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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Status
Claims 1-4, 6, 10-11, 13-16, 18, 20-26, and 29 are pending.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-4, 6, 10-11, 13-16, 18, 20-26, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Perry et al. (US20210145739A1, published 5/20/2021) in view of Rundfeldt et al. (US20110190245A1, published 8/4/2011).
Perry teaches a dry powder formulation comprising respirable/inhalable dry particles that contain itraconazole in crystalline particulate form, polysorbate 80, and one or more excipients (abstract). Perry teaches that this dry formulation is beneficial to overcome poor oral bioavailability, adverse side effects and toxicity, and drug-drug interactions (par. [0002]). This formulation also related to a method for treating allergic bronchopulmonary aspergillosis (par. [0028]) (cf. claim 29). Perry teaches that the respirable dry powder comprises homogenous respirable dry particles that comprise crystalline itraconazole, polysorbate 80 (i.e. a stabilizer as per par. [0063]; cf. claim 21), and one or more excipients. One such excipient taught as being useful in dry compositions is monovalent or divalent metal cation salts (par. [0072]), and Perry teaches that “a preferred sodium salt is sodium sulfate” (par. [0077]) (cf. claim 14). The composition may include further excipients, as well (cf. claim 13). Perry teaches that the itraconazole is a crystalline sub-particle with Dv50 of about 50 nm to about 5,000 nm (par. [0068]) (cf. claim 15). Perry teaches that the dry particles contain itraconazole in amounts from about 1 to about 95% by weight (par. [0067]) (cf. claim 16). Perry teaches that the ratio of itraconazole to stabilizer (i.e. polysorbate 80) is greater than about 10:1 (par. [0065]) and provides examples wherein the ratio is 12:1 (table 1) (cf. claim 18). Excipients may be present in certain embodiments in about 5 to about 50% by weight (par. [0071]) (cf. claim 20). Further excipients that may be present aside from the sodium salt are amino acids that form a powder under standard pharmaceutical processing techniques, and Perry teaches that a preferred amino acid is leucine (par. [0079]) (cf. claim 22). Perry teaches that these respirable dry particles have a volume median geometric diameter of about 10 microns or less, a tap density of between 0.2 g/cc and 1.0 g/cc, a 1 bar/4 bar dispersibility ratio of less than 1.5, and a 0.5 bar/4 bar dispersibility ratio of about 1.5 or less (pars. [0014]-[0019]) (cf. claim 24). It may also be characterized as having a MMAD of between about 1 micron and about 5 microns and a FPF of the total dose of less than 5 microns of about 25% or more (pars. [0017] and [0020]) (cf. claim 26). Perry teaches an embodiment wherein the composition comprises 50.0 wt. % crystalline itraconazole, 35.7 wt. % sodium sulfate, 10.2 wt. % leucine, and 5.00 wt. % polysorbate 80 (table 1 ex. XI) (cf. claim 23). Perry teaches that these embodiments “are characterized by a CEPM of 80% or greater and a VMGD of 5 microns or less when emitted from a passive dry powder inhaler having a resistance of about 0.036 sqrt(kPa)/liters per minute under the following conditions: an air flow rate of 30 LPM, run for 3 seconds using a size 3 capsule that contains a total mass of 10 mg” (par. [0096]) (cf. claim 26).
However, Perry does not teach a second therapeutic agent administered in conjunction with the formulation. Perry also does not teach the specific benefit of this formulation compared to oral itraconazole administration.
These deficiencies are made up for by the teachings of Rundfeldt.
Rundfeldt teaches a pharmaceutical composition that comprises itraconazole that has an improved therapeutic effect and reduced side effect profile (abstract). Rundfeldt teaches that typical administration routes, including oral administration, present a variety of issues. Rundfeldt teaches that systemic administration of drugs such as itraconazole can result in nausea, emesis, hypertonia, hypokalemia, headache, increased formation of edema, allergy like reactions, CNS symptoms, and more serious issues such as severe hepatotoxicity and toxic effects on other organ systems, rhabdomyolysis, and effects of lipid metabolism (par. [0015]). Rundfeldt teaches an inhalable nanocrystalline powder form of itraconazole that overcomes these contraindications (par. [0049]). Rundfeldt teaches that inhalation of these nanoparticles results in high pharyngeal and lung tissue exposure, making it efficacious and advantageous when compared to systemic or oral administration (par. [0052]) (cf. claim 1). Rundfeldt teaches that this composition is useful for the prevention and treatment of diseases including aspergillosis (par. [0088]) (cf. claim 29). Rundfeldt teaches that this composition can also be administered with a second therapeutic, which may be co-administered via inhalation or via alternative routes such as oral or parenteral (par. [0089]). One such therapeutic named that may be administered along with the inventive formulation is ciprofloxacin (par. [0090]) (cf. claims 2-4 and 6). Ciprofloxacin is also “a preferred antifungal combination” to combine with the itraconazole formulation, as it “appears to enhance the antifungal activity of azole derivatives” such as itraconazole (par. [0090]).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application to apply the teachings of Rundfeldt to the teachings of Perry, as both Perry and Rundfeldt provide direction for treating fungal infections of the lung via inhalable formulations. The resulting invention would be a method of treating disease in a subject for whom oral itraconazole is contraindicated, wherein the treatment comprises a respirable dry powder of itraconazole, ciprofloxacin, polysorbate 80, sodium sulfate, and leucine. One would be motivated to do so as Rundfeldt teaches the inhalation method to overcome systemic issues associated with more typical routes of administration of itraconazole such as oral administration, i.e., oral itraconazole is contraindicated. Further, Rundfeldt teaches that the effect of the itraconazole can be increased with the inclusion of ciprofloxacin. This reasoning provides clear motivation to include a drug such as ciprofloxacin into or alongside a composition comprising itraconazole (i.e. co-administering) (cf. claim 3). Rundfeldt teaches that these agents may be administered at the same time (cf. claims 10-11). Ciprofloxacin is listed in the instant application as one potential “second therapeutic agent” of the instant invention (instant specification par. [0011]). Ciprofloxacin is an antibiotic (cf. claim 6) that would necessarily bind and inhibit CYP3A4 isoenzyme (cf. claim 4), as evidenced by instant specification par. [0009], which is the same target as itraconazole (cf. claim 2).
One would have a reasonable expectation of success in applying the teachings of Rundfeldt to the teachings of Perry as Rundfeldt and Perry both teach dry powder compositions for treating fungal disease comprising itraconazole. Applying the teachings of one to the other would have been obvious as the references relate to treating the same diseases using the same approach: developing inhalable itraconazole compositions to overcome oral dosage systemic toxicity. Therefore, the method of treating a disease such as aspergillosis in order to overcome toxicity contraindications when using itraconazole comprising administering a dry powder comprising itraconazole, and optionally another drug such as ciprofloxacin, would have been prima facie obvious to one of ordinary skill in the art, especially in light of the benefits as taught by Perry and Rundfeldt.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the instant application.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4, 6, 10-11, 13-16, 18, 20-26, and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 3 of copending Application No. 17/047,585 (allowed but not yet issued) in view of Rundfeldt (US20110190245A1, published 8/4/2011).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-4, 6, 10-11, 13-14, 16, 18, 20-23, and 29 recite a method of treating disease that comprises administering an inhalable therapeutic, wherein the inhalable therapeutic comprises itraconazole, wherein it further comprises a second therapeutic agent that effects CYP3A4, wherein the second therapeutic is administered on the same day as itraconazole, wherein it further comprises a stabilizer of polysorbate 80, a salt of sodium sulfate, and an excipient of leucine, wherein the itraconazole is in an amount of about 30% to about 70% by weight, wherein the itraconazole to stabilizer is about 10:1, wherein the excipient is present in about 5% to about 20% by weight, wherein the respirable powder comprises about 50 wt.% itraconazole, about 35 wt.% sodium sulfate, about 10 wt.% leucine, and about 5 wt.% polysorbate 80, wherein the disease treated is an infection, allergic bronchopulmonary aspergillosis, a respiratory disease, an acute exacerbation of a respiratory disease, or cancer.
App. No. ‘585 claim 3 recites a method of treating allergic bronchopulmonary aspergillosis (ABPA) that comprises administering via inhalation an anti-fungal agent of itraconazole in crystalline form in an amount of 50% by weight and the itraconazole is in the form of a sub-particle with a VMGD of 60 to 175 nm, wherein the anti-fungal agent further comprises polysorbate 80 in 5% by weight, sodium sulfate in 35% by weight, and leucine in an amount of 10% by weight, wherein the agent is administered in an amount sufficient to achieve a lung concentration of between about 500 ng/g or ng/mL and 8100 ng/g or ng/mL and a plasma concentration of between about 0.2 ng/mL and about 25 ng/mL, wherein the concentrations are achieved for 24 hours following administration, wherein the itraconazole is at least a single dose, wherein each dose independently comprises 5 mg to 35 mg nominal dose of itraconazole.
App. No. ‘585 does not recite administering a second active ingredient, wherein the ingredient interacts with CYP3A4 isoenzyme, wherein it is administered on the same day as itraconazole.
This deficiency is made up for by the teachings of Rundfeldt.
Rundfeldt has been described supra.
Instant claims 1-4, 6, 10-11, 13-16, 18, 20-26, and 29 are an obvious variant of claim 3 of the ‘585 application because it would have been prima facie obvious to one of ordinary skill in the art to include ciprofloxacin as taught by Rundfeldt in the method of claim 3 of App. No. ‘585. As described supra, ciprofloxacin will increase the effectiveness of itraconazole. Ciprofloxacin necessarily interacts with CYP3A4 isoenzyme. The inclusion of ciprofloxacin would be motivated, and expected to be successful, by the teachings of Rundfeldt, wherein ciprofloxacin would be combined in the method comprising administering itraconazole to improve the activity as described supra. The instant claims are patentably indistinct from the claim as outlined in App. No. ‘585 in view of Rundfeldt, as the inclusion of ciprofloxacin as suggested by Rundfeldt in the method as taught by App. No. ‘585 would result in the instantly claimed invention, wherein the inhalable therapeutic will comprise itraconazole in crystalline form in an amount of 50% by weight in the form of a sub-particle with a VMGD of 60 to 175 nm, polysorbate 80 in 5% by weight (i.e. a ratio of itraconazole to polysorbate 80 in 10:1), sodium sulfate in 35% by weight, and leucine in 10% by weight, and further comprise ciprofloxacin, wherein the ciprofloxacin as part of the method of treatment will necessarily be administered alongside the itraconazole. Therefore, the instant claims are indistinct from the claim of ‘585.
This is a provisional nonstatutory double patenting rejection.
Claims 1-4, 6, 10-11, 13-14, 16, 18, 20-23, and 29 are directed to an invention not patentably distinct from claim 3 of commonly assigned App. No. 17/047,585. Specifically, see above.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned App. No. ‘585, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Claims 1-4, 6, 10-11 and 29 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 11, 13, 16-17 and 19 of copending Application No. 19/790,367 (reference application) in view of Rundfeldt (US20110190245A1, published 8/4/2011).
Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-4, 6, 10-11, and 29 recite a method of treating disease that comprises administering an inhalable therapeutic, wherein the inhalable therapeutic comprises itraconazole, wherein the method further comprises administering a second active ingredient, wherein the second active ingredient interacts with CYP3A4, wherein it is administered on the same day as itraconazole, wherein the disease treated is an infection, allergic bronchopulmonary aspergillosis, a respiratory disease, an acute exacerbation of a respiratory disease, or cancer.
App. No. ‘367 claims 1, 11, 13, 16-17 and 19 recite a method for treating a fungal infection comprising administering a therapeutic agent to the respiratory tract, wherein the agent is itraconazole, wherein it is administered in an amount sufficient to achieve a lung concentration of anti-fungal agent of between 500 ng/g or ng/mL and about 8100 ng/g or ng/mL and a plasma concentration of anti-fungal agent of between about 0.2 ng/mL and about 25 ng/mL, wherein the concentration is achieved for at least 24 hours following administration. App. No. ‘367 does not recite administering a second active ingredient, wherein the second active ingredient interacts with CYP3A4 isoenzyme, wherein it is administered on the same day as itraconazole.
This deficiency is made up for by the teachings of Rundfeldt.
Rundfeldt has been described supra.
Instant claims 1-4, 6, and 10-11 are an obvious variant of claims 1, 11, 13, 16-17, and 19 of the ‘367 application because it would have been prima facie obvious to one of ordinary skill in the art to include ciprofloxacin, which will necessarily interact with CYP3A4, as taught by Rundfeldt in a method as claimed by App. No. ‘367. The inclusion of ciprofloxacin would be motivated, and expected to be successful, by the teachings of Rundfeldt, wherein ciprofloxacin would be combined in the method comprising administering itraconazole to improve the activity as described supra. The instant claims are patentably indistinct from the claim as outlined in App. No. ‘367 in view of Rundfeldt, as the inclusion of ciprofloxacin as suggested by Rundfeldt in the method as taught by App. No. ‘367 would result in the instantly claimed invention. Therefore, the instant claims are indistinct from the claim of ‘585.
Claims 1-4, 6, 10-11, and 29 are directed to an invention not patentably distinct from claims 1, 11, 13, 16-17, and 19 of commonly assigned App. No. 19/790,367. Specifically, see above.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned App. No. ‘367, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MATTHEW RYAN BURKE whose telephone number is (571)272-8949. The examiner can normally be reached Mon-Fri. 8am-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, David Blanchard can be reached at 5712720827. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/MATTHEW RYAN BURKE/Examiner, Art Unit 1619
/DAVID J BLANCHARD/Supervisory Patent Examiner, Art Unit 1619
