manufacturing of the pharmaceutical composition starts with weighing degassed water for injection into a compounding tank and dissolving excipients. Then, to the excipient solution, dispensed amount of API is added followed by predetermined quantity of HCl. After completion of dissolution, pH of the solution is adjusted to the target pH of between 3 and 4 with further amount of HCl. The compounded bulk solution is continuously sterile filtered and filled into the container 11 or the barrel of the pre-filled syringe 10, which is then sealed with a rubber stopper under vacuum.”
7 “The pharmaceutical composition or epinephrine bulk solution can be sterilized by continuous filtration through two (redundant) sterile 0.22 μm PVDF filters during filling.”
Prosecution Insights