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 .
Claim Rejections - 35 USC § 112
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 1-2 and 13-30 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.
Claim 1 recites components “in 100 ml aqueous solution”. It is unclear if this is a recitation of a product that has a volume of 100 ml or if the recitation is of a product with a concentration of components present at the recited amounts relative to 100 mL of solution.
Claims that are rejected, but are not elaborated upon are also indefinite because they depend from an indefinite claim and do not add clarity.
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.
Claims 1-2 and 13-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Penkler et al. (previously cited) in view of Okumu et al. (US PGPub No. 2016/0038414), Arbelaez-Camargo et al. (International Journal of Pharmaceutics 2018 543(1-2):190-200), Pai et al (previously cited), and Benk et al. (EP 2821081).
Penkler et al. teach a clear, colorless, aqueous composition that includes propofol, 2-hydroxypropyl-b-cyclodextrin (HPBCD), and water for injection (see abstract and page 4 last paragraph-page 5 second full paragraph; instant claims 1, 15-16, and 23-25). The propofol forms a complex with the HPBCD (see page 4 last paragraph). b-cyclodextrin is not recited as a component of the HPBCD (see instant claim 19). They detail preparing the composition by dissolving HPBCD in water, then adding propofol, at ambient (room) temperature or at a temperature up to 50⁰C, while stirring until a solution forms (see page 9 third full paragraph; instant claims 14 and 21). Penkler et al. exemplify a ratio of propofol to HPBCD on a mass basis of 1:14.63 (see example 5; instant claims 2-3). The example also includes polyethylene glycol at 10 grams and a final volume of 100 ml (see example 5). The HPBCD has an average degree of substitution of 4.6 which corresponds to a molar mass of about 1402 g and a per glucopyranose degree of substitution of 0.657, thus example 5 provides a molar ratio of propofol to HBCD of 1:1.85 (see pages 10-11; as calculated by the examiner; instant claims 2 and 17-18). Penkler et al. exemplify preparing the composition such that the propofol and HPBCD are dissolved in a water at 45⁰C temperature, then the composition is cooled to ambient (room) temperature prior to the addition and dissolution of the PEG, then the composition is filtered through a 0.22 mm filter and the final propofol concentration is 1 g per 100 ml (see example 5; instant claims 1 and 21). Additionally, they also teach adding tonicity agents such as glycerin to adjust the osmolality to 280-320 mOsm/kg (see example 2; instant claim 20). The presence of sodium chloride is not explicitly detailed.
Okumu et al. teach that sodium chloride, glycerol, and polyethylene glycol are known tonicity adjusting agents for an injectable preparation (see paragraphs 201)
Arbelaez-Camargo et al. teach that polyethylene glycol (PEG) is a known tonicity (osmolality) adjusting agent (see abstract and graphics 1 and 3). An about 8g/100 ml concentration of PEG 400 in water yields an initial osmolality of about 300 mOsm/kg and this value increases or decreases as the concentration increases or decreases, respectively. (see page 191 second column first full paragraph and graphic 1).
Pai et al. teach a clear aqueous composition that includes propofol, HPBCD, and water that is suitable for parenteral administration (see abstract; instant claims 15-16). The propofol forms a complex with the HPBCD at about 10⁰C to about 50⁰C (see column 3 lines 35-39; instant claims 13, 21-22, 26, and 29). b-cyclodextrin is not recited as a component of the HPBCD (see instant claim 19). They further detail the inclusion of an isotonic diluent that may be a dextrose solution or a sodium chloride solution (see column 3 lines 17-20; instant claim 1).
Benk et al. teach that a sodium chloride solution at 0.9 wt% (0.9 g per 100 ml) is isotonic with the blood (see paragraph 11). Similar solutions that provide a higher osmolarity have a higher concentration of sodium chloride (see paragraph 11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the example 5 composition of Penkler et al., where sodium chloride is added as a tonicity adjusting agent instead of the PEG. This modification would have been obvious because Penkler et al. exemplify the inclusion multiple different tonicity modifying compounds and sodium chloride is known along with PEG as a tonicity modifying agent employed in injectable propofol compositions, in light of Okumu et al. The modification is also obvious as the simple substitution of one known element for another in order to yield a predictable outcome. It additionally would have been obvious to include sodium chloride at a concentration greater than 0.5 g per 100 ml because 1) the exemplified concentration of a PEG tonicity agent exemplified by Penkler et al. yields an osmolality close to (or within) the osmolality range envisioned by Penkler et al. and 2) sodium chloride yields an isotonic osmolality at proportions greater than 0.5 g per 100 ml as detailed by Benk et al. Since the osmolality is result effective variable, it also would have been obvious to optimize as a matter of routine optimization. It additionally would have been obvious to produce a composition with an osmolality in the range taught by Penkler et al. This yields a range of osmolality levels that overlaps with those instantly claimed, thereby rendering the claimed range obvious (see instant claim 20). “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. 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)” (see MPEP 2144.05). According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here the modified composition of Penkler et al. is a solution with all the instantly claimed components at the claimed proportions; therefore the properties of color for the composition would follow (see instant claim 1). In addition, Pai et al. teach that suitable temperatures for making the propofol and HPBCD solution are as low as 10⁰C. Thus the application of a component addition/dissolution temperature as low as or even slightly lower than 10⁰C in the method of making taught by Penkler et al. would have been obvious for the sodium chloride, given the proximity of the prior art range to these values. The results would be addition temperatures that meet or overall with the ranges instantly claimed, thereby rendering the instantly claimed ranges obvious (see MPEP 2144.05). Therefore claims 1-2, 13-26, and 29 are obvious over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al.
Claims 1-2, 13-26, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. as applied to claim 1-2, 13-26, and 29 above, and further in view of Garti et al. (US PGPub No. 2019/0008770).
Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. render obvious the limitations of instant claims 1-2, 13-26, and 29. The pH for the propofol composition is not explicitly detailed by Penkler et al.
Garti et al. teach an aqueous preparation for intravenous delivery of propofol (see abstract). Garti et al. also teach the solution pH to be 3 to 9 as suitable for such compositions where discrete values exemplified between 6.99 and 7.23 are detailed and pH adjusting additives may be included (see paragraphs 41 and 67 and example 8; instant claims 20 and 30). They also teach the composition to have an osmolality similar to (isotonic) the blood stream and envision a range of about 250-450 mOsm/kg (see paragraph 69; instant claim 1).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to adjust the pH of the composition of Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. to a level within the range taught by Garti et al. because it was known to be useful for an intravenous propofol composition. The modification is obvious as the application of the same technique to a similar product in order to yield the same improvement. The range and discrete pH values of Garti et al. meet or overlaps with the range instantly claimed thereby rendering the instantly claimed range obvious (see MPEP 2144.05). Therefore claims 1-2, 13-26, and 29-30 are obvious over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., Benk et al., and Garti et al.
Claims 1-2, 13-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. as applied to claim 1-2, 13-26, and 29 above, and further in view of Ulmann (US PGPub No. 2016/0081926).
Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. render obvious the limitations of instant claims 1-2 and 13-26. Penkler et al. exemplify preparing the composition such that the propofol and HPBCD are dissolved in a water at 45⁰C temperature, then the composition is cooled to ambient (room) temperature prior to the addition and dissolution of the PEG. Pai et al. teach a range of about 10⁰C to about 50⁰C as suitable for forming a complex between propofol and HPBCD. A precise temperature range for room temperature is not explicitly detailed.
Ulmann teach room temperature in the context of intravenous drug preparations to span form 15 to 25⁰C (see paragraph 38).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to dissolve the sodium chloride in the solution of propofol and HPBCD at a known room temperature when making the modified composition of Penkler et al. This choice would have been obvious in light of Ulmann who detail a numerical range contemplated as room temperature. The result is a range of temperatures that overlap with that instantly claimed. In addition, Pai et al. teach that suitable temperatures for making the propofol and HPBCD solution are as low as 10⁰C. Thus a component addition/dissolution temperature as low as or even slightly lower than 10⁰C would have been obvious for the sodium chloride, given the proximity of the prior art range to these values. The results would be addition temperatures that meet or overall with the ranges instantly claims, thereby rendering the instantly claimed ranges obvious (see MPEP 2144.05). Therefore claims 1-2, 13-26, and 29 are obvious over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., Benk et al., and Ulmann.
Claims 1-2 and 13-30 are rejected under 35 U.S.C. 103 as being unpatentable over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. as applied to claim 1-2, 13-26, and 29 above, and further in view of Buffe et al. (US PGPub No. 2021/025376).
Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., and Benk et al. render obvious the limitations of instant claims 1-2, 13-26, and 29. Penkler et al. more generally teach a degree of substitution of 2.5 to 9 hydroxypropyl groups per cyclodextrin molecule which converts to a degree of substitution of 0.357 to 1.28 pe glucopyranose (see page 11). While a 4.6 degree of substitution, corresponding to 0.657, is exemplified, a 0.69 degree of substitution is not explicitly noted.
Bufffe et al. teach HPBCD for pharmaceutical preparations with a low percentage of residual b-cyclodextrin impurity and a low degree of substitution, namely below 0.71, as an improved pharmaceutical ingredient (see paragraphs 15-16 and 22-23). They further detail a degree of substitution of 0.69 for a particular embodiment (see paragraph 50; instant claims 27-28). This HPBCD has a molecular weight in accordance with instant claim 28 (as calculated by the examiner).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select the HPBCD of Buffe et al. with a per glucopyranose group degree of substitution of 0.69 as a particular variety of the HPBCD envisioned in the modified product of Penkler et al. This modification is obvious because it falls within the range envisioned by Penkler et al. and as the simple substitution of one known element for another in order to yield a predictable outcome and as the application. Therefore claims 1-2 and 13-30 are obvious over Penkler et al. in view of Okumu et al., Arbelaez-Camargo et al., Pai et al., Benk et al., and Buffe et al.
Claims 1-2, 13-16, 19-26, and 29-30 are rejected under 35 U.S.C. 103 as being unpatentable over Thompson et al. (previously cited) in view of Benk et al.
Thompson et al. teach a clear aqueous solution that includes propofol and a sulfobutyl ether derivative of b-cyclodextrin (SAE-b-CD) that can be sterile filtered and administered parenterally (see column 6 lines 59-63, column 7 lines 26-35, and column 8 lines 51-57; instant claims 1 and 14-16). This compound meets the limitations of instant claim 16, where formula II has n = 5, at least one of R1 or R2 is -O-C4 alkylene SO3-, amongst R1 to R9 seven are -O-C4 alkylene SO3 and the remainder are -O-, and groups S1 to S9 are pharmaceutically acceptable cations that include metals (see column 12 lines 65-column 13 line 35 and column 14 lines 15-23; instant claims 24-25). The molar ratio of propofol to SAE-b-CD is envisioned at 1:2 to 2:1 and preferably 1:1, where an example has a narrower range of 1:1.1 to 2:1 propofol to SAE-b-CD (see column 14 lines 24-31 and example 2; instant claim 2). The exemplary molar ratio range converts to a weight range of 1:13.3 to 1:26.6 (1 g propofol with 13.3 g SAE-b-CD to 1 g propofol with 26.6 g SAE-b-CD) (see column 15 line 48-column 16 line 3; instant claim 1). Thompson et al. also teach the solution pH to be 4.5 to 9 (see column 23 lines 14-18; instant claims 20 and 30). They go on to teach sodium chloride as a tonicity modifier included in the composition (see column 21 lines 56-61 and claim 8). Complexation of the propofol and SAE-b-CD is discussed to occur with a steady binding constant over a temperature of 5 to 40⁰C and at a pH below 9 (see column 14 line 64-column 15 line 9 and figure 5; instant claims 13 and 21-22). Preparation of the composition occurs by stirring the SAE-b-CD and propofol until dissolution into water, where additional components are added along with or after the addition of these components (see examples 3 and 5). Thompson et al. teach a clear aqueous solution that includes propofol and a b-cyclodextrin derivative that can be sterile filtered and administered parenterally (see column 6 lines 59-63, column 7 lines 26-35, and column 8 lines 51-57). Thompson et al. also teach the solution pH to be 4.5 to 9 (see column 23 lines 14-18; instant claim 20). They go on to teach glycerin (glycerol) and sodium chloride as envisioned tonicity modifiers to include in the composition (see column 21 lines 56-61 and claim 8). Thompson also teach that a hypertonic vehicle containing the b-cyclodextrin for dissolving the propofol is suitable and ranges from about 220 to about 740 mOsm/kg (see column 17 lines 4-8). They further teach a pH of 5 to 7.5 obtained via the inclusion of an alkalizing agent, acidifying agent, or buffer as useful for the composition, noting exemplary values of 6.8, 7.3, and 7.4 (see column 23 lines 14-25 and table at bottom of column 24). An explicitly example with a claimed proportion of pharmaceutically acceptable salt or propofol to sulfurized alkyl ether of cyclodextrin proportion is not detailed.
Benk et al. teach that a sodium chloride solution at 0.9 wt% (0.9 g per 100 ml) is isotonic with the blood (see paragraph 11). Such solutions that provide a higher osmolarity have a higher concentration of sodium chloride (see paragraph 11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ sodium chloride as a tonicity modifier in the composition of Thompson et al. because they teach to include such agents and envision this particular compound in this role. The inclusion of sodium chloride at a concentration that achieves isotonicity would follow because Thompson et al. teach this level of osmolality to be desirable. In light of Benk et al., a concentration of sodium chloride at or near 0.9 wt% to achieve this end would have been obvious and meets the instant claim limitation concerning the salt proportion. The range of molar and weight ratios of propofol to SAE-b-CD yield a range that overlaps with those instantly claimed (1:13 to 1:15 weight ratio range claimed), thereby render obvious the instantly claimed range (see MPEP 2144.05). It additionally would have been obvious to select the highlighted SAE-b-CD amongst those envisioned for the composition because Thompson et al. state to do so. Application of taught pH values would follow and meet or yield ranges that overlap with those instantly claimed thereby rendering the claimed ranges obvious (see MPEP 2144.05). It also would have been obvious to add/dissolve components into the compositions at the 5 to 40⁰C temperature envisioned as useful for the complexation process that is responsible for solution formation. The result is a range of temperatures for the process of production that overlaps with the instantly claimed temperature range which renders the instant range obvious. Further, the order of addition of the components such that sodium chloride is added after the SAE-b-CD and propofol are combined into solution would have been obvious as one of a small finite number of options, absent evidence to the contrary (see MPEP 2144.04(IV)(C)). According to MPEP 2145II, mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979). In addition, the fact that an inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Here the composition of Thompson et al. has all the instantly claimed components and combines them under instantly claimed conditions, therefore the properties of color for the composition would follow. Therefore claims 1-2, 13-16, 19-26, and 29-30 are obvious over Thompson et al. in view of Benk et al.
Response to Arguments
Applicant's arguments filed July 17, 2026 have been fully considered. In light of the amendment to the claims, the rejections and objections are hereby withdrawn. New grounds of rejection are detailed to address the new claim limitations. The applicant’s arguments concerning prior art that has been reapplied are not persuasive and the arguments that apply to the new grounds of rejection are addressed below.
Regarding rejections under 35 USC 103 over Penkler et al. in view of others:
The applicant argues that the inclusion of a salt in a solution with propofol complexed with HPBCD has an unexpectedly superior outcome as compared to a composition with polyethylene glycol as is exemplified in Penkler et al. example 5. The applicant points to data in table 4 of the specification, comparing the stability constant that was obtained in preparations with two different salts or glycerol. The applicant argues that the selection of a salt additive yields an unexpectedly superior outcome as compared to glycerol and presumes the difference also applies polyethylene glycol. This argument is unpersuasive because the outcome is not placed in context in the art. While a difference was seen, the applicant has presented no evidence or discussion of the outcome that would have been expected based upon the art. In addition, the applicant presumes that all non-ionic additives would perform equally, but provide no reasoning as to why the much larger polyethylene glycol compound would behave like glycerol in this context. Loftsson et al. teach that salts and polyethylene glycol can increase the complexation efficiency of cyclodextrin via an increase in stability constant (see Journal of Pharmaceutical Sciences 2012 101:3019–3032; pages 3025 and 3030, and table 6). Al Omari et al. teach that salt concentration can impact the stability constant for cyclodextrin-drug complexes with increasing amounts increasing the stability constant (Journal of Inclusion Phenomena and Macrocyclic Chemistry 2007 58:227-235, abstract table 1). Thus the art appears to point to salt addition being expected to increase the cyclodextrin stability constant and toward the presence of polyethylene glycol also increasing the stability constant. Thus the applicant has not met their burden for demonstrating an unexpectedly superior outcome for the claimed composition.
Regarding rejections under 35 USC 103 over Thompson et al. in view of others:
The applicant argues that Thompson et al. do not exemplify concentrations of propofol and cyclodextrin within the instantly claimed range. To the contrary, Thompson et al. explicitly discuss an embodiment with a 11 mg/ml propofol and 159 mg/ml SAE-b-CD which corresponds to a mass ratio of 1:14.45 in their discussion of the compositions that populate a range of concentrations that they contemplate (see column 15 lines 53-58). In a 100 ml volume, this embodiment yields about 1 g propofol and about 15 g SAE-b-CD. Even if this embodiment were not discussed, the teachings of Thompson et al. provide an overlapping range of concentrations of propofol and cyclodextrin. There is no evidence of the criticality of the instantly claimed proportions. Thus the claimed range would have been obvious in light of Thompson et al. due to the overlap in teachings.
Conclusion
No claim is allowed.
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 CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/ Examiner, Art Unit 1615
/MELISSA S MERCIER/ Primary Examiner, Art Unit 1615
