DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Claim Rejections - 35 USC § 102/103
The following is a quotation of the appropriate paragraphs of pre-AIA 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negated by the manner in which the invention was made.
Claim 13 is rejected under pre-AIA 35 U.S.C. 102 (b) as anticipated by or, in the alternative, under pre-AIA 35 U.S.C. 103(a) as obvious over Steiner et al. (US Patent No. 5,503,852 - previously cited).
Steiner et al. disclose pulmonary microparticle drug compositions composed of diketopiperazine (see abstract and claims 1 and 6). They disclose the microparticle in dried state. Instant claim 13 is drafted as a product-by-process. “’[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.’ In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)….The structure implied by the process steps should be considered when assessing the patentability of product-by-process claims over the prior art, especially where the product can only be defined by the process steps by which the product is made, or where the manufacturing process steps would be expected to impart distinctive structural characteristics to the final product. See, e.g., In re Garnero, 412 F.2d 276, 279, 162 USPQ 221, 223 (CCPA 1979)” (see MPEP 2113). Therefore when no structure is implied, the product-by-process recitation does not add any limitations that affect patentability. Here the recited method steps do not imply any distinct structural characteristics unique to the process. Thus the product of Steiner et al. meets the limitations of the instantly claimed product. Therefore claim 13 is anticipated by or obvious over Steiner at al.
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-4, 6, and 8-14 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dalziel et al. (US PGPub No. 2003/0152500 – previously cited) in view of Richardson et al. (US PGPub No. 2009/110647 - previously cited), Champion et al. (Pharmaceutical Research 2008 25(8):1815-1821), Leone-Bay et al. (US PGPub No. 2006/0040953 - previously cited), the Tanner Industries Aqua Ammonia reference (1996 - previously cited), Kurokawa et al. (US PGPub No. 2004/0191667 - previously cited) and Sauer et al. (US Patent no. 4,915,509 - previously cited)
Dalziel et al. teach the production of microparticles via precipitation in a stator-rotor containing reactor as a continuous process (see abstract and paragraphs 1, 51, and 54). They teach that the precipitation product may be a pharmaceutical substance or other industrial substances, such as foods and food ingredients (excipients) (see paragraphs 17 and 57-58). Dalziel et al. tout their process as quickly producing a fine and controlled particle size without the need for post-process grinding which is of particular use for pharmaceutical ingredients (see paragraphs 20, 51, and 54). Average particle sizes are exemplified at 4 mm, 4.4 mm, and 6 mm (see examples 7-8 and 11). The stator-rotor may be configured in a variety of ways including a single stator-rotor pair, multiple rotors, and multiple concentric stators, where both may have teeth (see paragraphs 31 and 41 and figures 1 and 2A). The reactor contains at least two inlet pipes, an outlet orifice, and a stator-rotor assembly (see paragraph 37). The precipitation process may occur via a solvent/anti-solvent interaction, where at least two streams of liquid have a (predetermined) flowrate and enter at the same or different entry ports to the reactor (see paragraphs 10 and 49-50, figure 2 elements 9, 10, and 12; instant claim 6). The fluid streams are fed to the rotor (meet upon entry) (see paragraph 50). The ratio of the two or more inlet streams may vary and is exemplified with two provided at a 1:1 volumetric flowrate ratio (see paragraph 71 and example 1; instant claim 5). Additional liquids may be added as implied by the teachings of “at least two” and as exemplified in example 1 with the addition of a quenching solution to stop precipitation toward the exit (see instant claim 2). Dalziel et al. additionally teach removal of the precipitated particles from the liquid (collection after exit from the stator-rotor) and optionally drying (see paragraph 72; instant claims 1 and 13). They further teach low temperature operation and increased yields at room temperature (see paragraph 70; instant claim 9). Dalziel et al. envision the precipitation process as a substance dissolved in water at a high pH that precipitates upon combination with acidified water at lower pH (see paragraph 67; instant claim 1). A diketopiperazine is not explicitly taught as the precipitated compound and specific details of stator-rotor embodiments with teeth are not detailed.
Richardson et al. teach the preparation of a pulmonary medication from pharmaceutical ingredients (see abstract). They teach the benefit of combining microparticles of fumaryl diketopiperazine (FDKP) in acid form with glucagon like peptide-1 (GLP-1) agonists to facilitate inhalation delivery to alleviate the adverse effects of oral and subcutaneous administration of the GLP-1 agonist (see paragraphs 7-11 and 47; instant claim 4). Richardson et al. teach the particles to be sized at less than 10 mm and more preferably at 0.5 to 5.8 mm so as to reach the pulmonary alveoli and avoid degradation on their way to the pulmonary arterial circulation (see paragraphs 58 and 87). They further detail preparing the microparticles via precipitation, where FDKP and polysorbate 80 are dissolved in a dilute ammonia aqueous solution (second solution) and mixed with an acidic solution (first solution) to form particles (see paragraphs 133-134; instant claims 10-11). The resulting particles are washed and concentrated, then further combined with a GLP-1 agonist in deionized water and acid, and then freeze dried (see paragraphs 135-138).
Champion et al. teach that the size of particles delivered to the alveoli impacts their ability to avoid or encourage phagocytosis and clearance by macrophages (see abstract). Most drug delivery seeks to avoid phagocytosis (see page 1815 first column). They go on to teach that microparticles sized at 2-3 mm are particularly susceptible to phagocytosis by and binding to alveolar macrophages, whereas larger sized particles of 4.3 mm yielded little phagocytosis or binding (see page 1819 first column, page 1820 second column second full paragraph-page 1821 first column first partial paragraph, figures 1 and 2A).
Leone-Bay et al. teach dissolving an FDKP in ammonium hydroxide of an undisclosed concentration that provides a pH of 8.3 (see paragraph 92). Ammonia in water is synonymous with ammonium hydroxide and has a pH of 11.7 at 1% (see Tanner Industries Aqua Ammonia reference page 2 first and third paragraphs; instant claim 1).
Kurokawa et al. teach a stator-rotor reactor/mixer that yields a controlled and narrowly distributed collection of fine microparticles (see paragraphs 14-16, 84, and 95). The stator-rotor assembly may be multi-staged and provided as sets of concentric rings of circumferentially spaced comb-teeth (see paragraph 84 and 86). Figure 2 below depicts a stator 22 and rotor 21.
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An embodiment of a multistage system is provided below in figure 1:
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Here stators 3, 5, 7 and rotors 4, 6, 8 pair, respectively, provide layers of stator-rotors (see paragraphs 86-87). Stator 7 corresponds to the instant stator assembly while rotor 8 corresponds to the instant rotor assembly. Within a layer, one or more stages are included, where a stator ring of comb-teeth and a rotor ring of comb-teeth form one stage and correspond to an instant stator and an instant rotor, respectively. The component labelled A is a stator ring of comb-teeth shown projecting downward from the base of a stator assembly and the component labelled B is a rotor ring of comb-teeth shown projecting upward from the base of a rotor assembly. Thus the three stage layer, shown at the bottom of figure 1 with components 7 and 8, have stator 7 which corresponds to an instant stator assembly with first, second, and third stators and rotor 8 which corresponds to an instant rotor assembly with first, second, and third rotors. Kurokawa et al. teach that a three stage structure is preferred with each stage providing different sized/spaced teeth (see paragraph 87). They go on to teach pressure in the stator-rotor containing chamber to range from 0.01 to 15 MPa (about -0.1 to 2136 psig). Particle sizes produced are between 4 and 9 mm where particles sized 3 mm or less are minimized in the distribution (see paragraphs 2 and 114).
Sauer et al. teach a mixer for combining two free flowing substances so as to form a suspension without clumps and blockages (see column 1 lines 24-30). They detail a reactor with a stator-rotor mixing system, where stator disks and rotor disks have concentric collars of rods (circumferentially spaced teeth) and are attached to a rotatable shaft (see column 1 lines 32-57 and column 3 lines 34-53). At least one inlet through the casing of the reactor introduces a first substance axially to the shaft of the reactor and against a rotor disk (see column 1 lines 51-53). At least one inlet for introducing a second substance penetrates a stator disk and is located at a point radially outward from the first substance inlet (see column 2 line 44). Preferably the at least one inlet for the second substance is a nozzle that injects the second substance into the first substance (see column 2 lines 3-7). The second substance inlet is preferably present in a quantity greater than one and spaced at regular angles to one another (e.g., 90 degrees) (see column 2 lines 8-13 and lines 38-44). Figure 1, shown below, is reoriented such that the features common to the devices of Kurokawa and Sauer et al. are more readily discerned:
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Here, components 12 correlate to the layers of rotor and stator in Kurokawa et al. (see column 3 lines 31-43). Components 16 are concentric collars of rods (teeth) on a rotor disk and a stator disk, while component 11 is a rotor disk and component 10 is a stator disk (see column 3 lines 39-45). These correspond to the comb-teeth on the stators and rotors as well as an stators and rotors of Kurokawa. The figure depicts three collars of teeth on the stator and two collars of teeth on the rotor which meet the instant limitations for a stator assembly with three stators and a rotor assembly with two rotors. Component 6 is the inlet for the first component in the middle of the mixer casing (first radial location) and is described as part of the front wall (see column 3 lines 36-38; instant claim 14). Components 13, shown on both sides of inlet component 6 (second radial location), penetrate through the front wall and stator disk 10, located on the inner side of the front wall of the casing, to introduce the second component on the rotor disk and its rods (teeth) (see column 3 lines 42-45; instant claim 14). This meets the limitation of the instant plurality of second inlets with openings in the stator assembly. Sauer et al. describe a possible location of the first stator as formed out of the front wall of the casing and provided with the inlets, or in an equivalent arrangement where the first stator disc is on the inner side of the front wall of the casing (see column 2 lines 39-43). The second component inlets are radially inward of the second stator teeth on the stator disk (see instant claim 14). Sauer et al. further illustrate and discuss the inlets for the second substance extending into the interior of the mixer, through both the casing wall and a stator on the inner surface of the front wall of the casing, to a location directly in front of a rotor located some distance away from this stator (see figure 2 and column 3 line 54-column 4 line 14). Here again, the casing inner wall has the inlet for the first substance and, in this contemplated configuration, it is upstream of the end of inlets for the second substance.
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to practice the method of Dalziel et al. with a modified version of stator-rotor design of Kurokawa et al. operated at their taught pressure with layers having three stages of stator-rotor comb-teeth so as to generate a controlled, small sized FDKP microparticle product of Richardson et al. The choice to make the FDKP particles of Richardson et al. would have been obvious because the FDKP is a pharmaceutical ingredient for inhalation that would be served by having a uniform controlled particle size as Dalziel et al. intend. The desire to produce a narrow size distribution of FDKP microparticles to facilitate their pulmonary delivery to the alveolar arterial circulation and avoid phagocytosis would encourage a focus on the upper end of their size range that is larger than 3 mm and less than 10 mm size, in light of Champion et al. A size of particles that avoids the 2-3 mm size that is highly susceptible to phagocytosis makes the preferred stator-rotor design of Kurokawa et al. particularly useful to this end, given its minimization of particles of this size and design to produce sizes of 4 to 9 mm. The modification to Dalziel et al. in preparing the FDKP particles for Richardson et al. with the stator-rotor of Kurokawa et al. would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome (specific stator-rotor vs generic stator-rotor) and as the application of the same technique to a similar process in order to yield the same improvement. The pressure range then provided by Kurokawa et al. overlaps with the range instantly claimed, thereby rendering the claimed range obvious (see instant claim 8). “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). Similarly, the approximate nature of the claimed temperature range and the teaching of low and room temperature operation by Dalziel et al. yield an overlapping range that renders the recited temperature range obvious as well (see MPEP 2144.05; instant claim 9). It also would have been obvious to select a 1% aqueous ammonia solution as the dilute ammonia in water concentration of Richardson et al. to employ because it provides a pH that would be expected to dissolve the FDKP based upon Leone-Bay et al. It would follow that the stator-rotor containing reactor serves as the location for preparing the FDKP microparticles with the first and second solutions taught by Richardson et al. Employing deionized water in a third solution (precipitation quench solution) added to the reactor would have been obvious because Dalziel et al. suggest such an addition and this is the variety of water that Richardson et al. employ (see instant claim 3). It would then follow to wash the FDKP prior to combination with the GLP-1 agonist composition as Richardson et al. teach in deionized water and dry (freeze dry) the final composite product (see instant claims 12-13).
Concerning the modification to the stator-rotor device of Kurokawa et al., it would have additionally been obvious to a person of ordinary skill to apply the inlet configuration of Sauer et al. to the multi-layered stator-rotor mixing system of Kurokawa et al. so as to gain its benefit of forming a suspension without clumps and blockages. The modification is obvious as the application of the same technique to a similar product in order to yield the same improvement. Specifically, the application would translate to the mixer of Kurokawa et al., such that the inlet for the first solution is in the center of the mixer casing and a plurality of second inlets for the second solution are placed radially outward of the first (solution) inlet and penetrate the stator assembly of the stator-rotor layer closest to the first inlet. Given that there are only two options for which solution is introduced through the central first inlet and which is introduced through the more radially outward second inlets, this choice is obvious as a selection from a finite number of identified, predictable solutions, with a reasonable expectation of success. The location of the second inlets in the stator assembly depicted in the figure of Sauer et al. show each of them radially aligned and radially inward with a respective tooth of the second stator. While depth is not explicitly shown in the figure of Sauer et al., the options for the location of the stator inlets relative to the teeth of the second stator are limited to 1) radial alignment with a tooth, 2) radial alignment with a space between teeth, and 3) partial/overlapping radial alignment with a tooth and an adjacent space between teeth. Given these limited options and the depiction by Sauer et al., it would have been obvious to locate the second inlets that penetrate the stator assembly such that they are each radially aligned and radially inward with a respective tooth of the second stator. This choice would have been obvious because choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success is obvious. It additionally would have been obvious to shift the layers of stator-rotors such that the layer closest to the first inlet has its stator resting against the mixer casing, as envisioned by Sauer et al., to permit penetration of the second inlets into the stator assembly and mixing of the two solutions/substances after entry into the reactor/mixer as desired by Dalziel et al. and Sauer et al. This modification is obvious as the application of the same technique to a similar product in order to yield the same improvement (e.g., suspension free of clumps and blockages) and as an option known to be suitable for a stator-rotor system with multiple inlets. The second inlets would then terminate and release their contents at least a stator thickness downstream of the first inlet due to the latter being located in the casing wall and the former penetrating the casing wall and stator placed on the inner side of the wall. Therefore claims 1-4, 6, and 8-14 are obvious over Dalziel et al. in view of Richardson et al., Champion et al., Leone-Bay et al., the Tanner Industries Aqua Ammonia reference, Kurokawa et al., and Sauer et al.
Claims 1-4 and 6-14 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Dalziel et al. in view of Richardson et al., Champion et al., Leone-Bay et al., the Tanner Industries Aqua Ammonia reference, Kurokawa et al., and Sauer et al. as applied to claims 1-4, 6, and 8-14 above, and further in view of Hebel et al. (US PGPub No. 2005/0014245 - previously cited).
Dalziel et al. in view of Richardson et al., Champion et al., Leone-Bay et al., the Tanner Industries Aqua Ammonia reference, Kurokawa et al., and Sauer et al. render obvious the limitations of instant claims 1-4, 6, and 8-14, where a stator-rotor system is employed to generate small microparticles of a diketopiperazine from the combination of liquid streams. An instantly claimed flowrate is not explicitly detailed.
Hebel et al. teach preparing a biological product in a stator-rotor system from the combination of liquid streams (see abstract and paragraph 41). They detail a suitable range of flowrates to be 0.1 to 20 L/min (see paragraph 41; instant claim 7).
It would have been obvious to a person of ordinary skill in the art at the time the invention was made to employ a flowrate as taught by Hebel et al. in the production method of Dalziel et al. in view of Richardson et al., Champion et al., Leone-Bay et al., the Tanner Industries Aqua Ammonia reference, Kurokawa et al., and Sauer et al. because it was known to be suitable to produce biological materials in a stator-rotor. The 1% ammonia solution employed to dissolve the FDKP has a specific gravity of about 1 and the proportion of FDKP and polysorbate 80 present are quite small (see Tanner Industries Aqua Ammonia reference page 2 table). Thus approximating the density of the FDKP solution to be about 1 g/ml results in a 0.1 to 20 L/min flowrate range corresponding to 0.1 to 20 kg/min. This range overlaps with that instantly claimed, thereby rendering the claimed range obvious (see MPEP 2144.05). This modification would have been obvious as the simple substitution of one known element for another in order to yield a predictable outcome (specific flowrate vs. generic flowrate). Therefore claims 1-4 and 6-14 are obvious over Dalziel et al. in view of Richardson et al., Champion et al., Leone-Bay et al., the Tanner Industries Aqua Ammonia reference, Kurokawa et al., Sauer et al., and Hebel et al.
Response to Arguments
Applicant's arguments filed June 30, 2026 have been fully considered. The amendment to the claims overcomes the objections to claims 1 and 4. The rejections are modified in light of the amendment to address the new claims limitations. The arguments against the applicability of prior art already of record against the new claim limitations are not persuasive.
The applicant argues that the depiction of Sauer et al. for figure 1 show the entry of the first and second inlets into the reactor in the same vertical plane of the reactor/mixer and therefore Sauer et al. do not teach second inlets disposed downstream of first inlets. However, Sauer et al. discuss the stator through which the second inlets penetrate being part of the front wall of the casing or being on the inner side to the front wall (see column 2 lines 39-43 and claim 7). In the latter arrangement, the second inlets would be a stator thickness away from the inner wall of the casing. They also describe or depict the first inlet being part of an ending at the inner side of the front wall (see figure 1 and column 3 lines 36-49). Further, figure 2 shows the second inlets extending away from the front wall inner side, while the first inlet is shown being part of and ending at the inner side of the front wall (see column 3 in 54-columne 4 line 9). This demonstrates their contemplation of the second substance being dispensed into the first substance via a nozzle at a location downstream of the inlet of the first substance. Therefore when considered in whole, the teachings of Sauer et al. already suggested the configuration of first and second inlets that is now claimed.
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
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