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 without traverse of Group I (drawn to a method of improving stability of an injectable solution composition), in the reply filed on 04/17/2026 is acknowledged.
Claims 1-27 are pending of which claim 27 (Group II) is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention there being no allowable generic or linking claim. The restriction requirement is still deemed proper and is made Final.
Pending claims 1-26 have been examined on the merits.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Withdrawn Rejections
The rejection of claim 16 under 35 U.S.C. 112(b) is withdrawn in view of the claim amendment.
New Grounds of Rejection due to the Applicant’s Claim Amendments
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.
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 1-5, 7-23, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Crivaro et al., WO 2025/057112, in view of Jones et al. (Amer. J. of Health-Sys Pharm., vol. 50, no. 11, Nov. 1993, pp. 2364–65), Hurrey et al., WO 2018/207188, and Sensorcaine, https://www.medicinesfaq.com/media/pdf/ bupivacaine-hydrochloride-prescribing
-information.pdf (“USP”), https://pdf.hres.ca/dpd_pm /00001253.PDF (“Sensorcaine”).
Regarding claims 1-5, 7-19, and 22, Crivaro (page 5, 8, 23; abstract) discloses a flexible plastic container, including syringe, ready-to-administer formulation comprising a therapeutically effective amount of bupivacaine hydrochloride (from about 0.1 mg/mL to about 10 mg/ml), a tonicity agent, buffer, and water, wherein the formulation has an initial pH of from about 4.2 to about 4.5, and wherein the pH drift of the formulation is less than about 0.4 pH units. Crivaro (page 13) discloses that the tonicity agent comprises sodium chloride, dextrose, mannitol, trehalose, potassium chloride, glycerol, or a combination thereof.
Crivaro (page 7) also discloses bupivacaine formulations may also have an initial pH of from about 4.0 to about 5.0. Crivaro (page 7) discloses a suitable pH adjuster may include, for example, sodium hydroxide, potassium hydroxide, hydrochloric acid, or a combination thereof. The amount of pH adjuster included in a formulation may vary based upon the desired initial pH of the formulation. Crivaro (page 4) teaches bupivacaine formulation is stable for at least about 9 months, e.g., at least about 12 months, at least about 18 months, at least about 24 months, or at least about 36 months at room temperature (e.g., at 25 ±2° C / 60% RH ±5% RH) or at refrigerated temperature (e.g., at 5 ±3° C). Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to recognize that a syringe that is filled with a pharmaceutical composition is indeed a “pre-filled syringe.”
This is further supported by Jones (page 2364) disclosing the use of bupivacaine hydrochloride 1.25 mg/mL in 0.9% sodium chloride (9 mg/ml) injection in polypropylene syringes or pre-filled syringes. USP (page 1) disclosing bupivacaine and sodium chloride dose ranges:
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Crivaro, however, does not explicitly teach pH from about 5.4 to about 6.5 and specific buffer volume.
Hurrey (page 4 [0021], and page 12, [0092]) teaches a pharmaceutical composition comprising bupivacaine which may also contain acids such as citric acid and lactic acid. Hurrey (page 2, [009]; page 8, [0054]) discloses “The solubility of bupivacaine hydrochloride monohydrate has been reported to be 40-50 mg/mL in water between pH 1.8 and 6” and discloses aqueous composition comprising bupivacaine with a pH ranging from about 5.0 to about 5.5, which falls within the claimed range. Furthermore, Hurrey (page 17, Table 1 and [00124]) discloses that pH (e.g., 5.6) of the bupivacaine formulation remains stable for one month at room temperature following the preparation. In addition, Sensorcaine (page 18) further teaches the following regarding a composition comprising bupivacaine HCl:
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This is further supported by USP (page 14; emphasis added) disclosing bupavicaine HCl in various formulations including pre-filled syringe, with a broad pH range from 4.0 to 6.5, as also disclosed by the combined teachings of Hurrey, Jones, USP, and Sensorcaine, suggesting the claimed composition, reagents, concentration and pH are known in the art.
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The combined teachings of Hurrey, Crivaro, USP, and Sensorcaine disclose that the pH can remain stable at 5.6 for at least 1, 6, 9, 12 18, 24, and 26 months. Moreover, because of the pH range, pH stabilization methods, and the fact pH stability can be achieved, it would have been obvious to combine the prior art to arrive at the claimed invention and extend the pH stability to further improve long term storage. Thus, a POSITA would have reasonable expectations to adjust and maintain pH over longer storage periods to minimize injection-site reaction such as pain, irritation and inflammation. In addition, achieving a pH drift of less than 0.4 pH units after 12 months, as an example, would have been obvious optimization of the combined prior art’s teachings because the claimed composition is already known in the art.
Regarding claim 20-21, Crivaro (page 12) discloses the formulation comprising bupivacaine is filtered and filled into primary storage containers. Jones (page 2364) also teaches the stock solution was filtered with a 0.22-pm filter before being introduced into polypropylene syringes and sealed with syringe caps. Together, the prior art shows that sterilization of formulation of bupivacaine is known in the art.
Regarding claim 23, Crivaro (page 10) discloses the use of syringe, Jones and USP further teach polypropylene syringes and Abboject™ Syringe, respectively. Pre-filled syringes are well known in the art that inherently comprises a syringe barrel, a plunger moveably positioned within the syringe barrel and a plunger rod to dispense the contents. Thus, the instant claim merely recites basic structural features that a POSITA would expect to be found in a standard pre-filled syringe.
Regarding claim 26, Crivaro (page 5) discloses volume of the formulation is about 5 mL or more, e.g., about 10 mL or more, about 50 mL or more, about 100 mL or more, about 150 mL or more, about 200 mL. Furthermore, Jones (page 2364) teaches pre-filled syringes comprising bupivacaine hydrochloride at a volume of 34 ml. Therefore, a POSITA would understand, based on the combined teachings of Crivaro and Jones, that the fill volume is determined by the amount intended for administration, which varies with therapeutic dose. Thus, adjusting the volume in a pre-filled syringe to accommodate the required amount of composition is a routine design choice, thus, it would have been obvious to modify the volume as needed to arrive at the claimed invention.
Claims 24-25 are rejected under 35 U.S.C. 103 as being unpatentable over in view Crivaro Jones, Hurrey, USP, Sensorcaine, and as applied to claims 1, 9-19, 22, and 27 above, and in further view of Jarmusik et al., US 2023/0310749.
Regarding claim 24-25, and as applied to claims 1, 9-19, 22, and 27 above, Crivaro (page 10) teaches the innermost layer of the multi-layered bag comprises a polymer of cyclic olefin such as cycloolefin homopolymer or cycloolefin copolymer or mixture thereof. However, Crivaro does not explicitly teach syringe plunger is made of chlorobutyl or bromobutyl.
Jarmusik (abstract) discloses “prefilled syringes comprise a syringe barrel and a syringe tip comprising cyclic olefin monopolymer (“COP”) or cyclic olefin copolymer (“COC”) and having a plunger rod stopper comprising bromobutyl rubber.” Jarmusik (page 1, [(0001)]; page 2, [(0012]) teaches COC/COP and bromobutyl rubber are safe for use with a long-term stability, and plunger stoppers also showed no signs of degradation or deformation after 12 months. Therefore, because COC/COP and bromobutyl rubber are compatible with drug formulation, therefore, a POSITA would have been motivated to substitute conventional syringe materials such as polypropylene with COC/COP and bromobutyl rubber to achieve predictable improvements in stability and long-term storage.
Subject Matter Free of the Art of Record
The subject matter of claim 6 is free of the art of record. The closest prior art references are Crivaro et al., WO 2025/057112 and Jones et al. Amer. J. of Health-Sys Pharm., vol. 50, no. 11, Nov. 1993, pp. 2364–65 in view of Hurrey et al., WO 2018/207188. The combined teachings of Crivaro and Jones teach the stability of bupivacaine hydrochloride formulation injection 1.25 mg/mL in 0.9% sodium chloride injection in polypropylene syringes and stable at 3 or 25ºC. However, there is no motivation for an ordinary skilled person in the art to modify the teachings of Crivaro and Jones in view Hurrey to arrive at the instantly claimed invention.
Response to Argument
B. The Prior Art Fails to Recognize the Problem Solved by the Claimed Invention
Applicant argues that Jones does not teach pH instability, while Hurrey’s stability testing was conducted in glass containers and does not teach buffering to prevent pH drift. Thus, according to Applicant, a POSITA would not have been motivated to combine the cited prior art to obtain pH stability during long-term storage in a prefilled syringe. Applicant’s argument is not persuasive.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Furthermore, Crivaro explicitly teaches bupivacaine formulation stability and pH drift, thereby highlighting the specific teaching concerning control of pH during storage that Applicant alleges is missing from Jones and Hurrey. In fact, contrary to Applicant’s assertion, Hurrey demonstrates that maintaining bupivacaine concentration during storage was a recognized stability objective, which a POSITA would have recognized to be caused by a “pH drift.” Furthermore, Hurrey’s use of glass containers is not a teaching away of applying the stability concept to a syringe. Additionally, Jones explicitly discloses the use of bupivacaine hydrochloride injection in pre-filled syringes and evaluates its stability after days of storage, which aligns with Crivaro’s teachings regarding bupivacaine formulation stability and pH control stored in a syringe, as also supported by USP and Sensorcaine’s teachings. Therefore, contrary to Applicant’s assertation, the combined prior art clearly teaches stability and control of pH drift to improve storage duration.
C, E and F. The Experimental Data Demonstrate Unexpected Results/No Reasonable Expectation of Success// Dependent Claims 2-5, 7-23, and 26.
Applicant argues that the improved pH stability is an unexpected result, indicating that a POSITA would not have expected cyclic olefin copolymer (COC) to provide a greater pH stability than polypropylene, because pH instability is not material specific. Applicant further argues that the absence of a commercially available bupivacaine prefilled-syringe formulation having the claimed stability demonstrates that the prior art did not recognize the problem being solved. Applicant’s argument is not persuasive because Crivaro (page 2) explicitly recognizes the need for improved storage stability of ready-to-administer bupivacaine formulations. For example, Crivaro notes that commercially available bupivacaine products had shelf-lives of about two years, while compounded bupivacaine products supplied in syringes, as an example, generally had a shelf life of only 30-180 days, and explicitly states that there remained a need for bupivacaine formulations having improved storage stability, preferably for longer periods at room temperature. Furthermore, as discussed above in the 103 rejection, the combined prior art, including Crivaro, teaches that the ready-to-administer bupivacaine may be contained in a primary container such as a syringe. Crivaro also teaches that suitable plastic container martials include polypropylene, cyclic olefin polymers, and cyclic olefin copolymers. Thus, COC was not an unknown or unrelated material newly selected by Applicant for storage of bupivacaine. Not to mention, the combined prior art teaches bupivacaine HCl formulations containing a tonicity agent, pH adjustment, a buffer/pH stabilizer, and water, while also addressing formulation stability, pH control during storage; and the use of syringe material comprises COC. Additionally, Jarmusik discloses prefilled syringes are made from cyclic olefin monopolymer (“COP”) or cyclic olefin copolymer (“COC”) and having a plunger rod stopper comprising bromobutyl rubber. This further demonstrates that absence of a commercial product having the claimed stability does not by itself establish unexpected results. Thus, the problem allegedly newly recognized by Applicant was already known or recognized in the art. Thus, because the combined prior art teaches all the claimed limitations, including syringes containing COC and the need to improve bupivacaine storage, a POSITA would therefore view the claimed invention to be a routine variation of the known art, and unexpected results.
Conclusion
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 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JAMES H ALSTRUM-ACEVEDO can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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