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 . Claims included in prosecution are claims 1-3, 7, 9-10, 16-17, 19, 23, 26, 28-31, 36, 39, 41-46, and 64.
Previous Rejections
Applicants' arguments, filed 2/2/2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103 (Maintained)
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.
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.
1. Claim(s) 1-3, 7, 9-10, 16-17, 19, 39, 41, and 64 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hitt et al. (US 2015/0320740, Nov. 12, 2015) (hereinafter Hitt).
Hitt teaches inhalable compositions which comprise one or more respirable aggregates, the respirable aggregates comprising one or more poorly water soluble active agents (Abstract). The invention is able to overcome poor bioavailability of drugs for pulmonary delivery and is effective for treating local and systemic fungal/bacterial infections and can enable effective treatment of infection due to enhanced bioavailability (¶ [0010]). Suitable actives for use in the compositions include itraconazole (¶ [0019]). The active agent particle may have a particle size of less than about 1 μm (satisfies claim 2-3 and 7). The respirable aggregate may be a dry powder or a dry powder dispersed in liquid, forming one or more droplets. The respirable aggregates demonstrate a density of from about 0.1 g/mL to about 5 g/mL (satisfies claim 39) (¶ [0027]). The term "particle" is used to describe a particle comprising an active agent. The particles form individual units within a respirable aggregate, such that the respirable aggregate comprises one or more particles comprising the active agent, dispersed throughout the respirable aggregate (satisfies sub-particle of claim 1) (¶ [0028]). The respirable aggregates will generally have a mass median aerodynamic diameter of between about 1 and about 5 μm (satisfies claim 41) (¶ [0029]). The amount of an active agent or drug varies according to factors such as the potency of the particular drug, the route of administration of the formulation, and the mechanical system used to administer the formulation (¶ [0030]). The preferred methods of making the respirable aggregates create particles that are crystalline or amorphous in morphology (satisfies crystalline form of claim 1) (¶ [0040]). Delivery of the respirable aggregates to the lung can be achieved through any suitable delivery means, including a nebulizer, a dry powder inhaler, or a metered dose inhaler (¶ [0041]). The composition may include excipients and adjuvants. Suitable excipients include polymers, absorption enhancers, solubility enhancing agents, dissolution rate enhancing agents, stability enhancing agents, bioadhesive agents, controlled release agents, flow aids and processing aids (¶ [0046]). Excipients may be chosen alone or in combination to modify the intended function of the effective ingredient by improving flow, or bio-availability, or to control or delay the release of the effective ingredient (satisfies excipient of claim 1). Suitable excipients include Tween 80 (i.e., Polysorbate 80) (satisfies polysorbate of claim 1) (¶ [0047]). Polysorbate 80 is specifically used as a stabilizer (¶ [0060]). In comparative example 24 the ratio of itraconazole to polysorbate 80 was 9:1 (¶ [0111]).
Hitt differs from the instant claims insofar as not explicitly disclosing the recited ratio of itraconazole to polysorbate 80.
However, regarding the ratio recited in instant claim 1, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). As such, since the claimed ratio is close to the ratio disclosed by Hitt (i.e., 9:1 vs greater than 10:1), it would have been obvious for one of ordinary skill in the art to expect the composition of Hitt to have the same properties as that of instant claims, as supported by cited precedent.
Alternatively, 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. See MPEP 2144.05(II)(A). As discussed above, itraconazole is a therapeutic agent and polysorbate 80 is used as a stabilizer, which makes amounts thereof a result effective variable, since amounts itraconazole directly impact the therapeutic effect and amounts of a stabilizer directly impact composition stability. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed ratio of greater than 10:1 to yield the desired therapeutic and stability properties.
Regarding the proviso recited in instant claim 1, Hitt’s composition satisfies the proviso recited in claim 1 wherein the dry powder formulation does not comprise: 50% Itraconazole, 35% sodium sulfate, 10% leucine, and less than 5% polysorbate 80. As discussed above, Hitt does not limit the amount of itraconazole and polysorbate 80 and further does not teach the use of sodium sulfate and/or leucine. Accordingly, Hitt’s composition does not require exactly 50% Itraconazole, 35% sodium sulfate, 10% leucine, and less than 5% polysorbate 80. Therefore, a composition wherein the dry powder formulation does not comprise: 50% Itraconazole, 35% sodium sulfate, 10% leucine, and less than 5% polysorbate 80 would have been obvious.
Regarding the amounts and ratios of itraconazole/polysorbate 80 recited in instant claims 9-10, 16-17, and 19, 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. See MPEP 2144.05(II)(A). As discussed above, itraconazole is a therapeutic agent and polysorbate 80 is used as a stabilizer, which makes amounts thereof a result effective variable, since amounts itraconazole directly impact the therapeutic effect and amounts of a stabilizer directly impact composition stability. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have arrived at the claimed amounts and/or ratios to yield the desired therapeutic and stability properties.
Regarding claim 64, "[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." "The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product. See MPEP § 2113. Therefore, the method of making the composition of the instant claims does not distinguish the compositions from that of the prior art.
2. Claim(s) 23, 26, 28-29, and 31 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hitt et al. (US 2015/0320740, Nov. 12, 2015) (hereinafter Hitt) in view of Leonard et al. (US 2004/0092470, May 13, 2004) (hereinafter Leonard).
The teachings of Hitt are discussed above.
Hitt differs from the recited claims insofar as not disclosing wherein the excipients used are salts such as sodium chloride and/or a magnesium salt or an amino acid such as leucine. Hitt also does not specifically disclose the amount of excipient used.
However, Leonard teaches a dry powder formulation to treat respiratory tract and lung diseases (¶ [0002). The dry powder formulations may preferably contain excipients that are added to ensure or increase the stability of the active, and for long-term stability and flowability of the powder product. Suitable excipients include amino acids such as leucine and salts such as magnesium sulfate and sodium chloride. Excipients may be used in amounts ranging from 1% to about 100% (¶ [0041]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Hitt discloses wherein the composition may include excipients used to improve stability and flowability. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have formulated the composition of Hitt to comprise leucine, magnesium sulfate, and/or sodium chloride, in amounts ranging from 1% to about 100%, since they are known stability and flow enhancing excipients, and amounts thereof, for use in dry powder formulations to treat respiratory tract and lung diseases as taught by Leonard.
3. Claim(s) 30 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hitt et al. (US 2015/0320740, Nov. 12, 2015) (hereinafter Hitt) in view of Leonard et al. (US 2004/0092470, May 13, 2004) (hereinafter Leonard) and further in view of DeHaan et al. (US 2015/0136130, May 21, 2015) (hereinafter DeHaan).
The teachings of Hitt and Leonard are discussed above.
The combined teachings of Hitt and Leonard differ from the instant claims insofar as not disclosing wherein the excipients include sodium sulfate.
However, DeHaan teaches dry powders that contain a therapeutic agent (Abstract). The formulations may include sodium salts (¶ [0065]). Suitable sodium salts include sodium chloride and sodium sulfate (¶ [0066]).
Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. As discussed above, Hitt in view of Leonard disclose wherein the composition may include excipients and suitable excipients include salts. Accordingly, it would have been prima facie obvious for one of ordinary skill in the art to have formulated the composition of Hitt in view of Leonard to comprise sodium sulfate, since it is a known salt equivalent to sodium chloride for use in powders that contain a therapeutic agent as taught by DeHaan.
4. Claim(s) 36 and 42-46 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hitt et al. (US 2015/0320740, Nov. 12, 2015) (hereinafter Hitt) in view of DeHaan et al. (US 2015/0136130, May 21, 2015) (hereinafter DeHaan).
The teachings of Hitt are discussed above.
Hitt differs from the instant claims insofar as not specifically disclosing the type of inhaler used to deliver the powder and not disclosing specific powder properties such as VMGD, dispersibility ratio, FPF, and emitted powder mass.
However, DeHaan teaches dry powders that contain a therapeutic agent (Abstract). The dry powders have characteristics that provide advantages for formulating and delivering therapeutic agents to patients (¶ [0007]). The dry particles are characterized by having a volume median geometric diameter (VMGD) of about 10 micrometers or less and a fine particle fraction (FPF) of less than 5.0 microns of 30% or greater (¶ [0008]). It is preferred that the respirable dry particles are further characterized by a capsule emitted powder mass of at least 80% when emitted from a passive dry powder inhaler that has a resistance of about 0.036 sqrt (kPa)/liters per minute under the following conditions: an inhalation energy of 1.15 Joules at a flow rate of 30 LPM using a size 3 capsule that contains a total mass of 25 mg, the total mass consisting of the respirable dry particles that comprise a divalent metal cation salt, and wherein the volume median geometric diameter of the respirable dry particles emitted from the inhaler 5 microns or less (¶ [0022]). The dry powder may be delivered using a capsule-based dry powder inhaler (¶ [0024]). In some embodiments, the dry particles may have 1 bar/4 bar and/or 0.5 bar/ 4 bar dispersibility ratio of less than 1.5 (¶ [0205]).
Regarding the dry powder properties recited above, it would have been obvious for one ordinary skill in the art, prior to the filing of the instant application, to have modified the respirable aggregates of Hitt to have the VMGD, dispersibility ratio, FPF, and emitted powder mass recited above motivated by the desire to achieve advantages for formulating and delivering therapeutic agents to patients as taught by DeHaan.
Regarding the type of inhaler used, it would have been obvious for one of ordinary skill in the art, prior to the filing of the instant application, to have used capsule-based dry powder inhaler since it is a known inhaler for use in delivering dry powders that contain a therapeutic agent as taught by DeHaan.
Response to Arguments
Applicant’s arguments filed 2/2/26 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments with respect to the itraconazole to polysorbate 80 ratio, the Examiner first submits that a reference is relied upon for all it teaches and suggests, even non-preferred embodiments. See MPEP § 2141.02 (VI). As a threshold matter, regarding Applicant pointing to Example 4 and combining the ratio of poloxamer 407 and polysorbate 80, the instant claims are specifically related to the ratio of itraconazole to polysorbate 80. They are not related to a combination, and are not related stabilizers generically. As such, one of ordinary skill in the art, would not reasonably combine/aggregate the amount/ratio of poloxamer 407 and polysorbate 80 when the claims are directed to polysorbate 80 specifically. Furthermore, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See MPEP § 2123 (II). As such, while Applicant’s inventive compositions may have had ratios that were less than 10:1, this does not necessarily constitute a teaching away from having a very high ratio such as 9:1. In fact, a known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use. See MPEP § 2123 (II). In addition, while the Hitt disclosure does indeed disclose that Example 24 is comparative, the Examiner has not found where Hitt explicitly criticizes, discredits, or otherwise discourages the use of said example. Finally, although Hitt discloses the 9:1 ratio in a comparative embodiment, this disclosure nevertheless shows that compositions comprising itraconazole and polysorbate 80 were known to have ratios approaching the claimed range.
Regarding Applicant’s argument that the comparative example was an aqueous suspension, as discussed above, Hitt specifically discloses that polysorbate 80 functions as a stabilizer and discloses wherein the respirable aggregate may be a dry powder. One of ordinary skill in the art would reasonably concluded that this function would carry over across forms of the composition, absent evidence to the contrary. As such, one of ordinary skill in the art would reasonably conclude that the ratio of itraconazole to polysorbate 80 would have the same material effect across both composition forms as well, absent evidence of criticality unique to dry powders.
Regarding Applicant’s argument that the prior art’s disclosure of a ratio of 9:1 is excluded by the instant claims, while this disclosure may be numerically outside the claimed range, as discussed above, obviousness does not require an identical or overlapping range. A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. See MPEP 2144.05(I). In other words, the question here is whether one of ordinary skill in the art would have been led by the prior art to understand that nearby ratios, including slightly higher itraconazole to polysorbate 80 ratios, would have been expected or workable. The 9:1 ratio disclosed by Hitt demonstrates that the art has already taught formulations weighted heavily towards the itraconazole relative to the polysorbate 80. The slight change to greater than 10 is only a modest quantitative change rather than a major technical one. Finally, with respect to Applicant pointing to Titanium Metals Corp. of America v. Banner, while this is indeed an example where amounts were "merely close", another example can be found in In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934), where the prior art, which taught about 0.7:1 of alkali to water, rendered unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical. Looking to this precedent, “at least 1:1” would “exclude” 0.7:1 as argued by Applicant. However, this rejection was upheld. As such, one of ordinary skill in the art would find that even though the instant claims do recite a ratio of “greater than 10:1” this ratio is indeed close to the ratio disclosed by the prior art.
Regarding Applicant’s arguments with respect routine optimization, Hitt discloses that itraconazole is a therapeutic agent which must be administered in a therapeutically effective amount and discloses that this amount will vary and will be known to a skilled artisan. Hitt further discloses the suitable excpieints such as polysorbate 80 may be used to modify the intended function of the effective ingredient by improving flow, or bio-availability, or to control or delay the release of the effective ingredient and that polysorbate 80 is used as a stabilizer. As such, amounts/ratios of itraconazole and polysorbate 80 are result effective variables. 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. See MPEP 2144.05(II)(A). Specifically, since itraconazole is a therapeutic agent, the amounts/ratios it is used in would impact its therapeutic effect which would make said amounts/ratios a result effective variable. Furthermore, amounts/ratios of polysorbate 80 are a result effective variable because its amounts/ratios directly impact the stability of the active agent. Accordingly, it would have taken no more than the relative skills of one of ordinary skill in the art through routine experimentation to have adjusted and arrived at the claimed amounts/ratios of itraconazole and polysorbate 80, to yield the desired therapeutic effect and stability profile. Again, as discussed above, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. See MPEP § 2123 (II). As such, while Hitt’s inventive compositions may have had ratios that were less than 10:1, this does not necessarily constitute a teaching away from routinely optimizing amounts/ratios to arrive at a very high ratio such as greater than 10:1, especially in light of the comparative example disclosure of a ratio of 9:1 which indicates that such high active to stabilizer ratios are known, workable, and expected. As such, while it is understood that Hitt does not explicitly disclose an inventive composition with the claimed ratio, routine experimentation to arrive at the effective amounts/ratios of the compounds disclosed by Hitt would have been well within the capabilities of one of ordinary skill in the art prior to the filing of the instant application.
Regarding Applicant’s arguments with respect to a reasonable expectation of success, one of ordinary skill in the art would have a reasonable when formulating the composition of Hitt to have a ratio of polysorbate to itraconazole of greater than 10:1, where Hitt discloses these components as suitable for use together, where Hitt discloses that itraconazole is a suitable therapeutic and that therapeutics can be administered in amounts known to a skilled artisan and that polysorbate 80 is a stabilizer, and where Hitt discloses an embodiment with a close ratio that at the very least indicates that such high active to stabilizer ratios were known, workable, and/or expected.
Regarding Applicant’s argument that Hitt discloses “aggregates” and that such aggregates are a combination of smaller individual particles, Hitt discloses wherein the aggregate may be formed from one particle (¶ [0027]).
Regarding to Applicant’s argument with respect to spray drying, "[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." "The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. Once the examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product. See MPEP § 2113. Therefore, the method of making the composition of the instant claims does not distinguish the compositions from that of the prior art.
Regarding Applicant’s arguments that Leonard does not cure the alleged deficiencies of Hitt, the Examiner submits that Leonard cures any alleged deficiencies of Hitt where Leonard discloses that leucine, magnesium sulfate, and/or sodium chloride, are known stability and flow enhancing excipients for use in dry powder formulations to treat respiratory tract and lung diseases.
Regarding Applicant’s arguments that DeHaan does not cure the alleged deficiencies of Hitt, the Examiner submits that DeHaan cures any alleged deficiencies of Hitt where DeHaan discloses that sodium sulfate is a known salt for use in powders that contain a therapeutic agent and where it further provides motivation to utilize specific VMGD, dispersibility ratio, FPF, and emitted powder mass, and discloses known inhaler types for use in delivering powders that contain a therapeutic agent.
In light of the foregoing, the Examiner does not find Applicant’s arguments to be persuasive and the rejection is maintained.
Conclusion
Claims 1-3, 7, 9-10, 16-17, 19, 23, 26, 28-31, 36, 39, 41-46, and 64 are rejected.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 Abdulrahman Abbas whose telephone number is (571)270-0878. The examiner can normally be reached M-F: 8:30 - 5:30.
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/A.A./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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