DETAILED ACTION
Status of Claims
Claims 1-20 are currently pending. Claims 1-13 and 16-20 are currently under consideration and are the subject of this Office Action. This is the first Office Action on the merits of the claims. Non-elected claims 14-15 are withdrawn from consideration. 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 Office Action: Non-Final.
Election/Restrictions
Applicant’s election of the claims of Group I (claims 1-13 and 16-20) in the response filed on February 11, 2026 (to the December 22, 2025 Requirement for Restriction) is acknowledged. In response to applicant’s election, the claims of Group II (claim 14) and Group III (claims 15) are withdrawn from further consideration pursuant to 37 C.F.R. § 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant has elected the claims of Group I with traverse. The traverse is based on applicant’s argument:
In the Restriction Requirement, it is asserted that "the common technical feature is a loaded polyvinyl alcohol polymer with an active pharmaceutical ingredient." However, this assertion is not accurate as applicants' invention relates to loading a polymer with an active pharmaceutical ingredient in a melt granulation process wherein a mixture comprising at least one active pharmaceutical ingredient and polyvinyl alcohol is kneaded. (emphasis added) See, e.g., claim 1.
Further, the Restriction argues that Uramatsu et al. (US 2010/0120924) teaches a base for solid dispersion by melt extrusion in which "POV A" is mixed with nifedipine, citing Examples 7-9. As stated in paragraphs, for example, [0138] and [0171], "POVA" is POV ACOAT Type F which is a polyvinyl alcohol/acrylic acid/methyl methacrylate copolymer, not polyvinyl alcohol. Thus, contrary to the assertion in the Restriction, Uramatsu et al. do not suggest the special technical feature of applicants' claims.
02/11/2026 Remarks, p. 5, par. 7-8. In response: since the claims drawn to the instant process are not patentable over JAEGHERE (Int. J. Pharm. 492 (2015) pp. 1-9) per ALEKSOVSKI (Maked. Farm. Bilt., 62 (2016) pp. 3-24), as discussed below, restriction is still deemed proper.
Accordingly, the December 22, 2025 Requirement for Restriction is made FINAL, and claims 1-13 and 16-20 are examined as follows.
Claim Objections
The following claims are objected to because of the following informalities: Claim 1 is objected to because the claim should read:
1. ([…]) A process of loading a polyvinyl alcohol polymer with an active pharmaceutical ingredient in a melt granulation process comprising the steps of:
a) kneading a mixture comprising at least one active pharmaceutical ingredient and the polyvinyl alcohol polymer in a heated screw barrel of an extruder wherein the temperature in at least one zone along the length of the screw barrel is above aa polymer to form a kneaded mixture and
b) transporting the kneaded mixture through an outlet.
Appropriate correction is required.
Claim Rejections – 35 U.S.C. § 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. § 103(a) 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 C.F.R. § 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. § 102(b)(2)(C) for any potential 35 U.S.C. § 102(a)(2) prior art against the later invention.
Claims 1-13 and 16-20 are rejected under 35 U.S.C. § 103 as being unpatentable over De JAEGHERE (Jaeghere, W. De, et al., Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications, Int. J. Pharm. 492 (2015) pp. 1-9; hereinafter, “De Jaeghere”), in view of ALEKSOVSKI (Aleksovski, A., et al., Hot-melt extrusion and prilling as contemporary and promising techniques in the solvent free production of solid oral dosage forms, based on solid dispersions, Maked. Farm. Bilt., 62 (2016) pp. 3-24; hereinafter, Aleksovski) and BROUGH (US 2016/0250230 A1, Publ. Sep. 01, 2016; hereinafter, “Brough”), as evidenced by CELOCOXIB (LKT Labs, Celecoxib Product Information; accessed at https://lktlabs.com/product/celecoxib, on 04/04/2026; hereinafter, “Celocoxib”) and NIMODIPINE (Wikipedia, Nimodipine; accessed at https://en.wikipedia.org/wiki/Nimodipine, on 04/04/2026; hereinafter, “Nimodipine”).
De Jaeghere is directed to:
Hot-melt extrusion of polyvinyl alcohol for oral immediate release applications
ABSTRACT
The primary purpose of this study was to process partially hydrolyzed PVOH grades (degree of hydroxylation (DH): 33–88%) via HME and to evaluate them as carrier for oral immediate release dosage forms in order to improve the release rate of poorly water soluble drugs (i.e., HCT and CEL) via the formulation of solid dispersions. PVOH grades (DH >70%) were able to solubilize HCT and CEL up to 15%, but required higher extrusion temperature, due to the crystalline nature of PVOH. The highest drug release rate was observed from hot-melt extruded PVOH samples with a high DH. While drug release from extrudates consisting of PVOH with a low DH was affected by ionic strength, there was no influence of pH and ionic strength on HCT release from PVOH samples with a higher DH. However, PVOH (DH >70%) required higher extrusion temperatures, which could hamper its application for thermosensitive drugs. Therefore, the secondary purpose was to investigate the effect of sorbitol, a water-soluble plasticizer, on the thermal properties of hot-melt extruded PVOH (DH >70%). The melting of PVOH/sorbitol mixture was required to establish molecular interactions between PVOH and sorbitol. These molecular interactions were reflected in the HME behavior: whereas an extrusion temperature of 180 C was necessary to process physical mixtures of PVOH (DH >70%) and sorbitol, only 140 C was necessary during re-extrusion (after quench cooling and cryomilling) of the PVOH/sorbitol mixture. In addition, the in vitro and in vivo dug release of plasticized PVOH was examined; whereas the CEL/PVO/sorbitol system was able to maintain supersaturation during in vitro dissolution (0.1 N HCl) compared to Celebrex®, the in vivo pharmacokinetic parameters (AUC0–24 h, Cmax and Tmax) were highly comparable.
De Jaeghere, title & abstract. In this regard, De Jaeghere teaches “[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL [that] were processed using a co-rotating twin screw extruder ([…]) operating at a screw speed of 60 rpm and a processing temperature of 140 C”:
2. Materials and methods
2.1. Materials
Several PVOH grades (obtained from Kuraray, Hattersheim am Main, Germany) with varying degrees of hydrolysis were evaluated: type LM 25 (33–38% hydrolyzed), type LM 22 (47–53% hydrolyzed), type 505 (72–75% hydrolyzed). In addition, a pharmaceutical PVOH grade (type 4–88, 88% hydrolyzed, provided by Merck, Darmstadt, Germany) was included in the study. The LM-grades were end group-modified with carboxylic acid to provide good aqueous dispersibility. Hydrochlorothiazide (HCT) (Utag, Amsterdam, Netherlands), a BCS class III drug (Wu and Benet, 2005), and celecoxib (CEL) (Sanico, Turnhout, Belgium), a BCS class II drug (Turner et al., 2012), were used as model drugs. Sorbitol (Fagron, Waregem, Belgium) was used as water-soluble plasticizer of PVOH.
2.2. Hot-melt extrusion
Pure PVOH, mixtures of PVOH/HCT and mixtures of PVOH/sorbitol were processed using a co-rotating, fully intermeshing twin screw extruder (Prism Eurolab 16, Thermo Fisher, Germany), operating at a screw speed of 100 rpm and processing temperatures of 130–180 C. The extruder was equipped with a gravimetric feeder, two Archimedes screws with 3 mixing zones and a cylindrical die of 3 mm. Afterwards, the extrudates were either manually cut using surgical blades into mini-tablets of 2 mm length or quench-cooled in liquid nitrogen, cryomilled and sieved through a 300 micron sieve.
Mixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL were processed using a co-rotating twin screw extruder (Haake MiniLab II Micro Compounder, Thermo Electron, Karlsruhe, Germany), operating at a screw speed of 60 rpm and a processing temperature of 140 C. The extruder was equipped with a pneumatic feeder, two Archimedes screws and a 2 mm cylindrical die. The extrudates were quench-cooled in liquid nitrogen, cryomilled and sieved through a 300-micron sieve.
(De Jaeghere, p. 2, par. 2-4), and shows dissolution profiles of “hot-melt extruded formulations containing different grades of polyvinyl alcohol in combination with hydrochlorothiazide (ratio: 85/15)” (De Jaeghere, p. 5, Fig.’s 4-5).
Regarding independent claim 1 and the requirements:
1. ([…]) A process of loading a polymer with an active pharmaceutical ingredient in a melt granulation process comprising the steps of:
a) kneading a mixture comprising at least one active pharmaceutical ingredient and polyvinyl alcohol in a heated screw barrel of an extruder wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the decomposition temperature of the polyvinyl alcohol to form a kneaded mixture and
b) transporting the kneaded mixture through an outlet.
De Jaeghere clearly teaches “[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL [that] were processed using a co-rotating twin screw extruder ([…]) operating at a screw speed of 60 rpm and a processing temperature of 140 C” (De Jaeghere, p. 2, par. 4), WHEREBY it is noted:
“celecoxib (CEL)” (De Jaeghere, p. 2, par. 2-4) is encompassed by “poorly water soluble drugs” (De Jaeghere, abstract), which is “at least one active pharmaceutical ingredient” of claim 1, and having “poor solubility in water” required by claim 11:
11. ([…]) The process according to claim 1, wherein the active pharmaceutical ingredient has a poor solubility in water.
“PVOH” in “cryomilled PVOH/sorbitol extrudate (<300 μm)” includes “a pharmaceutical PVOH grade (type 4–88, 88% hydrolyzed, provided by Merck, Darmstadt, Germany)” (De Jaeghere, p. 2, par. 2; also at De Jaeghere, p. 5, Fig.’s 4-5), which is a “polyvinyl alcohol” of claim 1, “cryo-milled” of claims 9, as well as “PVA 4-88” of claims 6-8:
6. ([…]) The process according to claim 1, wherein the polyvinyl alcohol has a hydrolysis degree of 72% to 90% and a viscosity of a 4% solution at 20° ° C. of 2 mPas to 40 mPas.
7. ([…]) The process according to claim 1, wherein the polyvinyl alcohol is selected from a list consisting of PVA 3-80, PVA 3-81, PVA 3-82, PVA 3-83, PVA 3-85, PVA 3-88, PVA 3-98, PVA 4-88, PVA 4-98, PVA 5-74, PVA 5-82, PVA 6-88, PVA 6-98, PVA 8-88, PVA 10-98, PVAPVA 13-88, PVA 15-99, PVA 18-88, PVA 20-98, PVA 23-88, PVA 26-80, PVA 26-88, PVA 28-99, PVA 30-98, PVA 30-92, PVA 32-88 and PVA 40-88.
8. ([…]) The process according to claim 1, wherein the polyvinyl alcohol is PVA 4-88.
9. ([…]) The process according to claim 1, wherein the polyvinyl alcohol is cryo-milled.
mixtures “processed using a co-rotating twin screw extruder ([…]) operating at a screw speed of 60 rpm and a processing temperature of 140 C” (De Jaeghere, p. 2, par. 4) relates to a “heated screw barrel of an extruder” of claim 1, a “twin-screw melt granulation process’ of claim 5:
5. ([…]) The process according to claim 1, wherein the granulation process is a twin-screw melt granulation process.
as well as the active step requirement of claim 1 for “a) kneading a mixture comprising at least one active pharmaceutical ingredient and polyvinyl alcohol in a heated screw barrel of an extruder wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the decomposition temperature of the polyvinyl alcohol to form a kneaded mixture” but for the particular temperature requirements for “above the melting temperature of the at least one active pharmaceutical ingredient” (see par. [0023] at the instant published application, US 2024/0189239 A1, noting, “PVA 4-88 with a loss of drying of ≤ 5.0% has a melting temperature of approximately 170°C, […] and a decomposition temperature of >250° C”).
However it is noted that:
(i) the melting point of CEL is 157-159 °C (see Celocoxib, p. 2, as evidence that the melting point of HCT is 157-159 °C), and therefore, De Jaeghere DOES NOT TEACH the requirements of claim 1 for “wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient,” which relates to the requirements of claims 3-4 and 16-17 for:
3. ([…]) The process according to claim 1, wherein the active pharmaceutical ingredient in the granules is dispersed in an amorphous form within the polyvinyl alcohol.
4. ([…]) The process according to claim 1, wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the melting temperature of the polyvinyl alcohol and wherein the kneaded mixture is transported through an outlet to obtain granules.
[…]
16. ([…]) The process according to claim 1, wherein the temperature in said at least one zone along the length of the screw barrel is between 40° C. to 250° C.
17. ([…]) The process according to claim 1, wherein the temperature in said at least one zone along the length of the screw barrel is between 140° C. to 230° C.
(ii) De Jaeghere teaches a “a 2 mm cylindrical die” (De Jaeghere, p. 2, par. 4) relating to an “outlet” of claim 1, wherein mixtures “processed using a co-rotating twin screw extruder ([…]) operating at a screw speed of 60 rpm and a processing temperature of 140 C” and then, through “a 2 mm cylindrical die” (De Jaeghere, p. 2, par. 4) (De Jaeghere, p. 2, par. 4) relating on the active step requirement of claim 1 for “b) transporting the kneaded mixture through an outlet”; however, it is noted that the instant published application, US 2024/0189239 A1, at par. [0045] describes a “die” as leading to an “increase of velocity of a fluid at the expense of its pressure energy”:
[0045] The term “melt granulation process” or “HMG” generally refers to a size enlargement process in which the addition of a binder that melts or softens is used to achieve agglomeration of solid particles in the formulation. The process utilizes materials that are effective as granulating agents when they are in the softened or molten state. In the pharmaceutical industry this process can be used for the preparation of fast release or sustained released dosage forms. A binder or meltable binder is usually a low melting substance that melt or soften at relatively low temperatures (50° ° C. to 90° C.), such as a low melting wax or a low melting polymer. The meltable binders are used to achieve agglomeration of solid particles during the granulation process. In contrast to HME, the mixture in the melt granulation process is transported through an outlet which is an opening but not a nozzle or die. This means that the outlet is dimensioned in such a way that it does not exert pressure on the kneaded mixture. This is in contrast to a die that leads to increase of velocity of a fluid at the expense of its pressure energy.
therefore, De Jaeghere DOES NOT TEACH an “outlet” of claim 1, or per the requirements of claims 2 and 4 for:
2. ([…]) The process according to claim 1, wherein the outlet does not exert pressure on the mixture.
[…]
4. ([…]) The process according to claim 1, wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the melting temperature of the polyvinyl alcohol and wherein the kneaded mixture is transported through an outlet to obtain granules.
Based on the state of the art, an artisan of ordinary skill would have found each of these features obvious.
Regarding (i), Aleksovski, for instance, is directed to:
Hot-melt extrusion and prilling as contemporary and promising techniques in the solvent free production of solid oral dosage forms, based on solid dispersions
Abstract
Hot melt extrusion and prilling are gaining importance as solvent free and continuous techniques in the production of solid oral dosage forms with added value, by incorporating active compound in a molten carrier which is further solidified to form solid dispersion. This article reviews these two techniques in terms of understanding process basics, equipment characteristics, required properties of processed materials and application of the processes for development of solid oral dosage forms. Studies revealed that both hot-melt extrusion and prilling are regarded as simple, robust and continuous methods for processing different types of materials and production of solid dosage forms based on solid matrices. However, understanding of their concepts and requirements together with careful material selection is crucial for stable material processing and obtaining stable products of high-quality. Hot-melt extrusion proved to be a suitable method for production of modified release dosage forms, taste masked dosage forms and dosage forms offering improved drug dissolution rate and solubility. Prilling till now has been successfully applied just in the production of multiple unit drug delivery systems for immediate and sustained drug delivery. Further studies on product development and process understanding are required for full implementation of prilling in the pharmaceutical field.
Aleksovski, title & abstract. In this regard, Alekovski teaches “[i]n cases when solubility is limiting factor it is desired that drug is dispersed inside a carrier in its molecular form or as amorphous phase,” e.g., “[i]ncreasing the extrusion temperature (150 °C) and reducing the drug loading (15%) [of nimodipin] improved the dissolution of the drug since at these parameters it was completely transformed in its amorphous form”:
Fields of application of hot melt extrusion in oral solid dosage form development
Solid dispersions for solubility and bioavailability enhancement
Many of the new drug molecules discovered by combinatorial chemistry and high throughput screening are belonging to the BCS class II and BCS class IV and thus are considered as poorly soluble. The bioavailability of an active compound after oral administration depends, apart from its permeability, mainly on its solubility. It is required that molecules are in the dissolved state in order to be absorbed in the gastro-intestinal tract (Khadka et al., 2014). Low solubility of active compounds represents one of the major challenges in formulation development and thus gains attention of many pharmaceutical scientists. Improving drug solubility may be done by several approaches including: size reduction (Loh et al., 2015), formation of inclusion complexes (Miletic et al., 2013), salt formation (Melo et al., 2016), formulation of self (micro/nano) emulsifying systems (Čerpnjak et al., 2015), solid dispersions (Wlodarski et al., 2015). The term solid dispersion in general refers to dispersion of a solid drug in a solid carrier. Solid dispersions include several types of systems such as eutectic mixtures, solid (molecular) solutions, and solid suspensions. In cases when solubility is limiting factor it is desired that drug is dispersed inside a carrier in its molecular form or as amorphous phase. By constant screw rotation, providing efficient distributive and dispersive mixing of the components inside the barrel, hot-melt extrusion appears as very potent technique for (molecular) dispersing of poorly soluble APIs in different carriers, which subsequently leads to increased solubility of the used active compounds (Shah et al., 2013). Several examples of application of HME in improving drug solubility will be discussed in this chapter.
Jujin et al. used HME to increase the solubility of nimodipin by formulating it with Kollidon VA64 (copovidone) in stable amorphous solid dispersion which was further compressed into tablets. Results pointed that extrusion temperature and drug loading play a crucial role in increasing the solubility of the drug. Lower extrusion temperatures (130 °C) and high drug loading (20%) led to slower drug release due to the fact that drug was mainly present in its crystalline form. Increasing the extrusion temperature (150 °C) and reducing the drug loading (15%) improved the dissolution of the drug since at these parameters it was completely transformed in its amorphous form. Drug release was insignificantly affected by the medium’s pH. Interestingly decreasing the particle size of granules obtained from extrudates from 40 mesh to 80 mesh led into slower drug release after tablet disintegration due to agglomeration of the smaller particles on the dissolution medium’s surface, which decreased its contact surface and thus wettability. In-vivo studies showed a higher oral bioavailability of nimodipin after formulating it as a solid dispersion (Jijun et al., 2010).
Aleksovski, p. 10, par. 1-2, cont. on p. 11.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to perform De Jaeghere’s processing of “[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL” (De Jaeghere, p. 2, par. 4) with a temperature range suitable for obtaining an amorphous phase drug dispersed inside a carrier per Alekovski (Aleksovski, p. 10, par. 1-2, cont. on p. 11). One would have been motivated to do so with a reasonable expectation of success since both De Jaeghere and Alekovski are concerned with similar problems in the art, namely oral dosage forms obtainable by hot melt extrusion. De Jaeghere, abstract; Aleksovski, abstract. Further, it is well within the skill of the ordinary artisan to select suitable temperature conditions in order to obtain the advantage of an amorphous phase drug dispersed inside a carrier for increased solubility. Aleksovski, p. 10, par. 1. In this regard, it is noted that MPEP § 2144.05 (I), states, “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).” In this respect, it is further noted, “[w]here 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); and also MPEP § 2144.05(II)(A). In the instant case, the melting point for obtaining an amorphous phase drug is clearly a result-effective variable, because Alekovski teaches “[i]ncreasing the extrusion temperature (150 °C) and reducing the drug loading (15%) [of nimodipin] improved the dissolution of the drug since at these parameters it was completely transformed in its amorphous form” (Aleksovski, p. 10, par. 2, cont. on p. 11), wherein temperature is increased above the 125 °C melting point of nimodipin (See Nimodipine, Table, as evidence that the melting point of nimodipine is 125 °C). Therefore, it would have been customary for an artisan of ordinary skill to select appropriate processing temperatures, for instance, from 130–180 C per (De Jaeghere, p. 2, par. 3), to greater than the melting point of CEL at 157-159 °C in optimizing processing temperatures greater than the melting point of a particular active in obtaining an amorphous phase drug in a carrier, thereby rendering obvious the requirements of claim 1 for “wherein the temperature in at least one zone along the length of the screw barrel is above the melting temperature of the at least one active pharmaceutical ingredient and below the decomposition temperature of the polyvinyl alcohol,” and similarly for claims 3-4 and 16-17.
Therefore, the prior art renders (i), as noted above, obvious.
Regarding (ii), Brough, for instance, is directed to:
THERMO-KINETIC MIXING FOR PHARMACEUTICAL APPLICATIONS
ABSTRACT
Compositions and methods for making a pharmaceutical dosage form include making a pharmaceutical composition that includes one or more active pharmaceutical ingredients (API) with one or more pharmaceutically acceptable excipients by thermokinetic compounding into a composite. Compositions and methods of preprocessing a composite comprising one or more APIs with one or more excipients include thermokinetic compounding, comprising thermokinetic processing the APIs with the excipients into a composite, wherein the composite can be further processed by conventional methods known in the art, such as hot melt extrusion, melt granulation, compression molding, tablet compression, capsule filling, film-coating, or injection molding.
(Brough, title & abstract). In this regard, teaches “Hot-Melt Extrusion (HME)” with “twin, co-rotating conical screws” and an “outlet of the extruder barrel,” whereby “extruded materials were forced through the 1.0×4.0 mm rectangular outlet port”:
[0130] Hot-Melt Extrusion (HME). The hot-melt extruded compositions presented in the DSC analysis of the KTZ:Methocel™ E50 (1:2) and KTZ:Kollidon® (1:2) TKC processed samples were produced with a HAAKE Minilab II Micro Compounder (Thermo Electron Corporation, Newington, N.H.) equipped with twin, co-rotating conical screws ( 5/14 mm diameter). All powder blends were fed into the extruder barrel via the Minilab manual feeding device. No external dye was applied at the outlet of the extruder barrel, and therefore extruded materials were forced through the 1.0×4.0 mm rectangular outlet port. The operating parameters for both compositions presented were 170° C. and 300 RPM. After processing the extrudates were ground in a blade grinder (Capresso Inc., Closter, N.J.) for 2 minutes. The resulting ground product was then passed over a 60 mesh sieve. The material which passed through the sieve was manually milled in a porcelain mortar and pestle for 1 min to yield a fine powder. DSC analysis was then conducted on this finely milled powder.
(Brough, par. [0130]), which relates to an “outlet” of claims 1-2 and 4.
In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to perform De Jaeghere’s processing of “[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL” (De Jaeghere, p. 2, par. 4) through an “outlet” as taught by Brough (Brough, par. [0130]) in “conventional methods known in the art, such as hot melt extrusion, melt granulation, […]” (Brough, abstract). See MPEP § 2144.07 stating that the selection of a known material based on its suitability for its intended use is prima facie obvious, which cites Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), wherein “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.”
Therefore, the prior art renders (ii), as noted above, obvious.
Thus, the prior art renders claims 1-9, 11 and 16-17 obvious.
Regarding claims 10 and 18 and the requirements:
10. ([…]) The process according to claim 1, wherein the active pharmaceutical ingredient is present in the mixture in a weight ratio of active pharmaceutical ingredient to polyvinyl alcohol in the range of 1:99 to 90:10.
[..]
18. ([…]) The process according to claim 1, wherein the active pharmaceutical ingredient is present in the mixture in a weight ratio of active pharmaceutical ingredient to polyvinyl alcohol in the range of 10:90 to 30:70.
De Jaeghere teaches “hot-melt extruded formulations containing different grades of polyvinyl alcohol in combination with hydrochlorothiazide (ratio: 85/15)” (De Jaeghere, p. 5, Fig.’s 4-5), by which it would be obvious to De Jaeghere’s processing of “[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL” (De Jaeghere, p. 2, par. 4) in a similar proportion. See MPEP § 2123 [R-5] regarding the obviousness of rearranging a reference according to the teachings of that same reference; see MPEP § 2144.05 (I) regarding the obviousness of prior art overlapping claimed numerical ranges.
Thus, the prior art renders claims 10 and 18 obvious.
Regarding claims 12 and 19 and the requirements:
12. ([…]) The process according to claim 1, wherein the granules are further milled to an average particle size between 50 μm to 300 μm.
[…]
19. ([…]) The process according to claim 4, wherein the granules have an average particle size between 20-2500 μm.
“[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL were processed using a co-rotating twin screw extruder (Haake MiniLab II Micro Compounder, Thermo Electron, Karlsruhe, Germany),” and “extrudates were quench-cooled in liquid nitrogen, cryomilled and sieved through a 300-micron sieve” (De Jaeghere, p. 2, par. 2-4). See MPEP § 2144.05 (I) regarding the obviousness of prior art overlapping claimed numerical ranges.
Thus, the prior art renders claims 12 and 19 obvious.
Regarding claim 13 and the requirements:
13. ([…]) The process according to claim 1, wherein the granules are further processed into tablets.
Alekowski teaches “HME is applicable to production of solid dosage forms (granules, pellets, mini-matrices, tablets, films) and allows to achieve their special properties (increased drug solubility, extended drug release, masked taste etc.)” (Alekowski, p. 4, par. 3), which relates to “wherein the granules are further processed into tablets” of claim 13. In light of these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date to perform De Jaeghere’s processing of “[m]ixtures of cryomilled PVOH/sorbitol extrudate (<300 μm) and CEL” (De Jaeghere, p. 2, par. 4) for producing tablets (Alekowski, p. 4, par. 3) as a suitable dosage form. See MPEP § 2144.07 stating that the selection of a known material based on its suitability for its intended use is prima facie obvious, which cites Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945), wherein “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle.”
Thus, the prior art renders claim 13 obvious.
Regarding claim 20 and the requirements:
20. ([…]) The process according to claim 4, wherein the granules comprise at least 50% (w/w) of the active pharmaceutical ingredient.
it is noted, “[w]here 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); and also MPEP § 2144.05(II)(A). In the instant case, the melting point for obtaining an amorphous phase drug is clearly a result-effective variable, because Alekovski teaches extended release, wherein “[i]ncreasing the amount of the drug (25-50%) inside the formulation led into faster drug leaching due to the increased hydrophilicity of the system and the higher porosity
that is established during dissolution of the drug” (Alekowski, p. 12,par. 1). Therefore, it would have been customary for an artisan of ordinary skill to select amounts of active, i.e., 25-50%, in optimizing for extended release, thereby rendering obvious the requirements of claim 20 for “wherein the granules comprise at least 50% (w/w) of the active pharmaceutical ingredient.”
Thus, the prior art renders claim 20 obvious.
Conclusion
Claims 1-13 and 16-20 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to DOMINIC LAZARO whose telephone number is (571)272-2845. The examiner can normally be reached on Monday through Friday, 8:30am to 5:00pm EST; alternating Fridays out.
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/DOMINIC LAZARO/Primary Examiner, Art Unit 1611