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 .
Applicants’ arguments, filed 10/03/2025, have been fully considered. Rejections and/or objections not reiterated from previous office action are hereby withdrawn.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.
Specification – Abstract
Applicant is reminded of the proper language and format for 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 in length. 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. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
Claim Rejections - 35 USC § 112 – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 25 stands rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The terms “high dose, low dose” in claim 25 is a relative term which renders the claim indefinite. The terms “high dose, low dose” are not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is unclear because the thresholds for what qualifies as a ‘high dose’ or a ‘low dose’ have not been established.
Claim Rejections - 35 USC § 103--Previous
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 (i.e., changing from AIA to pre-AIA ) 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, 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) Claims 19, 20, 22, 24, 26, 27, 31-33 and 35-37 stand rejected under 35 U.S.C. 103 as being unpatentable over Borody (US 7,776,850 B2, date of patent 08/17/2010; cited in IDS).
Regarding the independent claim 24 and dependent claims 22, 26 and 27, Borody discloses that an “effective treatment of asthma and other respiratory tract mucositis can be achieved using at least one antifungal agent and at least one anti-bacterial agent” (col. 2, lines 1-3). “Typically the at least one anti-fungal agent is selected from the sub-group consisting of: amphotericin B, flucytosine, ketoconazole, miconazole, itraconazole…” (col. 2, 30-32). Borody discloses that the at least one anti-bacterial agent is selected from a group which contains azithromycin and rifabutin (col. 2, lines 58-56). Borody also discloses the treatment is typically administered orally (i.e., intraorally; col. 5, lines 47-48).
The prior art is not anticipatory as it does not disclose administering amphotericin B, azithromycin and rifabutin by inhalation, sublingually or intraorally in a single embodiment or example. However, given the disclosure of each component individually, it would have been prima facie obvious to a person having ordinary skill in the art at a time prior to the filing of the present patent application and following the teachings of Borody to have selected and combined known components for their established functions with predictable results. MPEP 2143 and 2144.06(I). Therefore, it would have been obvious for one of ordinary skill in the art, at the time of filling, to have administered amphotericin B, azithromycin and rifabutin intraorally (e.g., orally; limitation of instant claim 22) to treat asthma. Similarly, it would have been obvious for one of ordinary skill in the art, at the time of filling, to have additionally administered itraconazole.
Regarding instant claim 19, Borody discloses the anti-fungal and anti-bacterial are administered daily (col. 6, lines 39-44), in some cases twice daily for a period of two to four months (col. 10, lines 33-35).
In the absence of a formal definition in the instant specification, the examiner is interpreting ‘pulsed dosages’ to mean administering a therapy in an intermittent manner to enhance the therapeutic effect and reduce the side effects.1 Therefore, administering a single dose daily or twice daily for a set period of time falls withing the scope of pulsed dosage. As such, administering amphotericin B in a pulsed dose would have been obvious to one of ordinary skill in the art at the time of filling.
Regarding instant claim 20, Borody discloses the “method further includes the administration of one or more of a mucolytic agent, a steroid, a decongestant and/or a bronchodilator” (col. 13, claim 21).
Regarding instant claim 31-33, Borody discloses that "[t]ypically, an effective dose of the appropriate anti-fungal agent(s) and anti-bacterial agent(s) would be expected to be…..preferably about 100 mg per day to about 1000 mg per day" (col. 6, lines 63-64).
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP§2144.05(I). The instantly claimed dosages of 200 to 300 mg/day, 300 to 500mg/day and 100, 200, 300, 400, or 500 mg/day overlaps with the range of the prior art. Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have administered the amphotericin B, azithromycin and rifabutin in the dosages instantly claimed.
Regarding instant claim 35 and 37, Borody discloses the “antifungal and anti-bacterial agents are administered simultaneously” (col. 13, claim 20) and that the composition may be formed as a powder (col. 8, lines 47-49). It would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated the amphotericin, azithromycin and rifabutin in a single formulation and to have administered them together, as a powder, because Borody discloses they can be administered simultaneously and may be formulated as a powder.
Regarding instant claims 36, Borody discloses the pharmaceutical compositions of the anti-fungal and anti-bacterial may be in the form of powders (col. 8, lines 47-49). Borody also discloses that the “anti-fungal and anti-bacterial agents are administered sequentially” (col. 13, claim 19).
Administering the anti-fungal and anti-bacterial agents sequentially would require the amphotericin B, azithromycin and rifabutin to be each formulated individually. Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have formulated the amphotericin, azithromycin and rifabutin each individually as a powder because Borody discloses it as one option for the formulation.
2) Claims 23, 28-30 and 34 stand rejected under 35 U.S.C. 103 as being unpatentable over Borody (US 7,776,850 B2, date of patent 08/17/2010; cited in IDS) as applied to claims 19, 20, 22, 24, 26, 27, 31-33 and 35-37 above, and further in view of Jin et al. (US 6,153,217, date of patent 09/23/2000; cited in IDS).
Borody, which is taught above, differs from instant claims 23, 28-30 and 34 insofar as it does not teach administration by inhalation or a nano-encochleated formulation of amphotericin B. Borody does discloses that the pharmaceutical composition may in the form of a slow release (col. 8, line 51).
Jin discloses that lipid-based cochleates (i.e. multi-layered lipid crystals according to p. 15, last paragraph of the instant specification) protect drugs from proteolytic enzymes, the primary issue when administering drugs orally (col. 1, lines 24-29), and that cochleates provide for slow release of a drug (col. 1, line 46). In Example 2, Jin discloses an AmB-cochleate (amphotericin B cochleated) with a mean diameter of 407.3±233.8 nm (col. 7, lines 15-16). Finally, Jin discloses that the cochleate formulations can be administered by inhalation (col. 3, lines 49-50).
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have administered the amphotericin B of Borody as an encochleated (i.e. lipid-crystal) formulation, as disclosed by Jin. One would have been motivated to do so to gain the slow released desired by Borody and to protect the drug when administering orally. One would have had an expectation of success because Jin discloses amphotericin B cochleates can be formed. With respect to the size of the cochleate; in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP§2144.05(I). In the instant case the range of the prior art (407.3±233.8 nm or 173.5 nm to 641.1 nm) overlaps with the range instantly claimed (10 nm to 1000 nm) and a prima facie case of obviousness exists.
Therefore, it would have been obvious to one of ordinary skill in the art, at the time of filling, to have administered the amphotericin B by inhalation (i.e. instant claim 23) as an encochleated formulation (i.e. lipid-crystal; instant claim 28, 29 and 34) with a particle size as claimed in instant claim 30.
3) Claims 19, 21 and 25 stand rejected under 35 U.S.C. 103 as being unpatentable over Borody (US 7,776,850 B2, date of patent 08/17/2010; cited in IDS) as applied to claims 19, 20, 22, 24, 26, 27, 31-33 and 35-37 above, and further in view of Rudnic et al. (US 8,303,988 B2, date of patent 09/06/2012).
Borody, which is taught above, differs from instant claims 21 and 25 insofar as it does not teach administering sublingually or a pulsed dosage comprising multiple doses providing varied amounts of amphotericin B. While Borody teaches a pulsed dosage, purely en arguendo, the examiner will take the position that Borody does not teach a pulsed dosage.
Regarding instant claims 19 and 25, Rudnic discloses that a “product comprised of at least three antifungal dosage forms each having a different release profile” (i.e. a pulsed dosage) “is an improvement over a single dosage antifungal product comprised of an antifungal dosage form having a single release profile” (col. 2, lines 56-60). One embodiment with at least three antifungal dosage forms has a first immediate release dose and three delayed release components (col. 4, lines 39, 40 and 56-63). In this embodiment the immediate release (i.e., first pulsed dose) provides 20% - 50% of the total dosage of antifungal to be delivered (col 4., lines 17-21). The earliest delayed release component (i.e., second pulsed dose), of this embodiment “provides 20% to 35% by weight of the total antifungal provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, of the antifungal provided by the three delayed release components and the last in time provides the remainder of the antifungal provided by the three delayed release components” (col. 4, lines 57-63). Rudnic also discloses amphotericin B can be deployed in this manner (col. 6, line 22-24).
The three delayed releases normalized for the percent of the total dose are; first delayed dose (second overall dose) provides 10%-28% w/w of the total dosage, second delayed dose (third overall dose) provides 10%-32% w/w and the last dose provides 12.5%-48% w/w of the total dose. The overall dosing profile would then be: first dose at 10%-50%, second dose at 10%-28%, third dose 10%-32% and fourth dose 12.5%-48% of the total antifungal delivered by the product. See table below.
Table 1. Percent of total anti-fungal dose delivered by each release.
Order
Dose as described by Rudnic
Percent of Delayed Release Components (%)
Percent Total Dose (%)
1st
Immediate release
10-50
2nd
First delayed release
20-30
10-28
3rd
Next in time delayed release
20-40
10-32
4th
Last delayed release
25-60
12.5-48
It would have been obvious to one of ordinary skill in the art, at the time of filling, to have improved the method of administering amphotericin B, disclosed by Borody, by applying the known technique of multiple dosage forms having different release profiles (i.e. pulses dosage) disclosed in Rudnic. See MPEP 2143 I (C). One would have been motivated to do so because Rudnic discloses it is an improvement over single release dose forms. One would have had an expectation of success because Rudnic discloses amphotericin B can be employed in the disclosed multi release forms.
Furthermore, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05(I). The dosage profile of instant claim 25 is contained within the scope of the dose ranges disclosed by Rudnic. In other words, a dose profile where the second dose delivers less amphotericin B than the first dose, the third more than the second, and the fourth less than the third, overlaps with the ranges disclosed by the prior art. Therefore, a prima facie case of obviousness exists.
Alternatively, the dose profile of instant claim 25 is obvious because "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 IIA quoting In re Aller, 220 F.2d 454, 456 (105 USPQ 233)). It would have been obvious, through routine experimentation, to reach the instantly claimed dosage profile. The dose profile where the second dose is lower than the first dose, the third dose is greater than the second dose and the fourth dose is lower than the third dose is within the scope of the ranges disclosed by the prior art, and as a result, not inventive.
Therefore, it would have been obvious for one of ordinary skill in the art, at the time of filling, to have administered amphotericin B in a pulsed dosage (i.e. instant claim 19), where the pulsed dosage comprises a first dose of amphotericin B, then
a second dose providing less amphotericin B than was provided by the first dose, then
a third does providing more amphotericin B than was provided by the second dose, then
and a fourth dose providing less amphotericin B than was provided by the third dose.
Regarding instant claim 21, Rudnic discloses the composition can be administered sublingually (col. 6, lines 12-14). As a result, one would have expected nothing more than predictable results when combining the sublingual administration with the improved method of administration taught by Borody and Rudnic. Therefore, it would have been obvious for one of ordinary skill in the art, at the time of filling, to have administered the amphotericin B, rifabutin and azithromycin sublingually. Please refer to MPEP 2143 I (C).
4) Claim 21 stands rejected under 35 U.S.C. 103 as being unpatentable over Borody (US 7,776,850 B2, date of patent 08/17/2010) as applied to claims 19, 20, 22, 24, 26, 27, 31-33 and 35-37 above, and further in view of Jain (Jain, K., Methods in Molecular Biology, 2008, vol. 437).
Borody, which is taught above, differs from instant claim 21 insofar as it does not teach administering the amphotericin B, rifabutin and azithromycin sublingually. While sublingual administration is taught by Borody in view of Rudnic, purely en arguendo, the examiner will take the position that it is not. Borody does discloses the composition may be in the form of a sustained release (col. 8, line 51).
Jain discloses that buccal and sublingual drug administration has several advantages including sustained release effect (p. 7, paragraph 2). One would have been able to combine the known combination of amphotericin B, rifabutin and azithromycin taught by Borody with the known method of sublingual administration without changing the function of any component to yield nothing more than predictable results. One would have been motivated to do so in order to gain a sustained release, as disclosed by Jain. One would have had an expectation of success because Jain discloses sublingual administration is a known route for drug delivery. Therefore, it would have been obvious for one of ordinary skill in the art, at the time of filling, to have administered the amphotericin B, rifabutin and azithromycin sublingually. Please refer to MPEP 2143 I (C).
Double Patenting--Previous
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.
1) Claims 19, 20, 22, 24, 26, 27, 31-33 and 35-37 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of U.S. Patent No. 7,241,741 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because they both embrace administering at least one anti-fungal agent and two or more anti-bacterial agents to treat asthma (claim 1 and 13). The claims of ‘741 disclose the two or more anti-bacterial agents include rifabutin and azithromycin (claim 1). The specification of ‘741 discloses the at least one anti-fungal agents include amphotericin B and itraconazole (col. 2, lines 32-34). The claims of ‘741 also disclose the use of a mucolytic agent (claim 12). The specification also discloses the composition may be formed into a powder (col. 8, line 57) and that it may be administered orally (col. 5, line 49) in single daily doses (i.e. pulsed dosages; col. 5, line 54). The specification discloses the composition may be administered sequentially (i.e., each formulated individually) or simultaneously (i.e., formulated together; col. 2, lines 62-64). With respect to the dosing amounts the specification discloses that an effective amount of the anti-fungal agents and the anti-bacterial agents would be expected to be between 100 mg per day to about 1000 mg per day (col. 6 and 7, lines 65-67 and 1-3).
Claims 19, 20, 22, 24, 26, 27, 31-33 and 35-37 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 7,776,850 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim administering at least one anti-fungal agent and two or more anti-bacterial agents to treat asthma (claim 2 and 22). They both claim the two or more anti-bacterial agents include rifabutin and azithromycin (claim 6) and the anti-fungal agent may be amphotericin B (claim 4). The specification of ‘850 also discloses the anti-fungal may further include itraconazole (col. 2, line 32). They both also claim administering a mucolytic agent (claim 21). The specification also discloses the composition may be formed into a powder (col. 8, line 49) and that it may be administered orally (col. 5, line 47) in single daily doses (i.e. pulsed dosages; col. 5, line 51). The claims of ‘850 disclose the composition may be administered sequentially (i.e., each formulated individually; claim 19) or simultaneously (i.e., formulated together; claim 20). With respect to the dosing amounts the specification discloses that an effective amount of the anit-fungal agents and the anti-bacterial agents would be expected to be between 100 mg per day to about 1000 mg per day (col. 6, lines 59-64).
Response to Arguments
Applicant has responded that a continuation has been filed under a separate cover as a response to the AO (office action).
The claims stand rejected for the same reasons above and of record because no amendments or arguments were provided.
Technological Background
The prior art made of record is considered pertinent to applicant's disclosure. Sinha, A., Bagga, A., Pulse Steroid Therapy, Oct. 2008, Indian Journal of Pediatrics, Volume 75, p. 1057-1066. Sinha et al. is pertinent for teaching pulsed doses means administering the drugs in an intermittent manner to enhance the therapeutic effect and reduce the side effects, for example daily doses given for three days (p. 1057, Definitions).
Conclusion
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.
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/C.T.W./Examiner, Art Unit 1612
/WALTER E WEBB/Primary Examiner, Art Unit 1612
1 Definition: Sinha et al., Indian Journal of Pediatrics, 2008, Volume 75, October