FINAL 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 .
Status of the Claims
This action is in response to papers filed 07/29/2025 in which claims 1-20 and 39-40 were canceled; claim 35-38 and 41-48 were withdrawn; and claim 21 was amended. All the amendments have been thoroughly reviewed and entered.
Claims 21-34 are under examination.
Drawings
The objection to the drawings because FIG. 1 and FIG. 2 in the drawings filed 04/20/2022 were not legible, is withdrawn, in view of the replacement sheet filed 07/29/2025.
The Drawings (replacement sheet) filed 07/29/2025 are accepted.
Maintained-Modified Rejections
Modification Necessitated by Applicant’s Claim Amendments
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.
Claim(s) 21-26 and 29-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al (US 2012/0277249 A1; previously cited) in view of Schier et al (Acad Emerg Med, April 2004, 11(4): 329-334).
Regarding claim 21, Andersson teaches a parenteral formulation comprising a lipophilic pharmaceutical agent such as atropine or a salt thereof, sodium chloride, and water, wherein the pH of the composition is 1 to 6 and the concentration of the lipophilic pharmaceutical agent is about 1 to 10 mg/ml ([0018], [0020]-[0021], [0023]-[0026], [0028]-[0029], [0033], [0037], [0067], [0079], [0101]; claims 6, 16, and 27). Andersson teaches the parenteral formulation can be a infusion fluid containing normal saline as the aqueous diluent/solvent ([0023]-[0024], [0037], [0067], and [0079]), thereby concentration of the solvent in Andersson would be in the range of 95 vol.% to 99 vol.% as claimed.
It would have been obvious to one of ordinary skill in the art to optimize the concentration of atropine to 1 mg/ml to 6 mg/ml and pH of the formulation to in the range of 3.0 to 3.5, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Andersson provided the guidance to do so by teaching that to provide a stable parenteral formulation, the concentration of the pharmaceutical agent such atropine can be optimize from about 1 to 10 mg/ml and the formulation contains an acidified agent such citric acid such that the pH of the composition can be optimize in the range of 1 to 6 (Andersson: [0033], [0065]; claims 14 and 22). It is noted that the concentration of the pharmaceutical agent and the pH of the formulation as taught in Andersson overlaps the claimed concentration of 1 mg/mL to 6 mg/mL for atropine and pH range of 3.0 to 3.5, respectively. Furthermore, according to Schier, the stability of the aqueous atropine sulfate is enhanced in acid solution, as the ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4 (Schier: Abstract; pages 329-331). Thus, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results from the claimed parameters, the optimization of concentration of atropine and pH of the composition so as to achieve a stable parenteral formulation would have been obvious before the effective filing date of applicant's invention. “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, 105 USPQ 233, 235 (CCPA 1955). See MPEP §2144.05 (I)-(II).
It is noted that the claimed recitation of “to combat organophosphate nerve agent threats” is a recitation of intended use/function. A recitation of intended use/function does not change the structure of the claimed composition. It is noted that a recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim.
With respect to the claimed property of “wherein the composition has a shelf life of at least 24 months when stored at room temperature” as recited in claim 21, it is noted that this property would have been reasonably implicit in the atropine formulation of Andersson in view of Schier because Andersson teaches the formulation is stable for at least two years when stored at room temperature (Andersson: [0035]-[0037]). As discussed above, Schier the stability of the aqueous atropine sulfate is enhanced in acid solution, as the ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4 (Schier: Abstract; pages 329-331). Furthermore, in line with Andersson, Schier also established that the expiration date or standard shelf life requirement for a commercial product of atropine solution is usually two to three years (Schier: pages 331-332).
Regarding claims 22-24, as discussed above, Andersson provided the guidance for optimizing the concentration of the pharmaceutical agent such atropine in the range of about 1 to 10 mg/ml. Thus, it would have been reasonably obvious to optimize the concentrations as claimed in claim 22-24 by routine optimization because as discussed above, the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results from the claimed parameters, the optimization of concentration of atropine so as to achieve a desired parenteral formulation would have been obvious before the effective filing date of applicant's invention. “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, 105 USPQ 233, 235 (CCPA 1955). See MPEP §2144.05 (I)-(II).
Regarding claim 25 and 26, as discussed above, Andersson teaches atropine or a salt thereof. Schier teaches atropine sulfate as the suitable salt form of atropine for used in formulating an injectable formulation (Abstract; pages 329-331).
Regarding claims 29-31, Andersson teaches suitable solvents include water, and ethanol as a co-solvent ([0033]-[0034], [0063]; claim 18).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant's invention, as evidenced by the references, especially in the absence of evidence to the contrary.\
Response to Arguments
Applicant's arguments filed 07/29/2025 have been fully considered but they are not persuasive.
Applicant’s arguments in the Remarks filed 07/29/2025 relied on the Declaration from Michael Lloyd Radomsky, submitted on 07/29/2025 as the rebuttal for nonobviousness. Thus, Applicant’s arguments in view of the Declaration will be addressed together as set forth below.
The “Michael Lloyd Radomsky” (hereafter as “Radomsky Declaration”) under 37 C.F.R. §1.132 filed 07/29/2025 is considered, but found insufficient to overcome the 103 rejection over Andersson in view of Schier, as set forth in this office action for the reasons set forth below.
Applicant argues:
“Nothing in Andersson teaches or suggest to one of ordinary skill in the art that from the hundreds or thousands of possible combinations taught in Andersson that (1) atropine should be picked from one laundry list, (2) a pH of 3-3.5 should be picked from another laundry list, and (3) the concentration of the agent be picked from another myriad of options, and the three choices be used together in a single composition from the myriad of compositions taught. (See Radomsky Dec. para. 5).”
In response, the Examiner disagrees. To the extent paragraph [0029] and claim 6 of Andersson disclosed atropine in a long list of lipophilic pharmaceutical agents, all lipophilic pharmaceutical agents including atropine are indicated as suitable lipophilic pharmaceutical agents that are in need of improvement in solubility and stability, as they were addressed in Andersson to be known as having solubility and stability issues, especially in parenteral formulation (Andersson: [0003]-[0004], [0018]], [0029]; claim 6). The disclosure from Andersson is in line with Schier, which established that aqueous atropine solution, especially for injectable formulation, is known to have stability issue, especially in neutral and basic pH (Schier: page 331, right column to page 332), and per Schier, it is well-established that stability of atropine is enhanced in acid solution, in which ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4 (Schier: page 331, right column to page 332). Thus, it is maintained that, it is a prima facie obvious for an ordinary artisan, provided the combined teachings from Andersson and Schier, to formulate atropine in an acidic solution and at low concentration as claimed based on routine optimization, as per 103 rejection, to provide a stable parenteral formulation, the concentration of the pharmaceutical agent such atropine can be optimize from about 1 to 10 mg/ml (a range that overlaps the claimed range of 1 mg/ml to 6 mg/ml) and the formulation contains an acidified agent such citric acid such that the pH of the composition can be optimize in the range of 1 to 6 per Andersson (Andersson: [0033], [0065]; claims 14 and 22), particularly, for aqueous atropine solution, the ideal storage pH ranges approximately between 3 and 4 per Schier. The pH range of approximately between 3 and 4, as guided by Schier, substantially overlaps the claimed pH range of 3.0 to 3.5. Accordingly, the claimed pH range of 3.0 to 3.5 is known per Schier to be an optimum pH range for formulating a stable aqueous atropine solution. As such, as discussed in the 103 rejection, the Courts have made clear where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists.
Applicant argues:
“The Office Action cites Schier as teaching "the stability of the aqueous atropine sulfate is enhanced in acid solution, as the ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4." (Office Action page 6) This is a gross overstatement of Schier's teachings. (See Radomsky Dec. para. 6) "Schier teaches 0.4 mg/ml atropine sulfate solutions at pH of 3.88, 3.93, 3.82, and 4.02, and one 1 mg/ml atropine sulfate solution at a pH of 4.85. (Schier Table 1)" (Radomsky Dec. para. 6) None of Schier's tests occurred on compositions containing atropine or atropine sulfate in a concentration in the range of 1 mg/mL to 6 mg/mL a modifier of osmolarity to make the composition isotonic; a solvent in a concentration in the range of 95 vol.% to 99 vol.%; and wherein the pH of the composition is in the range of 3.0 to 3.5, as claimed by Applicant.”
In response, the Examiner disagrees. As discussed above, Andersson taught a composition in which atropine can be selected as the lipophilic agent in need of improvement in solubility and stability when formulated in a parenteral formulation, wherein Andersson further taught the concentration of the pharmaceutical agent such atropine can be optimize from about 1 to 10 mg/ml (a range that overlaps the claimed range of 1 mg/ml to 6 mg/ml) and the formulation contains an acidified agent such citric acid such that the pH of the composition can be optimize in the range of 1 to 6 per Andersson (Andersson: [0033], [0065]; claims 14 and 22), particularly, for aqueous atropine solution, the ideal storage pH ranges approximately between 3 and 4 per Schier, which is a pH range that substantially overlaps the claimed pH range of 3.0 to 3.5. With respect to the claimed “a solvent in a concentration in the range of 95 vol.% to 99 vol.%,” as discussed in the 103 rejection, Andersson teaches the parenteral formulation can be a infusion fluid containing normal saline as the aqueous diluent/solvent (Andersson: [0023]-[0024], [0037], [0067], and [0079]), thereby concentration of the solvent in Andersson would be in the range of 95 vol.% to 99 vol.% as claimed.
With respect to Table 1 of Schier, the sample that is not expired (“in date”), the measured pH value was 3.88, which is within the established optimum storage pH range of between 3 and 4 for atropine solution, as particularly indicated by Schier. Accordingly, the claimed pH range of 3.0 to 3.5 is known per Schier to be an optimum pH range for formulating a stable aqueous atropine solution. As such, as discussed in the 103 rejection, the Courts have made clear where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results from the claimed parameters, the optimization of concentration of atropine and pH of the composition so as to achieve a stable parenteral formulation would have been obvious before the effective filing date of applicant's invention. Applicant has not persuasively shown criticality of the claimed parameters in achieving a result that is unexpected or not appreciated by the cited prior arts even in light of the experimental data provided in the Radomsky Declaration, which are discussed in detail below.
Applicant argues:
“"pH is based on a logarithmic scale, which means each whole number change is a ten-fold change in acidity or basicity. Therefore, Schier's pH of 3.82 (its lowest pH) (on a more dilute solution) is not close to Applicant's pH of 3.0-3.5. (Radomsky Dec. para. 7) Schier does not remedy Andersson's deficiencies.
"Schier used tropine as a marker of degradation in formulations with a pH of 3.8 to 4.8." (Radomsky Dec. para. 8) Applicant's claimed invention shows from measuring all of the degradation substances, not just tropine, that the stability is surprisingly improved in the claimed pH range of 3.0-3.5. In fact, Schier did not monitor tropic acid, which is a much better marker of degradation than tropine. Applicant was able to test for very low levels of tropic acid with HPLC (rather than Schier's less exacting GC testing which did not measure tropic acid). (Radomsky Dec. para. 9) "Nothing in Schier teaches or suggests that there is surprising stability and less degradation (very low levels of tropic acid and other degradants) at a pH outside of Schier's test ranges (3.82-4.8). One of ordinary skill in the art would expect a pH closer to neutral (7.0) to be better than Applicant's claimed invention's pH 3-3.5, but that is not the case." (Radomsky Dec. para. 10).”
In response, the Examiner disagrees. As discussed above, per Schier, it is well-established that stability of atropine is enhanced in acid solution, in which ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4 (Schier: page 331, right column to page 332). Thus, the claimed pH range of 3.0 to 3.5 is known per Schier to be an optimum pH range for formulating a stable aqueous atropine solution. Contrary to Applicant’s and Declarant’s allegations, an ordinary artisan would expect, per guidance from Schier, that ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4, and not neutral pH (pH 7), as per Schier, atropine in solution is known to have stability issue at neutral pH (Schier: page 31, right column).
Applicant argues:
“"Applicant 's invention has another benefit of the pH range 3-3.5. The dissociation constant of water to OH- and H+ changes with temperature. While the pH at 3.0 was most desirable when degradation was measured of product was stored at 70°C, the pH at room temperature storage is better around 3.5. Nothing in Schier teaches or suggests this." (Radomsky Dec. para. 11).”
In response, the Examiner disagrees. As discussed above, per Schier, it is well-established that stability of atropine is enhanced in acid solution, in which ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4 (Schier: page 331, right column to page 332). Thus, the claimed pH range of 3.0 to 3.5 is known per Schier to be an optimum pH range for formulating a stable aqueous atropine solution. With respect to storage temperature, as discussed in the 103 rejection, Andersson teaches the formulation is stable for at least two years when stored at room temperature (Andersson: [0035]-[0037]). As discussed above, Schier also teaches the stability of the aqueous atropine sulfate is enhanced in acid solution, as the ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4 (Schier: Abstract; pages 329-331). Furthermore, in line with Andersson, Schier also established that the expiration date or standard shelf life requirement for a commercial product of atropine solution is usually two to three years (Schier: pages 331-332). Schier also established that stability of aqueous atropine sulfate is enhanced if maintained at a low pH values and temperatures (Schier: pages 333-334). Thus, the claimed storage condition of “the composition has a shelf life of at least 24 months when stored at room temperature” is a well-established storage condition for a stable aqueous atropine solution per the combined teachings of Andersson and Schier.
Applicant alleges that “[w]hile the pH at 3.0 was most desirable when degradation was measured of product was stored at 70°C, the pH at room temperature storage is better around 3.5.” However, Applicant has not shown by objective evidence that “the pH at room temperature storage is better around 3.5.” The Radomsky Declaration did not provide any data with respect to the alleged “the pH at room temperature storage is better around 3.5.” As discussed above, the claimed storage condition of “the composition has a shelf life of at least 24 months when stored at room temperature” is a well-established storage condition for a stable aqueous atropine solution per the combined teachings of Andersson and Schier.
Applicant argues:
“Applicant's claimed invention addresses a long felt need and has unexpected results [as shown in Table 1]. Applicant's claimed pH range of 3.0-3.5 surprisingly provides a much lower degradation rate of atropine as compared to pH outside of the claimed range and thus results in a desired multi-year shelf life of a ready to use, liquid injectable atropine drug product.
Radomsky was involved in experiments conducted to test the degradation results for compositions with varying pH. "Compositions were prepared with 4.0 mg/ml atropine sulfate monohydrate, 150 sodium chloride concentration (mM) with a citrate buffer (1.0 mM) and pH of 2.0, 3.0, 4.5 and 7.0. These compositions are covered by claim 21, except for the pH values of the comparative examples." (Radomsky Dec. para. 12).
The invention is not just optimizing pH in atropine compositions. Applicant's invention found an unexpected "sweet spot" in pH, which provides surprising lower levels of degradation and a very stable composition.
There has been a long felt need to have atropine compositions that contain sufficient concentrations of atropine and may be shelf-stable for long periods of time.
While Applicant asserts that there is no prima facie case of obviousness, unexpected results and solving a long felt need overcome the obviousness rejection.”
In response, the Examiner disagrees. The experimental data shown in Table 1 from Radomsky Declaration are not persuasive and insufficient to obviate the standing 103 rejection over Andersson and Schier.
First, it is noted that while the composition with pH of 3.0 from Table 1 showed less tropic acid and fewer total degradants when compared to composition with pH of 2.0, 4.5, and 7.0, claim 21 is not commensurate in scope with the composition of 4 mg/ml atropine sulfate, 1 mM of citrate buffer, 140 mM sodium chloride, and the pH of 3.0. It is noted that claim 21 is much broader than the composition containing 4 mg/ml atropine sulfate, 1 mM of citrate buffer, and 140 mM sodium chloride. Claim 21 is also drawn to a pH range of 3.0 to 3.5. Applicant has not shown data for upper pH limit of 3.5. Furthermore, claim 21 is also drawn to the composition having a shelf life of at least 24 months when stored at room temperature, yet the Radomsky Declaration and evidence provided therein did not show any data with respect to the composition having “a shelf life at least 24 months when stored at room temperature.” Thus, claim 21 is not commensurate in scope with the composition of pH 3.0 that is used for showing the alleged unexpected results. It is noted that [w]hether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). See MPEP §716.02 (d).
Second, the experimental data shown in Table 1 from the Radomsky Declaration may not be unexpected because as discussed above, Schier established that, it is known that, for aqueous atropine solution, the ideal storage pH ranges approximately between 3 and 4 per Schier. Accordingly, the claimed pH range of 3.0 to 3.5 is known per Schier to be an optimum pH range for formulating a stable aqueous atropine solution. While Applicant has provided data in the Radomsky Declaration showing compositions of pH that were outside of the claimed pH range of 3.0 to 3.5 (i.e., pH 2.0, 4.5 and 7.0) were inferior to the composition having a pH of 3.0, Applicant has not shown any data with respect to pH values above 3 (i.e., 3.5, 3.8, 4.0, etc), which are pH values that encompassed not only the claimed upper limit of pH 3.5, but the pH range of between 3 and 4 that was established by Schier to be known as the ideal storage pH for aqueous atropine solution. Thus, Applicant in view of the Radomsky Declaration have failed to show criticality of the claimed pH range in achieving unexpected superior results not appreciated by the prior art (the pH range of between 3 and 4 of Schier). It is noted that [t]he law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).
Third, Applicant’s argument and rebuttal evidence of long-felt need are not persuasive because Applicant has not sufficiently established the requirement for long-felt need. The Courts have stated per MPEP §716.04, establishing long-felt need requires objective evidence showing: (i) a need has been a persistent one that was recognized by ordinarily skilled artisans; (ii) the long-felt need must not have been satisfied by another before Appellant’s invention; and (iii) the invention must, in fact, satisfy the long-felt need. In re Gershon, 372 F.2d 535, 538 (CCPA 1967). As discussed above, Schier have already established that aqueous atropine solution, especially for injectable formulation, is known to have stability issue, especially in neutral and basic pH, and per Schier, it is well-established that stability of atropine is enhanced in acid solution, in which ideal storage pH for aqueous atropine sulfate solution ranges approximately between 3 and 4. Thus, Applicant’s alleged long-felt need argument did not established the long-felt need requirements from MPEP §716.04, particularly, Applicant’s alleged long-felt need has been satisfied by another (Schier) before the invention by Applicant and per MPEP §716.04 (I), "[O]nce another supplied the key element, there was no long-felt need or, indeed, a problem to be solved." Newell Companies v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988).
For all the reasons above, Applicant’s alleged arguments of unexpected results and evidence provided in the Radomsky Declaration are insufficient to obviate the 103 rejection over the combined teachings of Andersson and Schier.
As a result, for at least the reasons discussed above, claims 21-26 and 29-31 remain rejected as being obvious and unpatentable over the combined teachings of Andersson and Schier in the standing 103 rejection as set forth in this office action.
Claim(s) 27-28 and 32-33 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al (US 2012/0277249 A1) in view of Schier et al (Acad Emerg Med, April 2004, 11(4): 329-334), as applied to claim 21 above, and further in view of Buchine et al (US 2020/0139048 A1).
The composition of claim 21 is discussed above, said discussion being incorporated herein in its entirety.
However, Andersson and Schier do not teach the buffer of claims 27 and 28, and the scopolamine of claims 32 and 33.
Regarding claims 27-28 and 32-33, Buchine teaches a parenteral formulation comprising medicaments such as atropine and scopolamine, solvents such as water and ethanol, sodium chloride, and an acidic buffer such as citrate buffer or tartrate buffer ([0058], [0064], [0281], [0283], [0333], [0335], [0341], [0347], and [0365]-[0366]). Buchine teaches the formulation is optimize to an acidic pH below 6 using the acid buffer ([0033]). Buchine teaches the concentration of the buffer can be optimize to as low as from 1 μm to 1 mM so as to produce a stable formulation ([0328 and [0329). Buchine further teaches the concentrations of the medicaments can be optimize to as high as 1 M ([0328]).
It would have been obvious to one of ordinary skill in the art to incorporate citrate buffer or tartrate buffer as the acidic buffer, as well as, further include scopolamine as one of the pharmaceutical agents in the formulation of Andersson, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Buchine provided the guidance to do so by teaching that citrate and tartrate as both suitable acidic buffers to acidify the formulation so as the pH can be optimize to below 6, as well as, Buchine further teaches that atropine and scopolamine can be used in combination as the pharmaceutical agents in a parenteral formulation. One of ordinary skill in the art would have reasonable expectation of success in incorporating citrate buffer or tartrate buffer as the acidic buffer, as well as, further including scopolamine as one of the pharmaceutical agents in the formulation of Andersson because Andersson indicated that any organic acids including citric acid are suitable acidic component for optimizing the pH of the formulation to be lower than 6, and further indicate that antimuscarinic agents are suitable pharmaceutical agents (Andersson:[0033]). Thus, an ordinary artisan provided the guidance from Buchine would have looked to known acidic buffers in the art including citrate and tartrate so as to formulate an acidic formulation, as well as, looked to using a combination of atropine and scopolamine so as to provide a parenteral formulation that has at least an additive antimuscarinic effect, and achieve Applicant’s claimed invention with reasonable expectation of success.
It would also have been obvious to one of ordinary skill in the art to optimize the concentration of buffer to 1 mM, as well as, the concentration of scopolamine in the range of 0.8 mg/ml to 9 mg/ml, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Buchine teaches Buchine teaches the concentration of the buffer can be optimize to as low as from 1 μm to 1 mM so as to produce a stable formulation, and the concentrations of the medicaments can be optimize to as high as 1 M (Buchine: [0328]), which are ranges that falls within the claimed concentrations for buffer and scopolamine. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see 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); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results from the claimed concentrations, the optimization of concentrations of buffer and scopolamine so as to achieve a desired stable parenteral formulation would have been obvious before the effective filing date of applicant's invention. “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, 105 USPQ 233, 235 (CCPA 1955). See MPEP §2144.05 (I)-(II).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant's invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 07/29/2025 have been fully considered but they are not persuasive.
Applicant argues:
“Buchine does not teach a composition comprising atropine and scopolamine in a solvent with a shelf life of at least 24 months when stored at room temperature.”
In response, the Examiner disagrees. First, dependent claims 27-28 and 32-33 are not drawn to “a shelf life of at least 24 months when stored at room temperature” The “a shelf life of at least 24 months when stored at room temperature” was recited in claim 21, which was sufficiently render obvious by the combined teachings of Andersson and Schier. See pages 5 and 7-13 of this office action, said pages being incorporated herein in its entirety.
Nevertheless, its noted that paragraph [0329] of Buchine teaches “the components can also include combination of any oxime powders with scopolamine powders and an atropine-based diluent, which is stable as a liquid, and can thus be utilized as the liquid component” and paragraph [0390] of Buchine further teaches that the resultant solution is stable for up to 10 years or for greater than 10 years.
As a result, for at least the reasons discussed above, claims 27-28 and 32-33 remained rejected as being obvious and unpatentable over the combined teachings of Andersson, Schier, and Buchine in the standing 103 rejection as set forth in this office action.
Claim(s) 34 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andersson et al (US 2012/0277249 A1) in view of Schier et al (Acad Emerg Med, April 2004, 11(4): 329-334), as applied to claim 21 above, and further in view of Webb et al (US 2020/0138952 A1).
The composition of claim 21 is discussed above, said discussion being incorporated herein in its entirety.
However, Andersson and Schier do not teach the concentration of sodium chloride of claim 34.
Regarding claim 34, Webb teaches an intravenous injection formulation comprising a pharmaceutical agent and sodium chloride solution in a concentration of about 150 mM, wherein the formulation is isotonic (Abstract; [0007], [0008], [0017], [0019]-[0020],[0027]).
It would have been obvious to one of ordinary skill in the art to optimize the concentration of sodium chloride in the formulation of Andersson to 150 mM, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Webb indicated that for an intravenous formulation as those of Andersson, sodium chloride be used at a concentration of 150 mM so as to provide a resultant formulation that isotonic. Thus, an ordinary artisan seeking to formulate an isotonic formulation would have looked to optimizing the concentration of sodium chloride in the formulation of Andersson to 150 mM, and achieve Applicant’s claimed invention with reasonable expectation of success.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant's invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 07/29/2025 have been fully considered but they are not persuasive.
Applicant argues:
“Claims 34 depends from claim 21. The arguments regarding Andersson in view of Schier as applied to claim 21 are reasserted here. Webb does not remedy the deficiencies. In the event there is a prima facie case, Applicant's unexpected results and long felt need are restated here and overcome the rejection.”
In response, the Examiner disagrees. As discussed above, claim 21 was sufficiently render obvious by the combined teachings of Andersson and Schier. Applicant’s alleged unexpected results and long felt were also insufficient to obviate the 103 rejection over the combined teachings of Andersson and Schier for the reasons discussed on pages 7-17 of this office action, said pages being incorporated herein in its entirety.
As a result, for at least the reasons discussed above, claim 34 remained rejected as being obvious and unpatentable over the combined teachings of Andersson, Schier, and Webb in the standing 103 rejection as set forth in this office action.
Conclusion
No claim is 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.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613