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 .
Formal Matters
Receipt of Applicant’s response dated 06/23/2026 is acknowledged.
Claims 1-16 are pending.
Election/Restriction
Applicant's election with traverse of Group I, claims 1-9, in the reply filed on 06/23/2026 is acknowledged.
Applicant has also elected the following species in the reply filed on 06/23/2026: sodium chloride as the species of the tonicity agent.
The traversal of the restriction requirement is on the grounds that the standard for restriction requires that the inventions must be independent or distinct and there must be a serious burden on the Examiner if restriction is not required. Specifically regarding burden, Applicant argues that the prior art search has been already carried out as shown by the ISR and as well as by the Written Opinion of the International Searching Authority and are already of record in the present application and should considerably reduce any burden on the Examiner to search and consider all of the groups of invention together. The traversal of the restriction requirement and the election of species requirement is on the grounds that the claims of Groups I and II relate to a single inventive concept that contribute a special technical feature over the prior art. The traversal of the election of species requirement is on the grounds that the because the Office action is silent on the burden issue with respect to examining the entire tonicity agent species, there would be no serious burden on the Examiner.
The arguments regarding search and examination burden are not found persuasive because search and examination burden are not criteria for lack of unity of invention for national stage applications per PCT rule 13.1 and 13.2. Secondly, prosecution of the instant application is conducted independently of prosecution at the international stage and, therefore, the argument regarding the prior art search by the ISR and the Written Opinion of the International Searching Authority is not relevant to prosecution of the instant case. The arguments alleging that Groups I and II contribute a special technical feature are not found persuasive because per PCT Rule 13.1, the international application shall relate to a group of inventions so linked as to form a single general inventive concept or a “unity of invention” (see MPEP 1850). Per PCT Rule 13.2, “unity of invention” is fulfilled by defining a special technical feature that is shared amidst the claimed inventions. The Rule further specifies that “[t]he expression “special technical features” shall mean those technical features that define a contribution which each of the claimed inventions, considered as a whole, makes over the prior art.” Lack of unity of invention may be directly evident “a priori,” or before considering any prior art when no special technical feature is common to each of the independent claims. Alternatively, lack of unity of invention may only become evident “a posteriori,” or after considering the claims in relation to the prior art. By a posteriori analysis, the claimed invention still lacks unity of invention because the special technical feature lacks inventive step in the art as demonstrated by the teaching of Mohammed et al (US 10,869,845 B1, published 12/22/2020, cited in IDS dated 09/04/2025) in view of Pramanick et al (Pharma Times, (2013), 45, 3, 65-77, published March 2013) discussed in the instant Office action below (See rejection under 35 USC 103 below).
The requirement is still deemed proper and is therefore made FINAL.
Claims 10-16 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-9 are being examined in the instant Office action to the extent of the elected species, i.e., the tonicity agent is sodium chloride.
Priority
This application is a 371 of PCT/IB2022/061283 filed 11/22/2022, which is a CON of 17/542,432 filed 12/05/2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed 09/04/2025 has been considered by the Examiner. A signed copy of the IDS is included with the present Office Action.
Claim Rejections - 35 USC § 112(b)
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.
Claims 5 and 9 are 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.
a) The term “substantially free of” in claim 5 is a relative term which renders the claim indefinite. The term “substantially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It appears that some amount of “a pH adjuster which is separate or distinct from the citrate buffer” is permitted, and the claim will be examined accordingly.
b) Claim 5 is indefinite in the recitation of “a pH adjuster which is separate or distinct from the citrate buffer” because it is unclear if/how ‘a pH adjuster which is separate from the citrate buffer’ is different than ‘a pH adjuster which is distinct from the citrate buffer’, i.e., it is unclear whether ‘separate or distinct’ is a duplicative phrase or whether ‘separate’ and ‘distinct’ are intended to limit the pH adjuster differently from the citrate buffer. As written, one skilled in the art would not be reasonably apprised of the metes and bounds of the claims.
c) Claim 9 recites each of the limitations “the syringe barrel” and “the stopper”. There is insufficient antecedent basis for each of these limitations in the claim because neither claim 9 nor claim 1 earlier recite “a syringe barrel” or “a stopper”. The Examiner suggests amending claim 9 to the following in order to overcome this rejection: “A syringe comprising the formulation of claim 1, wherein the syringe comprises a barrel and a stopper, and wherein the syringe barrel comprises cyclic olefin copolymer and the stopper comprises uncoated bromobutyl rubber.”
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over Mohammed et al (US 10,869,845 B1, published 12/22/2020, cited in IDS dated 09/04/2025) in view of Pramanick et al (Pharma Times, (2013), 45, 3, 65-77, published March 2013).
Mohammed et al teach storage-stable, ready-to-use pharmaceutical formulations suitable for injectable use comprising ephedrine or a pharmaceutically acceptable salt thereof, water, an excipient, and a tonicity agent (See entire document, Abstract, e.g., Col. 1 Lines 6-9, Col. 2 Lines 39-40, Col. 8 Lines 4-6, Col. 10 Lines 56-57, Col. 11 Line 18).
The ephedrine or a pharmaceutically acceptable salt thereof is preferably ephedrine sulfate (e.g., Col. 3 Lines 56-59). The ephedrine or a pharmaceutically acceptable salt thereof may be present in an amount of between 3 mg/mL and 4 mg/mL, between 4 mg/mL and 5 mg/mL, or between 5 mg/mL and 6 mg/mL, or between 6 mg/mL and 7 mg/mL, or between 7 mg/mL and 8 mg/mL, or between 8 mg/mL and 9 mg/mL, or between 9 mg/mL and 10 mg/mL (e.g., Col. 6 Lines 45-56).
The excipient may be one or more pH adjusters or may be buffers (e.g., Col. 11 Lines 18-21 and 37-38). Mohammed et al teach that suitable buffers are generally buffers that stabilize the pH of the contemplated liquid formulations in a pH range of about 4.5 to 5.0, however, of course, it should be appreciated that there are many types of buffer systems and buffers known in the art, and all of those are deemed suitable for use (e.g., Col. 8 Lines 20-22 and 28-30). Mohammed et al teach that suitable buffers include citrate buffer (e.g., Col. 11 Lines 37-39). Mohammed et al teach that buffer strength is typically relatively low, e.g. equal or less than 100 mM, equal or less than 75 mM, equal or less than 60 mM, equal or less than 50 mM, or between 5 mM and 50 mM (e.g., Col. 8 Lines 23-27).
The tonicity agent may be sodium chloride and is to be used in an amount in order to obtain osmolality of the formulations in the range of 260 to 340 mOsm/kg (e.g., Col. 2 Lines 40-41, Col. 9 Lines 6-9 and 16-19, Col. 14 Lines 44-45).
The formulations are taught as having a substantially stable pH over an extended period of time, and most preferably, the pH drift is less than 0.5 pH units after storage over at least 2 months, preferably at least 6 months, more preferably at least 12 months, even more preferably at least 18 months, and most preferably at least 24 months, at 25° C and 60% relative humidity (e.g., Col. 7 Lines 23-25 and 45-49). The formulations are taught as containing about 5% or less total impurities after storage for 6 months at 25° C and 60% relative humidity as determined by HPLC (e.g., Col. 2 Lines 34-38). Inventive formulations were tested after long-term storage conditions of 25 ± 2° C and 60 ± 5% relative humidity for related compounds and impurities and none were detected (e.g., Table 7 in Examples). Inventive formulations are described by Mohammed et al as clear, colorless solutions (e.g., Tables 2-3 in Examples).
Mohammed et al teach that the formulation may be disposed in a sealed container or vessel that can maintain sterility or prevent contamination, such as a syringe, and Mohammed et al found that the type of container used for making and/or storing the formulations may be important for stability (e.g., Col. 12 Lines 39-43 and 59, Col. 20 Lines 48-51).
Although Mohammed et al teach that suitable buffers are generally buffers that stabilize the pH of the contemplated liquid formulations in a pH range of about 4.5 to 5.0, Mohammed et al also teach that all buffers known in the art are suitable for use (see supra), and Mohammed et al do not provide a teaching as to why a person of ordinary skill in the art would specifically choose citrate buffer and what the resulting pH range of the formulation would be.
This deficiency is made up for in the teaching of Pramanick et al.
Pramanick et al teach that excipients are the integral part of pharmaceutical products development to achieve desired product profile with respect to stability and efficacy, and Pramanick et al review different classes of excipients for use in parenteral formulations including buffers (See entire document, e.g., Title, Abstract, Page 69 Col. 1, Page 72 Col. 1). Pramanick et al teach that buffers are added to a formulation to adjust and stabilize pH and optimize drug solubility and stability, and that for parenteral preparations it is desirable that the product pH be close to physiologic pH (e.g., Page 72 Col. 1 Par. 1). Pramanick et al teach use of citrate buffers in the range of 5-15 mM as safe for formulations for injection, and that citrates are commonly used buffers that serve a dual role as chelating agent (e.g., Page 72 Col. 1 Par. 1). Pramanick et al teach use of citric acid for a drug product pH range of 2.5-9.0 and use of sodium citrate for a drug product pH range of 3.0-8.5 (e.g., Table 7 on Page 71, Page 72 Col. 1 Par. 1).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to provide a storage-stable, ready-to-use pharmaceutical formulation suitable for injectable use comprising ephedrine sulfate in an amount of between 3 mg/mL and 4 mg/mL, between 4 mg/mL and 5 mg/mL, or between 5 mg/mL and 6 mg/mL, or between 6 mg/mL and 7 mg/mL, or between 7 mg/mL and 8 mg/mL, or between 8 mg/mL and 9 mg/mL, or between 9 mg/mL and 10 mg/mL, comprising water, comprising citrate buffer in the range of 5-15 mM in order to adjust and stabilize the pH of the formulation to within the pH range of 2.5-9.0 (citric acid) and/or the range of 3.0-8.5 (sodium citrate) and in order to optimize ephedrine sulfate solubility and stability, and comprising sodium chloride in an amount in order to achieve an osmolality of the formulation in the range of 260 to 340 mOsm/kg, wherein the formulation has a substantially stable pH over an extended period of time, preferably having a pH drift of less than 0.5 pH units after storage over at least 2 months, preferably at least 6 months, more preferably at least 12 months, even more preferably at least 18 months, and most preferably at least 24 months, at 25° C and 60% relative humidity, wherein the formulation contains zero up to about 5% of total impurities after storage for 6 months at 25° C and 60% relative humidity as determined by HPLC, wherein the formulation is a clear, colorless solution, and wherein the formulation is disposed in a sealed container or vessel that can maintain sterility or prevent contamination such as a syringe.
One of ordinary skill in the art would have been motivated to use citrate buffers being citric acid and/or sodium citrate specifically as buffer because Pramanick et al teach use of citrate buffers including citric acid and sodium citrate for formulations for injection and, additionally, teach the advantage of use of citrate buffers being that they serve a dual role as chelating agent. There would have been a reasonable expectation of success because Mohammed et al teach the compatibility of the formulation with buffers such as citrate buffer. One of ordinary skill in the art would have been motivated to use the citrate buffer in the range of 5-15 mM because Pramanick et al teach use of citrate buffers in the range of 5-15 mM as safe for formulations for injection. There would have been a reasonable expectation of success because Mohammed et al teach the compatibility of the formulation with overlapping ranges of buffer strength being equal or less than 100 mM, equal or less than 75 mM, equal or less than 60 mM, equal or less than 50 mM, or between 5 mM and 50 mM.
Regarding the ranges required by the instant claims, a prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art (In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003)).
Regarding instant claim 8, the above formulation being colorless meets the limitation of instant claim 8 as evidenced by Par. [0022] of the instant specification.
Thus, the modified pharmaceutical formulation of Mohammed et al in view of Pramanick et al renders obvious instant claims 1-8.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Mohammed et al (as cited above) in view of Pramanick et al (as cited above) as applied to claims 1-8 above, and further in view of Larose (KR 20180104009 A, published 09/19/2018).
The modified pharmaceutical formulation of Mohammed et al in view of Pramanick et al has been discussed in detail supra.
Although Mohammed et al teach that the formulation may be disposed in a syringe, neither Mohammed et al nor Pramanick et al teach the syringe comprising a barrel comprising cyclic olefin copolymer or comprising a stopper comprising uncoated bromobutyl rubber.
These deficiencies are made up for in the teaching of Larose.
Larose teaches a syringe for storing and delivering fluid, such as a pharmaceutical composition, comprising a barrel and a stopper (See entire document, e.g., Abstract, Page 4 Par. 1-2 of English translation). The barrel of the syringe may be substantially a rigid or rigid material such as polymeric materials e.g. cyclic olefin copolymer (COC) (e.g., Page 4 Par. 2 of English translation). The stopper may include an elastomeric body such as bromobutyl rubber (e.g., Page 5 Par. 5 of English translation) and may optionally include a coating (e.g., Page 6 Par. 2 of English translation).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, to dispose the modified pharmaceutical formulation of Mohammed et al in view of Pramanick et al in a syringe comprising a barrel being cyclic olefin copolymer and a stopper being bromobutyl rubber, wherein the barrel is optionally coated. One of ordinary skill in the art would have been motivated to dispose the aforementioned modified pharmaceutical formulation in the aforementioned syringe taught by Larose, and there would have been a reasonable expectation of success, because Larose teach the compatibility of the syringe with injectable drugs including injectable ephedrine hydrochloride (See Bottom of Page 11 of English translation of Larose).
Thus, the modified pharmaceutical formulation of Mohammed et al in view of Pramanick et al further disposed in the syringe of Larose renders obvious instant claim 9.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KAELEIGH ELIZABETH OLSEN whose telephone number is (703)756-1962. The examiner can normally be reached M-F 8-5 PM.
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/K.E.O./Examiner, Art Unit 1619
/NICOLE P BABSON/Primary Examiner, Art Unit 1619
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