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
Prosecution is reopened in this application for new matter, as detailed below, and the finality of the office action mailed on June 16, 2025 is withdrawn. The time for reply is reset to begin from the mailing date of the instant office action.
Claims 1, 4-7, 9, and 18-21 are pending.
Priority
This application claims the following priority:
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Election/Restrictions
Applicant elected the invention of Group I, the composition, and the following species:
Ethanol as the solvent,
Malic acid as the stabilizing agent, and
HFO-1234ze as the propellant,
in the reply filed on 06/24/2024.
Claims 9 and 20 withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 4-7, 18-19, and 21 are examined on the merits herein.
Claim Rejections - 35 USC § 112(a)-New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(New) Claims 1, 4-7, 18-19, and 21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
This is a new matter rejection.
In claim 1, the recitation, “wherein a calculated ratio of the amount of maleic acid to the amount of at least one of the at least one pharmaceutically acceptable tiotropium compound is not greater than about 1:10,” and in claim 18, the recitation “wherein a calculated ratio of the amount of maleic acid to the amount of the tiotropium bromide is not greater than about 1:10,” is new matter.
In the 02/04/2025 Response, Applicant states that “The specification provides support for this amendment throughout its disclosure, e.g., in paragraphs [1015]-[1016]).” However, these paragraphs generically state that a single component/compound/agent of the invention can be in any ratio with any one or more other single component/compound/agent of the invention. And while Table 1 in [1016] provides “Exemplary Ratio Array” between a specific compound/component to another specific compound/component, it does not provide support for any numerical ranges. As such, neither [1015] nor [1016] provide support for “wherein a calculated ratio of the amount of maleic acid to the amount of at least one of the at least one pharmaceutically acceptable tiotropium compound is not greater than about 1:10,”, or the recitation “wherein a calculated ratio of the amount of maleic acid to the amount of the tiotropium bromide is not greater than about 1:10.”
It is further noted that [0076] of the specification states the following:
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. While this paragraph provides support for specific ratio ranges between a small compound stabilizing agent, wherein maleic acid is such an agent, and an anticholinergic compound, wherein tiotropium is such a compound, this paragraph also does not provide support for “wherein a calculated ratio of the amount of maleic acid to the amount of at least one of the at least one pharmaceutically acceptable tiotropium compound is not greater than about 1:10,”, or the recitation “wherein a calculated ratio of the amount of maleic acid to the amount of the tiotropium bromide is not greater than about 1:10.”
A careful review of the specification did not uncover support for a ratio of maleic acid to a tiotropium compound or tiotropium bromide, that is not greater than about 1:10.
All other claims not specifically recited are rejected for depending from an indefinite claim and failing to cure the deficiency.
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 (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.
(Maintained) Claims 1, 4-7, 18-19, and 21 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2019/236559 to Dalvi (published 2019, PTO-892 of 11/04/2024) in view of Suissa (Comparative Effectiveness and Safety of LABA-LAMA vs LABA-ICS Treatment of COPD in Real-World Clinical Practice, CHEST, published 2019, PTO-892) and Halpin (Why choose tiotropium for my patient? A comprehensive review of actions and outcomes versus other bronchodilators, Respiratory Medicine, published 2017, PTO-892 of 02/27/2025).
Dalvi teaches pharmaceutical compositions comprising a beta2 agonist, a propellant, a co-solvent, and an organic acid, (pg. 13, claim 1).
Dalvi exemplifies the following solutions:
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(pg. 7);
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(pg. 8);
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(pg. 9);
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(pg. 10).
Regarding claim 1, while Dalvi teaches a pharmaceutical formulation in the form of a solution comprising beclomethasone dipropionate, 0.010% formoterol fumarate dihydrate, 9.5-16% ethanol, 0.002-.0033% maleic acid, and HFA134a, it differs from that of instant claim 1 in that it does not teach tiotropium.
Dalvi further teaches that its pharmaceutical composition can comprise a corticosteroid or a long acting muscarinic receptor antagonist (LAMA), wherein tiotropium is taught as the LAMA that can be added to its compositions in the amount of 0.001%-1% by weight (pg. 6 lines 30-35; pg. 14, claims 13 and 16).
Dalvi teaches its compositions for the treatment of COPD (abstract).
Suissa teaches the comparative effectiveness and safety of LABA-LAMA vs LABA-ICS treatment of COPD (title). Suissa teaches that LABA-LAMA inhalers are as effective as LABA-ICS inhalers in preventing COPD exacerbations and that the LABA-LAMA combination is preferred because it is associated with fewer severe pneumonias (abstract; pg. 1163, Table 2, Fig. 2; pg. 1164, Table 3, last paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective fling date of the instantly claimed invention, to substitute the beclomethasone dipropionate of Dalvi with 0.001-0.05 wt.% tiotropium, to arrive at instant claim 1. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Dalvi and Suissa are both directed toward methods of treating COPD,
-Dalvi teaches that its pharmaceutical compositions can comprise a corticosteroid (ICS), i.e. beclomethasone dipropionate), or a long acting muscarinic receptor antagonist (LAMA), i.e. tiotropium in combination with a beta2 agonist (LABA), i.e. formoterol,
-Suissa teaches that LABA-LAMA inhalers are as effective as LABA-ICS inhalers in preventing COPD exacerbations and that the LABA-LAMA combination is preferred because it is associated with fewer severe pneumonias,
-Halpin teaches tiotropium as effective for bronchodilation, improved lung function, exacerbation efficacy, and as having positive effects on symptom control, exercise capacity, and quality of life across a broad patient population, and
-Halpin teaches tiotropium as having a higher affinity for muscarinic receptors than other long-acting muscarinic antagonists, and teaches that the benefit of tiotropium is that it has a more extensive clinical evidence base than other long-acting bronchodilators, with demonstrated efficacy and safety in COPD.
As such, an ordinary skilled artisan would have been motivated to make such a substitution to predictably arrive at a formulation that is safe, provides effective bronchodilation, improved lung function, and improved exacerbation efficacy, has positive effects on symptom control, exercise capacity, and quality of life in COPD patients, and decreases the chance of severe pneumonia.
Regarding the ratio of maleic acid to tiotropium, the optimization of known percent amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Thus, an ordinary skilled artisan would have been motivated to modify the amounts of maleic acid and tiotropium, to predictably arrive at ratios optimized for stability and therapeutic effect.
Regarding the wherein clauses “wherein each constituent of the active pharmaceutical ingredient component is at least substantially dissolved such that the solution is sufficiently homogeneous so as to allow light to at least substantially uniformly passthrough the compounds,” and “wherein the maleic acid prevents or delays any change in the homogeneity of the composition resulting in (i) a reduction in the amount of light passing through the composition or (ii) the composition no longer being a solution,” in claim 1, since the combination of Dalvi, Suissa, and Halpin teaches the instantly claimed solution, these limitations are met. See MPEP 2112.01.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Regarding claim 4, Dalvi teaches 9.5-16% ethanol.
Regarding claim 5, Dalvi teaches ~87% w/w HFA134a, wherein HFA134a is the only propellant. Regarding the ratio, ~87% % w/w HFA134a: 0.002 wt.%-0.0033wt% maleic acid, is greater than 320:1.
Regarding claims 6 and 7, the combined composition of Dalvi, Suissa, and Halpin does not comprise HFA-227 or a surfactant.
Regarding claim 18, while the combination of Dalvi, Suissa, and Halpin teaches a composition comprising 0.001%-1% by weight tiotropium, 0.010% formoterol fumarate dihydrate, 0.002-.0033% maleic acid, and HFA134a, it differs from that of instant claim 18 in that it does not teach 0.01-0.1% maleic acid, the tiotropium as tiotropium bromide, or the calculated ratio of maleic acid to tiotropium bromide as not greater than about 1:10.
Dalvi further teaches the organic acid as comprising 0.001-1% by weight and preferably 0.001-0.1% by weight of the organic acid.
Dalvi further teaches tiotropium or pharmaceutically acceptable salts thereof and teaches tiotropium bromide as a salt of tiotropium known for use in aerosol solutions comprising a beta2 agonist (pg. 2, lines 4-13; pg. 6, lines 30-35; pg. 14, claim 16).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention to select 0.01-0.1% maleic acid as the amount of maleic acid, tiotropium bromide as the salt of tiotropium, and a ratio of less than or equal to 1:10 of maleic acid to tiotropium bromide, to arrive at instant claim 18. One of ordinary skill in the art would have been motivated to make such selections, with a reasonable expectation of success, because:
-Dalvi teaches the organic acid in its compositions as comprising 0.001-1% by weight and preferably 0.001-0.1% by weight of the organic acid,
-Dalvi teaches salts of tiotropium and specifically teaches tiotropium bromide as a known salt for use in aerosolized compositions comprising beta2-agonists,
-Halpin teaches tiotropium bromide as the form of tiotropium used in long-acting bronchodilators (pg. 29, Col. 1, 2nd full paragraph), and
-"[W]here 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" (MPEP 2144.05(II)).
As such, an artisan having ordinary skill in the art would have been motivated to make such selections to predictably arrive at an optimized amount of maleic acid, and optimized form of tiotropium, and an optimized ratio of maleic acid to tiotropium, that provides both a stable and therapeutically effective formulation.
Regarding the wherein clauses “wherein each constituent of the active pharmaceutical ingredient component is at least substantially solubilized and the composition is a solution that is sufficiently homogeneous so as to allow light to at least substantially uniformly pass through the composition,” in claim 18, since the combination of Dalvi, Suissa, and Halpin teaches the instantly claimed solution, these limitations are met. See MPEP 2112.01.
Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed product. In the absence of evidence to the contrary, the burden is on the applicant to prove that the claimed product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Regarding claim 19, the combination of Dalvi, Suissa and Halpin teaches 0.001-1% tiotropium bromide and 0.010% w/w formoterol fumarate dihydrate, and further teaches the beta2agonist, i.e. formoterol fumarate dihydrate, as comprising 0.001% to about 0.2% by weight of the composition.
An ordinary skilled artisan would have been motivated to modify the amounts of tiotropium bromide and formoterol fumarate dihydrate to about 0.008 wt.% to predictably arrive at a solution optimized for stability and therapeutic effect. The optimization of known percent amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Regarding claim 21, the combined composition of Dalvi, Suissa, and Halpin does not contain beclomethasone.
Response to Arguments
Since the above rejections are new, the arguments are no longer pertinent to the rejection of record.
Conclusion
Claims 1, 4-7, 18-19, and 21 are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
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, James (Jim) Alstrum-Acevedo can be reached at (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LAUREN WELLS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622