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 .
DETAILED ACTION
Claims 1-20 are currently pending and the claims filed on 03/03/2026 are acknowledged.
Election/Restriction
Applicant's election with traverse of Group I, claim 1-8 in the Reply filed on 03/03/2026. Additionally, Applicants’ election of the following species is acknowledged: ‘vemurafenib(VF)’ for drug; ‘DMSO’ for low volatility solvent; and ‘acetone’ for high volatility solvent which is reading on claims 1-8.
Response to Arguments
Applicant’s arguments have been fully considered, but are not persuasive.
Applicant argues that Groups I, II and III should be examined together for the reasons as noted in the Reply of 03/03/2026. In particular, Applicant argues that Groups I and II are clearly disclosed in the present disclosure and thus since there is no serious burden, they should be examined together.
The Examiner responds that Applicant’s arguments as to Groups I and III are persuasive, and thus the restriction requirement has been withdrawn, and accordingly claims 15-20 are examined; and however, Applicant’s arguments as to Group I and II and Group II - III are not persuasive because Group II directed to a method for identifying processing parameters for spray draying is different from Group I and/or III. Specifically, Group II requires distinct steps of identifying a process map and generating an equivalent plot on the process map to identify the process parameters for a spray drying process, but which steps are not found in Group I and III, and thus Group II invention is structurally independent invention. Please note that for the restriction requirement, the question is whether the groups are independent or distinct inventions, not whether they are merely whether they are related or not, and therefore searching Groups I-III together gives the Examiner a serious burden.
Consequently, claims 9-14 have been withdrawn. Claims 1-8 and 15-20 are being examined at this time.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/14/2026 was filed before the mailing date of the instant first action on the merits. The submission thereof is in compliance with the provisions of 37 CFR 1.97. It is noted that the foreign references have only been considered to the extent that an English language abstract, translation or statement of relevance has been provided to the examiner. Accordingly, the information disclosure statement has been considered by the examiner, and signed and initialed copy is enclosed herewith.
Specification
The abstract of the specification is objected to a minor informality.
Applicant is reminded of the proper content of an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. The form and legal phraseology often used in patent claims, such as "means" and "said," should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, "The disclosure concerns," "The disclosure defined by this invention," "The disclosure describes," etc. See MPEP 608.01(b)
In the instant case, the abstract exceeds 150 words, i.e., 157 words. Accordingly, substitute abstract to meet the said guideline is requested:
Allowable Subject Matter
Claim 6 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 of this title, 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 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.
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 CFR 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.
As indicated above, the present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-5, 7, 8 and 15-20 are rejected under 35 U.S.C. 103 as being unpatentable over Appel et al. (EP1027887B1) in view of Vergauwen et al., US2019/0083629A1 and further in view of Dobry et al., “A model-based methodology for spray-drying process development”, J Pharm Innov. 2009 July 25; 4(3):133-142 and Ardena “Formulation and process considerations for optimizing spray-dried solid dispersions”, Whitepapers, October 2021, pp. 1-15, and Beyerinck et al. (US2005/0031692A1, IDS of 01/14/2026).
Applicant claims the below claims 1 and 15 filed on 03/03/2026:
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Determination of the scope and content of the prior art (MPEP 2141.01); Ascertainment of the difference between the prior art and the claims (MPEP 2141.02) and Finding of prima facie obviousness Rational and Motivation (MPEP 2142-2143)
Regarding instant claims 1, 3, 4, 15 and 16, they are rejected by Appeal in view of Vergauwen and further in view Dobry and Ardena.
Appel teaches a controlled release dosage form for a low solubility drug that is a spray-dried or spray-coated amorphous solid dispersion of the drug (abstract); the drug includes anti-neoplastic agent such as chlorambucil, lomustine and echinomycin; (e.g., [0022]-[0023]), diuretic agent such as spironolactone, etc. (e.g., [0023]); the solvents suitable for spray-drying may generally be as non-aqueous having less than 30% water, for example, the organic solvent having b.p. of 150C or less which reads on the claimed both low-volatility and high-volatility solvents as supported by the instant publication at [0018] that the term “low volatility solvent” refers to a solvent having a boiling point of at least 110° C whereas the term “high volatility solvent” refers to a solvent having a boiling point that is less than 110° C; as the low volatility solvent DMSO (elected species of low volatility solvent) or NMP can be used in order to enhance drug solubility in an amount of 2-25% (e.g., [0042]) which overlaps the claimed at least 10% of instant claim 15; further, preferred solvents include ketones such as acetone (elected species of high volatility solvent), methanol, ethanol, n-propanol, isopropanol, ethyl acetate, acetonitrile, etc. which reads on the claimed high volatility, and however, the lower volatility solvents such as DMSO may also be used and mixtures of solvents may be used (e.g., [0043]), and accordingly, Appel teaches/suggests selecting a mixture of low/high volatility solvents; the solid amorphous drug dispersion of the drug delivery device may contain a wide variety of excipients, generally aimed at enhancing the bioavailability of the drug (e.g., [0046]) which can be added to co-dissolved in the solvent (e.g., [0041]) and the excipients comprise hypromellose acetate succinate cellulosic polymer (e.g., [0010]), HPMC (e.g., [0054]), polyvinylpyrrolidone (e.g., [0055]) which reads on the claimed excipients, and the solvent is removed by spray-drying with a spray-dryer (e.g., [0035]-[0036] and [0039]) which means removal based on kinetic and thermodynamic properties as evidenced by the below Dobry (see entire document including Figs. 3-4 of Dobry). Please note that any spray-dryer would be configured to receive the solution and a stream of drying gas, and thus the spray-dryer is taught; and the dispersion is formed by dissolving the drug and matrix polymer in a solvent which reads on the claimed forming step and then removing the solvent by spray-drying ([0005]) which reads on the claimed spray-drying step to produce spray-dried dispersion (SDD)(instant claims 1 and 15 (in part), and claims 3-4 and 16).
However, Appel does not expressly teach the elected species of vemurafenib drug of the claimed invention. The deficiency is cured by Vergauwen.
Vergauwen discloses spray-dried API such as vemurafenib (e.g., [0023], [0085], [0366] and the Examples including Example 11) which reads on the claimed elected species of poor solubility drug.
It would have been obvious to a person having ordinary skill in the art to further define or replace the drug of Appel with the vemurafenib of Vergauwen depending on the intended purpose, treating condition, etc. in preparing the drug by using spray-drying.
However, Appel in view of Vergauwen does not expressly teach the claimed spray drying mass ratio and outlet temperature of instant claims 1, 15 and 17. The deficiencies are cured by Dobry and Ardena.
Dobry discloses spray-drying process for preparing solid amorphous dispersions to improve the solubility and, thus the bioavailability of poorly soluble active pharmaceutical ingredients (APIs); and the spray-drying process has the below flowchart on page 136:
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As shown in above Fig. 3 of Dobry, the spray-drying process generally includes 1. Selection of solvent: stability performance and solvent selection, 2. Process constrains, 3. Thermodynamics: solution feed rate and drying-gas outlet temperature. Further, an example of thermodynamic operating space is shown in Fig. 4 wherein the specific drying ratio is defined as the mass ratio of solution feed rate to drying gas flow rate (last para. on page 137 and Fig. 4 on page 138) which reads on the claimed spray drying mass ratio; and the key parameter of spray drying process includes solution feed rate (M soln), drying gas flow rate (M gas), drying-gas inlet temperature (T in), drying-gas outlet temperature (T out), and relative saturation (or humidity) of the solvent at spray-dryer outlet conditions (see e.g., Thermodynamic design space section, left column on page 137); and further as part of this methodology, constraints can be placed on the process based upon equipment limitations (e.g., maximum M gas or T in values) or formulation properties (e.g., glass-transition temperature [Tg] or thermal stability).
Ardena discloses process parameters including liquid feeding rate, inlet temperature, outlet temperature, type of gas and flow rate, wherein the liquid feeding rate dictates the time in which the particles are in the drying chamber, as well as the amount of solvent present in the gas stream and the subsequent outlet temperature observed; this prior art further teaches keeping the outlet temperature below the Tg of the formulation prevents stickiness, and in particular please see "Outlet temperature. Two aspects of outlet temperature should never be overlooked. If the outlet temperature is above the Tg of the product, it can adhere to the walls of the equipment due to the sticky characteristics of the compound, reducing process yield." (see e.g., Process parameters on pages 9-10). That is, Ardena teaches outlet temperature should be less than Tg of the product for stability of product with preventing stickiness of equipment.
That is, Dobry teaches optimizing spray drying using solution feed rate (M soln), drying gas flow rate (M gas), and their drying ratio of solution feed (M soln) to gas flow rate (M gas), drying-gas inlet temperature (T in), drying-gas outlet temperature (T out), and relative saturation (or humidity) of the solvent as the spray-drying process parameters Ardena teaches maintaining outlet temperature below Tg to avoid product instability, and stickiness.
Therefore, it would have been obvious to modify the teachings of Appel/Vergauwen with specific spray-drying process parameters including drying mass ratio based on relative saturation of solvent as taught by Dobry and outlet temperature that is less than the glass transition temperature of API as taught by Ardena. One of the ordinary skill would have recognized that adjusting liquid-to-gas feed ratio in Dobry would inherently allow control of outlet temperature as taught by Ardena in order to provide stable spray dried dispersion without stickiness. Further it would have been obvious to combine the applied art such that the liquid-to-gas feed ratio is adjusted to maintain a relative saturation-controlled drying environment while ensuring the outlet temperature remains below the Tg of the composition containing drug and excipient, thereby preventing thermal deformation and achieving predictable stability. The combination merely involves routine optimization of known parameters to achieve predictable results (instant claims 1, 15 and 17).
Regarding instant claims 2, 19 and 20, they are rejected by Appel/Vergauwen in view Dobry and Ardena and further in view of Beyerinck.
Appel/Vergauwen in view of Dobry/Ardena was discussed above with respect to instant claims 1 and 15.
Appel teaches a mixture of acetone and DMSO for poorly soluble drug, and excipients for enhancing the bioavailability of the poorly soluble drug (e.g., [0043] and [0046]). Vergauwen teaches the elected species of vemurafenib (see e.g., the Examples).
Dobry further discloses drying mass ratio of M sol/M gas (e.g., Fig. 4 on pages 137-138) and Ardena discloses outlet temperature <Tg of the product for preventing stickiness. However, it appears that those applied references do not expressly disclose Tg varies as a function of the mass ratio of instant claim 2. The deficiencies are cured by Beyerinck. Further, maximum mass ratio of instant claims 19-20 would be obvious over the those applied references.
Beyerinck discloses spray-drying process wherein the feed rate of the spray solution will depend on a variety of factors such as the dry gas inlet temperature TIN, drying gas flow rate, the size of the drying chamber and atomizer, and another limit on the spray drying process is the relationship between TOUT (temperature of the exhaust drying gas at the outlet) and both the melt and the glass transition temperature of the resulting solid amorphous dispersion particles (e.g., [0088]-[0089] and [0092]). Further this prior art discloses the energy and mass balances of the inlet streams (spry solution and drying gas) allow prediction of the outlet conditions of the process; namely, the outlet temperature of the drying gas existing the drying chamber (e.g., [0089])(instant claim 2); and this prior art further teaches the process is used to spray dry large quantities of spray solution must be capable of balancing the need to rapidly evaporate solvent to form homogenous solid amorphous dispersions with the need to form particles that have the desired levels of residual solvent and handling characteristics (e.g., [0005]); in particular, the solid amorphous dispersions have a low residual solvent content which means the amount of solvent present in the solid amorphous dispersion following spray-drying immediately upon exit from the spray dryer, and the presence of solvent in the dispersion lowers the glass transition temperature of the dispersion ([0041]), which reads on the claimed Tg varies function of the mass ratio.
Here, from the teachings/suggestions of Dobry/Ardena/Beyerinck, it can be inferred that lower spray-drying mass ratio means there is a greater mass of hot drying gas relative to the liquid load, which drives a higher rate of solvent evaporation, yielding lower residual moisture and consequently result in a higher Tg of product; and a higher spray-drying mass ratio (high liquid feed and low gas) means that the drying gas has a limited heat capacity and solvent capacity relative to the amount of liquid, which leads to incomplete drying, leaving residual moisture and causing significantly lowers Tg of product. Thus a skilled artisan would have been motivated to combine Appel, Dobry and Ardena because those relate to standard spray drying process control, and Beyerinck further teaches residual solvent critically impacts Tg, which is the parameter used in Ardena to define product stability. Therefore, it would have been obvious to adjust the liquid-to-gas feed ratio in Dobry in order to control drying kinetics and residual solvent content with respect to Tg as taught/suggested by Ardena and Beyerinck. Further, a skilled artisan would have adjusted or maximized the spray-drying mass ratio to increase processing efficiency while ensuring outlet temperature remains below Tg which prevent stickiness of spray-dryer, thereby increased producibility.
It would have been obvious to select specific solvent mixture for the poorly soluble drug/excipient because the solubility of drug/excipients and maximum spray drying mass ratio is deeply impacted by the choice of solvent as taught by the applied art including Appel and Dobry as noted above.
Regarding instant claim 5, it is rejected by Appel/Vergauwen in view Dobry and Ardena.
Appel/Vergauwen teach mixture of solvents DMSO/acetone for enhancing stability of the spray dried solid dispersion containing drug vemurafenib; Dobry teaches increasing mass ratio changes drying rate and process intensity (see entire document including Figs. 3-4) and Ardena teaches outlet temperature exceeds Tg, product instability and stickiness of spray-dryer and therefore there exists a minimum operating region of mass ratio and when below that ratio, thermal conditions fails, and accordingly, a skilled artisan would empirically or routinely adjust mass ratio upward until outlet temperature satisfies Tout <Tg.
Regarding claims 7-8, they are rejected by Appel/Vergauwen in view of Dobry/Ardena.
Appel/Vergauwen/Ardena were discussed above.
Dobry further discloses process outlet temperature 80C (e.g., Fig. 4) which is lower than upper threshold process outlet temperature 90C. Thus, it would have been obvious to modify the teachings of Appel/Vergauwen with outlet temperature condition of Dobry less than upper threshold process outlet temperature of 90C in order to effectively and efficiently perform the spray-drying process without drawbacks of stickiness (instant claims 7-8).
Regarding claim 18, they are rejected by Appel/Vergauwen in view of Dobry/Ardena.
Appel/Vergauwen/Ardena were discussed above.
Dobry further teaches relative saturation of the solvent at spray-dryer outlet conditions (%RSout) and its relevant equation (see e.g., page 137) and 10-40% (e.g., Fig. 4) which is within the claimed range of 5-50%.
It would have been obvious to modify the teachings of the applied art with desired range of relative saturation of solvent according to the equation of Dobry from the standpoint of ordinary artisan in order to control spray-drying process parameter.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYUNG S CHANG whose telephone number is (571)270-1392. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Yong (Brian-Yong) S Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYUNG S CHANG/ Primary Examiner, Art Unit 1613
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