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 .
Priority
This Application filed on 07/27/2021 is a continuation of 16/738,147 (PAT 11234925) filed on 01/09/2020.
DETAILED ACTION
Applicant’s response filed on September 12, 2025 to the Non-Final rejection mailed on June 18, 2025 is acknowledged.
Status of the Claims
Claims 1-3, 5-14, 17-23 are pending. Claims 17-20 are withdrawn from further consideration pursuant to 37 C.F.R. 1.142(b), as being drawn to non-elected subject matter. The claim corresponding to the elected subject matter is claims 1-3, 5-14, 21-23 and is herein acted on the merits.
Information Disclosure Statement
No new information disclosure statement(s) (IDS) filed.
Response to Arguments
Applicant’s arguments over the 35 U.S.C. 112 (pre-AIA ), second paragraph of claims 1-16 is persuasive in view of amendment of the claim. The rejection is herewith withdrawn.
Applicant’s arguments over the 35 U.S.C. 103 rejection of claims 1-16 over Kannan et al (“Kannan”, US 20160263059 A1, published May 23, 1984) and Gupta et al (“Gupta”, US 20150246009A1, published September 3, 2015) is not persuasive. The rejection is herewith maintained.
Applicant argues and presents in the Declarations filed on 9/12/2025 “epinephrine formulations containing 0.05 mg/mL to 0.15 mg/mL epinephrine, butylated hydroxyl anisole (BHA), a sulfite antioxidant, an organic acid, and a chelating agent have significantly greater stability in the absence of both inorganic acids and inorganic bases (other than the sulfite antioxidant).” “Additionally, the inventors discovered that the addition of BHA and a chelating agent significantly reduces the formation of impurities in epinephrine solutions containing an organic acid (such as tartaric acid) and a sulfite antioxidant (such as sodium metabisulfite), including the formation of d-epinephrine. Dr. Bhowmick tested two formulations which are identical, except one formulation (Example A) contained a chelating agent (disodium edetate) and BHA, while the other (Comparative Example B) did not. Bhowmick Decl. #2 at §6. The two formulations were stored for 2 months under accelerated storage conditions (namely, 40° C and 75% relative humidity). Example A produced about half the total impurities and d-epinephrine as Comparative Example B. Id. at §7 (including Table 2). The addition of chelating agent and BHA resulted in the significantly improved stability.” “Bhowmick compared inventive Example 1 of the Specification (claimed composition containing only an organic acid, free of an inorganic acid or base) and a first comparative example with an inorganic acid (HCI) and an inorganic base (NaOH), two comparative solutions with only inorganic base (NaOH) and no inorganic acid. Bhowmick Decl. #1, 5. It was shown that the solutions with inorganic acid, inorganic base or both were not so stable, having unacceptable level of undesirable impurities. The inventive example 1 most stable sample, having only 0.90 % of epinephrine sulfate impurity after 6 months of storage at 40°C and 75% RH. Bhowmick Decl. #1, 97 and Table 5. The comparative examples on the other hand, exhibited 1.01 to 1.878 % of epinephrine sulfate impurity under the same storage conditions. /d.”
In response, the Examiner’s contention is that Applicant provides comparison with a very specific formulation comprising a specific organic acid, chelating agent and a formulation with a specific pH, while the claims broadly read on any organic acid and any chelating agent, and any pH. The Examiner points out that the arguments do not commensurate in scope with the claims. The Examiner suggests amending the claims.
Applicant’s state that the provisional ODP rejection be held in abeyance until patentable subject matter is determined. The rejection is herewith maintained.
The rejections are as below:
Claim Rejections –
35 USC § 112 Notice of Pre-AlA or AIA Status
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 22 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. It is unclear what Applciant means the solution has an oxygen content “or 2ppm or less.”
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.
Claims 1-3, 5-14, 21-23 are rejected under 35 U.S.C. 103 as obvious over Kannan et al (“Kannan”, US 20160263059 A1, published May 23, 1984) and Gupta et al (“Gupta”, US 20150246009A1, published September 3, 2015).
Kannan is directed to pharmaceutical compositions comprising epinephrine and methods of use via subcutaneous, intravenous, and intramuscular injection, infusion, intra-arterial administration (abstract and [0008], read on the limitation of the active agent epinephrine in the instant claim 1). Kannan teaches that the composition comprise at least one of an active agent including epinephrine and its salt (abstract and [0026], read on the ingredients of component a) in the instant claim 1), an antioxidant (abstract), which comprise one or more of sulfite (e.g. sodium bisulfite, sodium metabisulfite ( [0049]), an amino acid sulfite (e.g. L-lysine sulfite), ascorbic acid (an organic acid), butylhydroxyanisole (BHA), sodium edetate (a chelating agent), sodium erythorbate, etc. ( [0053], read on the ingredients b-c and e in the instant claim 1, and the limitation of the instant claim 7), a pH raising agent, preferably, the pH raising agent comprises at least one of tartaric acid and sodium hydroxide (abstract and [0040], read on the ingredients d) in the instant claim 1 and the limitation of the instant claim 9), a transition metal complexing agent (interpreted as a chelating agent, the ingredients e) in the instant claim 1), a pH lowering agent, a tonicity regulating agent. Kannan also teaches that, in some embodiments, the pH raising agent may have a buffer range from a pH of about 2 to 5, preferably from a pH of about 3 to 4.5, and most preferably from a pH of about 3.5 to 4.5 ([0032], falling within the claimed pH ranges in the instant claims 2 and 3). Kannan further teaches that the active agent is present at a concentration sufficient for any of the uses described herein. In some embodiments, the active agent is present at a concentration of about 0.1 to 2 mg/mL ([0027], encompassing the concentration in the in the instant claims 4 and 5). Additionally, Kannan teaches that the antioxidant may be present at a concentration of in the range of about 0.1 to 0.9 mg/mL; the antioxidant is to limit the formation of oxidative degradants in the composition to less than about 0.009%, after a certain period of shelf life ([0047], read on the limitations of the instant claims 6 and 11). Furthermore, Kannan teaches that, in some embodiments, the transition metal complexing agent may be present in the composition at a concentration of about 0.1 and 0.5 mg/mL ([0059], falling within the claimed range of the instant claim 8). The transition metal complexing agent inhibit degradants formed from the interaction of epinephrine, bisulfite, and oxygen [0057]. Kannan indicates that degradants are impurity A, impurity B, and/or unknown C ([0096]). It is noted that impurities A and B are epinephrine sulfates ([0097], different isomers). The headspace gas may be manipulated in order to reduce the amount of oxygen present therein. In some embodiments, the amount of oxygen in the headspace gas is most preferably about 0%. Thus, the limitation of the instant claim 12 and 21-22 are met. Kannan states that uses for epinephrine include emergency treatment of allergic reactions (Type 1), including anaphylaxis, cardiogenic, hemorrhagic, and traumatic shock. Kannan does not describe the use of a co-solvent. Thus, the limitation of the instant claim 22.
While teaching the pH raising agent comprises at least one of tartaric acid and sodium hydroxide, Kannan does not expressly teach a composition without sodium hydroxide. This deficiency is cured by Gupta.
Gupta is directed to stable injectable pharmaceutical composition of epinephrine or salts thereof (title). Gupta teaches that the composition of epinephrine or salts thereof comprising sodium metabisulfite, wherein the ratio of the amount of epinephrine or salt thereof to sodium metabisulfite in the composition ranges from about 1:0.005 to about 1:1.5 by weight (abstract). Gupta teaches that the stabilized injectable pharmaceutical composition comprising epinephrine or salt thereof, sodium metabisulfite, one or more tonicity-adjusting agents, one or more pH adjusting agents, aqueous vehicle, and optionally one or more other pharmaceutically acceptable excipients ([0024]). Gupta also teaches that the examples of suitable pH adjusting agents includes organic acids of citric acid, ascorbic acid, acetic acid, tartaric acid, salts of sodium citrate, potassium citrate, sodium bicarbonate, etc. and organic base of ethanolamine, diethanolamine, triethanolamine, hexane-1,2-diamine, etc. and the pH of the pharmaceutical composition preferably ranges from 2.2 to 5.0 ([0050]). Gupta further teaches that examples of suitable tonicity adjusting agents includes sodium chloride, dextrose, sucrose, xylitol, etc. ([0054]). Gupta exemplifies a stable epinephrine injection without inorganic base (i.e. sodium hydroxide) with a pH in the range of 2.2 to 5.0 ([0063], example 1), implying an acid alone without inorganic base is sufficient to maintain a desired pH range.
"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) (citations omitted). In this case, Kannan teaches that tartaric acid is one of the preferred pH adjusting agent for epinephrine injectable solutions while Gupta teaches a stable injectable pharmaceutical composition of epinephrine is achieved by using an acid alone, i.e. without using an inorganic base. Thus, in view of the teachings of Kannan and Gupta, there would have been a reasonable expectation that a composition comprising an organic acid (e.g. tartaric acid) as the pH adjusting agent could be successful.
1. regarding the specific concentrations of each ingredient in the instant claims 4-6, 8, 10-11, the principles of law are “[Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456 (CCPA 1955). This rule is limited to cases in which the optimized variable is a “result-effective variable.” In re Antonie, 559 F.2d 618, 620 (CCPA 1977). In this case, Kannan teaches the general conditions of epinephrine formulations, some fall within the claimed ranges; while others encompass claimed ranges. Thus, it would have been the optimum or workable ranges by routine experimentation, particularly absent evidence to the contrary.
2. regarding the specific prefilled glass syringe in the instant claim 13, Kannan teaches that a commercial product, AdrenalinRTM, is a clear, colorless solution containing 1 mg/mL epinephrine in a clear glass vial ([0005]). Another commercial product, SYMJEPIRTM, (approved by FDA on 06/15/2017) comes as a 2-pack syringe in a convenient carrying case (See attached PDF under relevant art). Thus, it would be obvious to choose a design choice (prefilled glass vial or syringe) to achieve the effect desired, absent evidence of unexpected results.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/forms/. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-3, 5-14, 21-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 11234925. Although the claims at issue are not identical, they are not patentably distinct from each other because copending claims are drawn to a stable, aqueous injectable solution comprising (a) epinephrine or its pharmaceutically acceptable salt in an amount ranging from about 0.05 mg/ml to about 0.15 mg/ml, equivalent to epinephrine base, (b) a sulfite antioxidant, (c) butylated hydroxyl anisole, (d) tartaric acid, and (e) a chelating agent selected from the group consisting of disodium edetate, disodium edetate dihydrate, ethylenediamine tertaacetic acid, diaminoethane tetraacetic acid, and mixtures thereof, wherein the solution is free of inorganic acid and inorganic base other than a sulfite antioxidant, wherein the pH of the solution is in the range of is 3.8±0.3 whereas the claims herein are drawn to a stable, aqueous injectable solution comprising epinephrine or its pharmaceutically acceptable salt, a sulfite antioxidant, butylated hydroxyl anisole, an organic acid and a chelating agent, wherein the solution is free of an inorganic acid and an inorganic base. The independent and dependent claims herein overlap in scope with the US Pat.
Conclusion
No claims are allowed.
The arguments are not persuasive and the rejection is made FINAL.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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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/LAYLA SOROUSH/ Primary Examiner, Art Unit 1622