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 .
Summary
Receipt of Applicant’s Remarks and Amendments filed on 03/27/2026 is acknowledged. Claims 1-6 and 9 are pending.
Claim 4, 5 and 10 have been have been cancelled.
Claim 1 is amended.
Claims 7-8 and 11-14 remain withdrawn pursuant to the restriction requirement. The election were made FINAL.
Claims 1-3, 6 and 9 are pending and under examination in this application.
Maintained Rejections
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.
Claims1-3, 6 and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Ye (WO 2017036408 A1).
Ye teaches sustained-release suspension formulation for ropivacaine comprising (A) ropivacaine; B) a carrier comprising one or more surfactants, one or more suspending agents, one or more fillers, one or more preservatives, one or more isotonic agents, one or more buffers and C) water for injection (page 3, top ¶). Moreover, Ye teaches the suspension preparation according to the present invention is preferably in the range of 1 to 40% by weight, more preferably 2 to 20%, still more preferably 2 to 8% by weight of ropivacaine (page 3, ¶ 5), surfactant in the amount of 0.01 % to 20 % (page 4, ¶ 2), isotonicity adjusting agent in the amount 0.05 % to 20 % (mannitol or sodium chloride) (page 4, ¶ 8), and 0.1 to 2% of the suspending agent (page 2 middle, ¶ C) and the suspending agent is selected from the group consisting of carboxymethylcellulose or a sodium salt thereof, hydroxy-propylcellulose, methylcellulose, hydroxyethylcellulose, hydroxypropyl Methylcellulose, sodium hyaluronate and polyvinylpyrrolidone, preferably sodium carboxymethylcellulose and polyvinylpyrrolidone; said surfactant is selected from the group consisting of polysorbate 20 (Tween-20), polysorbate 40 (Tween-60), Polysorbate 60 (Tween-60), Polysorbate 65 (Tween-65), Polysorbate 80 (Tween-80), Polysorbate 85 (Tween-85) , Polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycol, polyoxyethylene and polyoxypropylene ethers (poloxamer 188 and poloxamer 407, etc.) 15-hydroxystearic acid polyethylene glycol ester, preferably Tween-20, Tween-80, 15-hydroxystearic acid polyethylene glycol and poloxamer 188; the filler is selected from the group consisting of mannitol, sucrose Maltose, xylitol, lactose, glucose, starch, sorbitol or the like, preferably mannitol and sucrose; said preservative is selected from the group consisting of benzoic acid, benzyl alcohol, butylated hydroxytoluene, butylated hydroxytoluene, Chlorobutanol, gallate, hydroxybenzoate, EDTA, phenol, chlorocresol, m-cresol, benzethonium chloride, myristyl-γ-methylpyridine chloride, mercaptoacetate, Thiomersal, preferably benzyl alcohol and hydroxybenzoate; said isotonicity agent is selected from the group consisting of mannitol, sorbitol, sodium chloride, glucose, sucrose, fructose, lactose, preferably mannitol, sodium chloride and glucose; The buffering agent is selected from the group consisting of phosphates, acetates, citrates or TRIS buffers, preferably phosphates (2nd page of Description, Bottom page).
Regarding claims 1-3, as noted above, Ye teaches ropivacaine formulation comprising suspending agents, isotonic agents, surfactants and the primary suspension of ropivacaine is mechanically ground or homogenized to reduce the particle size of ropivacaine to the desired level, such as 0.1 to 50 microns, and to prepare a sterile ropivacaine suspension formulation having the desired average particle size (page 5, ¶ 3) and isotonicity agent mannitol and sodium chloride (page 2, bottom page).
Regarding claim 6, Ye teaches to adjust the pH of the suspension to a range of 6 to 8.5 (page 4, ¶ 4-5).
Regarding claim 9, Ye teaches Freeze-drying (page 5, ¶ 5-6).
Ye does not teach within a single embodiment in order to anticipate but renders obvious the instant claims. As such it would be obvious at the time the invention was filed to rearrange the components of ropivacaine, suspending agent, iso-osmotic adjusting agent, surfactant, pH adjusting agent and optimize the median particle size D50 of the suspension injection to the desired range within 1 µm to 40 µm and obtain a composition as claimed. A reference is analyzed using its broadest teachings. MPEP 2123 [R-5]. Where, as here, the specific combination of features claimed is disclosed within the broad teachings of the references but the reference does not disclose the specific combination of variables (for example, the specific median particle size D50 of the suspension injection in 1 µm to 40 µm, 3 µm to 40 µm, 5 µm to 20 µm), in a specific embodiment or in a working example, “picking and choosing” within several variables does not necessarily give rise to anticipation. Corning Glass Works v. Sumitomo Elec., 868 F.2d 1251, 1262 (Fed. Circ. 1989). However, "when a patent simply arranges old elements with each performing the same function it had been known to perform and yields no more than one would expect from such an arrangement, the combination is obvious". KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007)(quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976). "[W]hen the question is whether a patent claiming the combination of elements of prior art is obvious", the relevant question is "whether the improvement is more than the predictable use of prior art elements according to their established functions." (Id.). Addressing the issue of obviousness, the Supreme Court noted that the analysis under 35 USC 103 "need not seek out precise teachings directed to the specific subject matter of the challenged claim, for a court can take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR v. Teleflex, 127 S.Ct. 1727, 1741 (2007). The Court emphasized that "[a] person of ordinary skill is ... a person of ordinary creativity, not an automaton." Id. at 1742. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention was made to rearrange the disclosed elements and embodiments of Ye, to include an example of the specific median particle size D50 of the suspension injection, to prepare the claimed composition. Such a rearrangement by a person of ordinary skill in the art who is not an automaton to yield the instantly claimed compositions and methods is within the purview of the ordinary skilled artisan upon reading Ye, as cited above, and would yield predictable results.
Response to Arguments
Applicant’s arguments have been considered but are not found persuasive for the reasons set forth below.
Regarding the Amendment to Claim 1:
Applicant has amended claim 1 to recite specific quantitative amounts of excipients per 100 mL of suspension injection: 2-3.5 g ropivacaine, 0.5-0.63 g sodium carboxymethyl cellulose (NaCMC), 0.6-0.7 g sodium chloride or 4.5-5.5 g mannitol, and 0.4-0.6 g poloxamer 188 or 2-3 g egg yolk lecithin. These amendments do not overcome the rejection.
As noted in the previous Office Action and confirmed herein, Ye explicitly teaches each of these excipients for use in ropivacaine suspension formulations. Ye teaches NaCMC as a preferred suspending agent (Ye, 2nd page of Description, ¶C), in a concentration range of 0.1% to 2% by weight (Ye, page 2, middle, ¶C). Applicant’s claimed NaCMC amount of 0.5-0.63 g per 100 mL (i.e., 0.5-0.63% w/v) falls squarely within Ye’s disclosed range of 0.1-2%. Ye teaches sodium chloride and mannitol as isotonicity agents at 0.05% to 20% (Ye, page 4, ¶8). Applicant’s claimed sodium chloride amount of 0.6-0.7 g/100 mL (0.6-0.7% w/v) and mannitol amount of 4.5-5.5 g/100 mL (4.5-5.5% w/v) both fall within Ye’s disclosed concentration range. Ye teaches poloxamer 188 as a preferred surfactant (Ye, page 4, ¶2) at concentrations of 0.01% to 20% by weight. Applicant’s claimed poloxamer 188 amount of 0.4-0.6 g/100 mL (0.4-0.6% w/v) falls within Ye’s disclosed range. Ye further teaches egg yolk lecithin as a surfactant option. The ropivacaine amount of 2-3.5 g/100 mL (2-3.5% w/v) falls within Ye’s disclosed preferred range of 2-8% by weight (Ye, page 3, ¶5).
Because all claimed excipients and their recited concentration ranges are encompassed within the broader ranges explicitly taught by Ye, the amendment does not distinguish the claims from the prior art. It is well established that “overlapping ranges create a prima facie case of obviousness.” In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). Where claimed ranges overlap with prior art ranges, the burden shifts to applicant to show criticality of the claimed range or unexpected results commensurate in scope with the claims. In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). Applicant has not established that the specific sub-ranges recited in claim 1 produce any unexpected result not suggested by Ye’s broader teachings.
Regarding Applicant’s “Teaches Away” Argument:
Applicant argues that Ye teaches away from optimizing particle size D50 to achieve improved efficacy, relying on data from Ye’s Examples 35-37 purporting to show that half-life and analgesic duration tracked ropivacaine concentration rather than particle size. This argument is not persuasive.
A reference teaches away only when it “suggests that the line of development flowing from the reference’s disclosure is unlikely to be productive of the result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). Ye does not suggest that micron-sized ropivacaine suspensions within the claimed D50 range of 1-40 µm are unproductive or undesirable. To the contrary, Ye’s working examples demonstrating sustained analgesic efficacy (Examples 8 and 9) utilize micron-sized particles that fall within or near the claimed D50 range. The fact that Ye’s nanosized formulation (Example 15, D50 < 0.43 µm) did not improve over the micron-sized formulations demonstrates that the micron-sized range is the productive range — not that it should be avoided. Furthermore, applicant’s teach-away argument conflates two distinct propositions: (1) that Ye does not establish that particle size alone drives efficacy, and (2) that Ye teaches away from the claimed combination of particle size and specific excipient amounts. The latter proposition does not follow from the former. The claimed composition does not rest on particle size as the sole determinant of performance. A finding that a reference does not optimize a particular variable does not constitute teaching away from a claimed composition that includes that variable as one of several defined parameters.
Regarding Applicant’s Argument of No Reasonable Expectation of Success: Applicant asserts that the art is unpredictable and that achieving an optimal sustained-release and safety profile requires significant creative effort. This argument is not persuasive because it relies on a generic characterization of pharmaceutical formulation as a complex and unpredictable art, without identifying any specific technical barrier to combining the claimed components at the recited concentrations.
All components of the claimed formulation — ropivacaine, NaCMC, sodium chloride or mannitol, and poloxamer 188 or egg yolk lecithin — are individually known to Ye, which teaches these components in a ropivacaine suspension context at overlapping concentrations. Where, as here, a claimed formulation combines known components in known concentration ranges to achieve their known functions (suspending, isotonicity adjustment, surfactancy), a person of ordinary skill in the art would have had a reasonable expectation of success in preparing the claimed composition. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007) (“A finding of obviousness does not require absolute predictability of success… all that is required is a reasonable expectation of success.”). General unpredictability in a field does not defeat a prima facie case of obviousness where the prior art specifically teaches the claimed components and their concentration ranges for the same intended use. Applicant has not identified any component or concentration in claim 1 that is outside Ye’s teachings or that would have been technically challenging to combine.
Regarding Applicant’s Unexpected Results Argument: Applicant argues that the claimed formulation exhibits unexpected results in the form of a reduced peak plasma concentration (Cmax), citing a Cmax of 456.03 ng/mL for applicant’s formulation versus 990±394 ng/mL for Ye’s 2% ropivacaine suspension. This argument is not persuasive for the following reasons.
First, applicant’s unexpected results argument rests solely on attorney argument pointing to data in the specification. No declaration under 37 CFR 1.132 has been filed to substantiate the unexpected results with sworn testimony from a person having relevant expertise. Attorney argument in a brief cannot take the place of evidence. In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997).
Second, and more fundamentally, the comparative data cited by applicant does not constitute a proper showing of unexpected results because the comparison is not made against the closest prior art with all other variables held constant. Applicant compares its Example 1 formulation against Ye’s Example 35 (2% ropivacaine suspension). These two formulations differ in multiple variables simultaneously, including excipient identities, excipient concentrations, particle size, and preparation method. A proper unexpected results showing requires a side-by-side comparison that isolates the effect of the claimed feature over the closest prior art. In re Baxter Travenol Labs, 952 F.2d 388, 392 (Fed. Cir. 1991). Where the comparative examples differ in multiple respects, it is impossible to attribute any observed difference in Cmax to the specific combination recited in claim 1 rather than to other differences between the formulations.
Third, even accepting the Cmax comparison at face value, a lower Cmax in applicant’s formulation compared to Ye’s formulation is consistent with the expected behavior of a sustained-release formulation — reduced peak concentration is a predictable consequence of sustained-release delivery, which is the explicit purpose of Ye’s formulation as well. Applicant has not established that the magnitude of Cmax reduction is unexpected given what Ye already teaches about sustained-release ropivacaine suspensions.
Accordingly, applicant’s arguments are not persuasive, and the rejection is maintained.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ANDRE MACH whose telephone number is (571)272-2755. The examiner can normally be reached 0800 - 1700 M-F.
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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 571-272-0323. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ANDRE MACH/Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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