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 .
Response to Amendment
The Amendment filed 01/29/2026 has been entered. Applicant’s amendments are in response to in the Non-Final Office Action mailed 08/01/2025. Applicant’s claims have been amended in the following manner: independent claim 1 has been modified by inclusion of a limitation for the term “freeze-dried”, the 77.5-92.54 wt% amount of solvent and a surface tension of less than 70 mN/m (which are supported in Applicant’s Specification at [0003, 0028, 0033]), where surface tension is also amended in instant claim 19. Note Buckton is added to address the new surface tension limitation (drawing a new ground of rejection), while the other limitations are found within the Art from the previous Action. The following objections/rejections are withdrawn: none.
The Examiner further acknowledges the following:
Claims 1-23, and 41-42 are pending.
Claims 20-23, and 41-42 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-19 are presented for examination and rejected as set forth below.
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 1-4, 8-15, and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Fuhrherr (WO2018158459A1 - machine translation provided), Remon (US6010719), Buckton (Journal of Pharmaceutical Sciences 1997), Nilsson (US20050232997A1), and Wong (US 2005/0271719 A1; cited on the IDS filed 07/21/2025).
Applicant’s claims are directed to a pharmaceutical formulation for preparing a freeze-dried pharmaceutical dosage form, the formulation comprising: an active pharmaceutical ingredient; 0.01-0.3 wt. % of a surfactant; 77.5-92.54 wt% of a solvent; 4-6 wt. % of high molecular weight (HMW) fish gelatin; and a specified structure former, wherein the surface tension is less than 70 mN/m.
Fuhrherr teaches orodispersible tablets (abstract), which are fast melt tablets [0026]. Fuhrherr teaches both processes to make freeze-dried forms suitable for use [0048-0050] (Fuhrherr – claim 18) with adequate disintegration or dissolution behavior that includes surfactants (Fuhrherr – claim 8).
Regarding claims 1, 3-4, 8-12, and 14-15: Fuhrherr teaches a solution for freeze-drying [0059-0062], comprising burlulipase (reads on active pharmaceutical ingredient), 5 parts fish gelatin (reads on 5 wt%, within the instant range of 4-6 wt%), and 4 parts mannitol (reads on 4 wt%, for structure former and instant 3-5 wt% amount of claims 9-10), which is all incorporated into about 89.56 parts water (reads on 89.56 wt%, which covers the newly added “solvent” limitation with the instant range of 77.5-92.54 wt% in claim 1) (i.e., the water amount in Fuhrherr’s Example 1 [0059-0060] is considered the addition of 26.11 parts water + 63.45 parts burlulipase aqueous solution = about 89.56 parts water, because the burlulipase is only a fractional amount of the solution at 23.64 mg/g; or only 2.3 wt% of the aqueous solution is burlulipase, and thus, about 97.7 wt% of the burlulipase aqueous solution is water), and all combined ingredients total 100 parts (or 100 wt%) [0060], which ultimately produces an orodispersible tablet (abstract). Fuhrherr teaches all types of fish gelatin [0027]. Fuhrherr teaches preferred formulations that incorporate poloxamer or polysorbate and the pH-modifier citric acid [0030]. Fuhrherr teaches that the surfactant (i.e., poloxamer or polysorbate), are used for improving the disintegration or dissolution behavior (Fuhrherr – claim 8).
Regarding claim 13: Fuhrherr teaches the pH to be adjusted (Fuhrherr – claim 8, [0032]) to an appropriate amount, and preferably within pH 4-9 to maintain activity of the active [0014].
In summary, Fuhrherr teaches the freeze-dried pharmaceutical formulation of the instant claims (including fish gelatin [0027] and the incorporation of a surfactant, as in Fuhrherr – claim 8). However, Fuhrherr does not teach the amount or surfactant (instant claims 1-2), is silent on the surface tension used during formulation (instant claim 1 and 19), and does not teach the specified high molecular weight (HMW) fish gelatin (instant claim 1).
Remon teaches freeze-dried disintegrating tablets (abstract) that proceed through an intermediate solution preparation (see Example 1). Fuhrherr teaches surfactants in the amount of 0.001-3 wt% for the purpose of increasing active ingredient solubility (col 5, lines 45-53, Remon – claims 7 and 15). The addition of these quantity of surfactants inherently lowers the surface tension of aqueous solutions, as shown by Buckton.
Buckton teaches that poloxamer surfactants effectively lower the surface tension of water to less than 70 mN/m at amounts of 0.01-10 wt% (pg 164, Figures 1-2), which is an inherent feature of poloxamer surfactants in aqueous environments (pg 163, ‘introduction’, pg 164, ‘results and discussion’). Thus, an aqueous solution with an amounts of 0.01-10 wt% poloxamer surfactant is expected to have a surface tension less than 70 mN/m (instant claims 1 and 19).
Nilsson teaches surfactants help prevent freeze-dried product from sticking to the surface of molds (i.e., affecting final appearance) and to disperse active ingredients [0075], within the context of orodispersible dosage forms comprising fish gelatin (Nilsson – claim 5). Furthermore, Nilsson discusses mold depressions for the purpose of tablet making [0075-0078]. Thus, the amount of surfactant would be modified by routine optimization in order to optimize the appearance of the final dosage form and to disperse active ingredients. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that 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).
Wong teaches fast dispersing dosage forms comprising high molecular weight (HMW) fish gelatin (abstract). Wong teaches the viscosity issues of HMW fish gelatin ([0040] and Tables 1-3, 5-6), but still incorporates HMW fish gelatin in fast dispersing dosage forms (Tables 1-3, 5-6). Particularly, Wong teaches incorporation of HMW fish gelatin and/or standard gelatin into pharmaceutical freeze-dried formulations as obvious (abstract, [0018]), where HMW fish gelatin consistently provides good appearance above 4 wt/wt% [0055].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use the surfactant amount suggested by Remon of 0.001-3 wt% (which would inherently lower the surface tension value, as demonstrated by Buckton, where solutions with 0.01-10 wt% poloxamer surfactant demonstrate surface tensions less than 70 mN/m), because Fuhrherr teaches surfactants for use in orodispersible tablets to improve disintegration or dissolution behavior (Fuhrherr – claim 8), and Remon just teaches the specific amounts used to achieve this behavior (0.001-3 wt%), which would additionally result in a reduction of surface tension due to the inherent functionality of the surfactants (as taught by Buckton). With regard to the numerical range (i.e. surfactant amount and surface tension of the Prior Art), note that "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003) (see 2144.05(I)). Furthermore, the amount of surfactant would be further optimized to optimize disintegration and/or dissolution behavior (as taught by Fuhrherr) and/or in order to optimize the appearance of the final dosage form and to disperse active ingredients (as taught by Nilsson). Thus, the rationale for these modification is supported because Fuhrherr teaches both processes to make freeze-dried forms suitable for use (where appropriate appearance is implied) [0048-0050] (Fuhrherr – claim 18) with adequate disintegration or dissolution behavior that includes surfactants (Fuhrherr – claim 8).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to use the HMW fish gelatin of Wong in Fuhrherr’s invention because Fuhrherr teaches a wide range of fish gelatin for preferred use as a binder in orodispersible tablet forms [0027], and Wong’s HMW fish gelatin is just a specific type of fish gelatin. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Thus, Wong teaches incorporation of HMW fish gelatin and/or standard gelatin into pharmaceutical freeze-dried formulations as obvious (abstract, [0018]), where HMW fish gelatin consistently provides good appearance above 4 wt/wt% [0055], which aligns with Fuhrherr’s teaching of fish gelatin for preferred use as a binder in orodispersible tablet forms [0027].
Claims 1-19 are rejected under 35 U.S.C. 103 as being unpatentable over Fuhrherr (WO2018158459A1 - machine translation provided), Remon (US6010719), Buckton (Journal of Pharmaceutical Sciences 1997), Nilsson (US20050232997A1), and Wong (US 2005/0271719 A1; cited on the IDS filed 07/21/2025), as applied to claims 1-4, 8-15, and 19 above, and in further view of Vasanthan (J. Young Pharm, 2016), Sherman (US6197335), Patel (Journal of Pharmaceutical Sciences, 2017), Carvalho (DTU, 2018), Wilkes (Fluid Mechanics for Chemical Engineers, 2017), and Dillaha (US20080260823A1).
As discussed above, the prior art teaches pharmaceutical formulations that are useful for drug delivery, including freeze-dried formulations based on mannitol, HMW fish gelatin, and surfactants. However, The prior art does not teach the specific nonionic surfactant as poloxamer 188 (instant claim 5), the additional specific anionic surfactants (instant claims 6-7), the specified active ingredient (instant claim 16), viscosity (instant claim 17), and relative density (instant claim 18) in the description of the pharmaceutical formulations.
Vasanthan teaches fast dissolving tablets containing poloxamer 188 in order to affect solubility and dissolution rate of drug substances (abstract).
Sherman teaches solid pharmaceutical compositions incorporating the anionic surfactant sodium lauryl sulfate (abstract) in 0.1 wt% (col 3, lines 47-48) that can be made by freeze-drying (col 4, lines 38-39).
Patel teaches parameters important for lyophilized drug products, including surface tension and viscosity, as far as appearance, uniformity, and texture (pg 1714, paragraph 8 and 9 and pg 1715). Carvalho teaches density affects the sublimation rate in freeze-drying processes (pg 23, paragraph 3). Wilkes further teaches surface tension, viscosity, and density as important for fluid physical properties (pg 1). Water is demonstrated to have a density of 1 g/mL (Table 1.1), a viscosity of 29.76 centipoise (Table 1.4), and a surface tension of 72.75 dynes/cm (Table 1.6). Since water is the primary constituent of the intermediate solutions used by Fuhrherr (see above), the physical property values of the solutions used in processing would be something a PHOSITA would optimize in order to optimize the manufacturing process and improve the final dosage form appearance and uniformity, according to the prior art above. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that 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).
Dillaha teaches the active ingredient glycopyrrolate in orally disintegrating tablets for pharmaceutical use for treating sialorrhea (abstract) that involves freeze drying [0019].
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the secondary references above with Fuhrherr’s general solution formulation intended for a freeze-dried orodispersible tablet, because they teach elements of orodispersible pharmaceutical formulations and the making of that are generally taught by Fuhrherr, such that Fuhrherr teaches surfactants to improve solubility/dissolution (Fuhrherr – claim 8) (i.e., the surfactants poloxamer 188 or sodium lauryl sulfate would be reasonable to incorporate by serving the same function, as taught by Vasanthan and Sherman), intermediary homogeneous solutions for conversion into a final dosage form [0023] (i.e., the physical properties of the intermediary solution is expected to be optimized for handling, such that Patel and Wilkes teaches viscosity, density, and surface tension, as important properties of liquid pharmaceutical solutions, including for the purpose of making lyophilized drug products), and an active ingredient (where Dillaha shows that glycopyrrolate is an active ingredient treating sialorrhea that is suitable for use in freeze-dried oral disintegrating tablet formulations).
Response to Arguments
Applicants arguments, see pg 6-10, filed 01/29/2026, with respect to the 103 rejection of claims 1-19 under rejection have been fully considered but they are not persuasive. The 103 rejection has been modified with respect to amendments made to the claim set. The thrust of the rejection has been altered, now including Buckton to address the surface tension limitations (instant claims 1 and 19).
On page 7, Applicant argues that Fuhrherr’s Example 1 only discusses 26.11 parts of water that is substantially less than 77.5-92.54 wt% of a solvent. Note that Fuhrherr also teaches aqueous burlulipase solution (Fuhrherr – claim 18, [0060]) (i.e., the water in the freeze-drying process is considered the addition of 26.11 parts water + 63.45 parts burlulipase aqueous solution = about 89.56 parts water, because the burlulipase is a fractional amount of the water at 23.64 mg/1000 mg, and the ingredients total 100 parts or 100 wt%) [0060]. Thus, the about 89.56 wt% water found in Example 1 [0060] reads on 77.5-92.54% water.
On pg 8, Applicant argues that the surface tension of less than 70 mN/m is not taught or suggested in the Prior Art. The amendment of this limitation (i.e., where only 60-80 mN/m was previously found in claim 19) prompted the introduction of Buckton, who teaches less than 70 mN/m surface tension (pg 164, fig 1-2), as the natural result of introducing poloxamer surfactants to reduce surface tension of water (i.e., water’s surface tension is 72 mN/m). Thus, the Buckton reference clearly demonstrates that the <70 mN/m surface tension is the inherent result of adding surfactants such as poloxamer to aqueous solutions (pg 163-164).
On page 8-10, Applicant argues that introduction of Poloxamer 188 unexpectedly produced more consistent dosage forms with improved appearance. Thus, argument focus on a narrower embodiment of Fuhrherr’s larger teachings (by attempting to demonstrate the criticality of the surfactant range, where Fuhrherr is silent on surfactant amount). The combined Prior Art demonstrates the wider 0.001-3 wt% surfactant range as obvious to affect dissolution profile.
However, Nilsson teaches the benefit of including a surfactant to improve dosage form appearance. Nilsson teaches surfactants help prevent freeze-dried product from sticking to the surface of molds (i.e., thus, affecting final appearance, when there is difficultly removing the dosage form or uneven adherence results in uneven freeze-drying; additionally, in Applicant’s Specification there is a suggestion that the wedging defect occurs by clinging to a side of the blister pocket [0036]) and to disperse active ingredients [0075], within the context of orodispersible dosage forms comprising fish gelatin (Nilsson – claim 5). Thus, the sticking of surfaces to the mold described by Nilsson and the clinging of material to the blister pocket side described by Applicant, appear to describe the same pathway to generating dosage form defects. Furthermore, Nilsson discusses mold depressions for the purpose of tablet making by freeze-drying [0073-0076].
Thus, Applicant is demonstrating a benefit predicted by the Art, as taught by Nilsson, by optimizing the amount of surfactant required to improve final dosage form appearance (i.e., 0.01 wt% is minimum amount of surfactant required as a threshold to begin improving dosage form appearance; 0.2 wt% is the minimum amount of surfactant require to reach the threshold to completely remove process defects). In this case, the beneficial results of the instant invention (i.e., dosage for appearance) are expected based on the teachings of the prior art (specifically Nilsson): “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof.” In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967), see also In re Skoner, 517 F.2d 947, 950 (CCPA 1975). It would be obvious to start from the formulation of Fuhrherr that incorporates a surfactant, and experiment with the surfactant amount to improve the final appearance of the freeze-dried dosage form, as taught by Nilsson.
Furthermore, because Nilsson suggests non-limiting examples of surfactants such as Tween 80 (polyoxyethylene (20) sorbitan mono-oleate), as capable of improving dosage form appearance by preventing sticking to the mold surface [0075], a PHOSITA would reasonably expect docusate sodium, sodium lauryl sulfate, and poloxamer 177 (all known surfactants, that are defined by Applicant’s Specification as having surfactant properties) to provide the same beneficial effect (because Nilsson teaches surfactants help prevent freeze-dried product from sticking to the surface of molds [0075]), which is what Applicant demonstrates in Table 1 and 7 of the Specification. Thus, the selection of poloxamer 188 and/or sodium lauryl sulfate and docusate sodium in claims 5 and 7 respectively, to demonstrate improved dosage form appearance, is not compelling in terms of unexpected results, with respect to Nilsson’s teachings of using surfactants to prevent a freeze-dried product from sticking to the mold surface. Therefore, the claim set does not demonstrate non-obviousness by unexpected results.
Correspondence
Applicant's amendment necessitated the new ground 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 extension fee 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 date of this final action.
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/R.P./Examiner, Art Unit 1614 3/5/2026
/SEAN M BASQUILL/Primary Examiner, Art Unit 1614