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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07 August 2026 has been entered.
Status of Claims
Receipt is acknowledged of the claim amendments filed on 07 August 2026.
Claims 1-225, 252-254 and 256 are cancelled.
Claims 226-235 and 238-242 have been amended.
Claim 236-237, 243-251, 255 and 257-259 remains withdrawn from consideration.
Claims 226-235 and 238-242 are examined herein to the extent that the R1 is hexadecyl and the sugar is mannitol, e.g., applicant’s elected species.
Information Disclosure Statement
The information disclosure statement (IDS) filed 08/07/2026 and 09/11/2026 have been considered by the Examiner. A signed and initialed copy of the IDS is included with the instant Office Action.
Rejections Withdrawn
The rejection of claims 226-235 and 238-242 under 35 U.S.C. 103(a) as being unpatentable over MALININ (US 9,255,064; cited in IDS filed 06/16/2023; patent date of 09 February 2016) in view of PAN (CN 1593414 A, date published: 16 March 2005, cited in IDS filed 04/30/2026), is withdrawn in view of the claim amendments filed on 07 August 2026.
New Grounds of Rejections
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 226-235 and 238-242 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over MALININ (US 9,255,064; cited in IDS filed 06/16/2023; patent date of 09 February 2016) in view of WEILER (WO 2010/060875 A1, publication date of 03 June 2010) and MCINTOSH (US 2014/0294969 A1, publication date of 02 October 2014) as evidenced by SHARMA (“To scale or not to scale: the principles of dose extrapolation”, British Journal of Parhmacology, 157, 907-921, 2009).
Malinin is primarily directed towards prostacyclin compounds, compositions comprising the same, and methods for treating including pulmonary hypertension (abstract).
Regarding claims 226-229 and 242, Malinin a composition comprising a prostacyclin compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for including pulmonary administration to treat pulmonary hypertension (PH) (column 7, lines 10-11; 7, lines 24-28). Malinin discloses composition including composition for pulmonary administration including by a dry powder inhaler (column 7, lines 24-28). Malinin discloses specifically a treprostinil alkyl esters Formula (A):
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl) (column 51, lines 55-58; column 52, Formula (A); column 53, compound C16-TR). Malinin discloses inhaled C16-TR (e.g., R1 is hexadecyl) at a dose of 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2) as evidenced by Sharma at Table 1 of Sharma) was well tolerated with no evidence of body weight and organ weight change after dosing for 14 consecutive days (column 82, lines 49-51). Malinin discloses dose of 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma) (column 81, lines 55-62).
Malinin does not specifically teach that the composition comprises from about 0.5 wt% to about 5 wt% of the compound of Formula (A) including a linear C16 alkyl (e.g., R1 is hexadecyl), from about 25 wt% to about 61 wt% of leucine, and a balance of mannitol for 100% of the entirety of the compound of Formula (A) including a linear C16 alkyl (e.g., R1 is hexadecyl), the leucine and the mannitol. The deficiencies are made up for by the teachings of Weiler and Mcintosh.
Weiler is primarily directed towards powders for inhalation that are stable (see abstract and entire English translation of the patent publication).
Regarding claims 226, 230-232 and 238-240, Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Therefore, Weiler teaches a capsule consisting of a capsule (e.g., contains a shell) filled with a spray-dried powder that does not require DSPE-PEG2000 because Weiler teaches spray-dried powder that only requires an active and matrix former which are filled in a capsule (page 3, eighth paragraph and tenth paragraph; page 14, first paragraph; page 16, last paragraph).
Mcintosh is primarily directed towards dry powders for inhalation (abstract).
Regarding claim 226, 233-235 and 242, Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Regarding claim 241, Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph).
It would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a capsule (e.g., contains a shell) for inhalation that is filled with a spray-dried powder for inhalation (e.g., capsule consisting of a shell and spray-dried particles) that comprises a compound having the following formula:
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl), water-matrix former including mannitol, and L-leucine (e.g., powder does not require DSPE-PEG2000); wherein the ratio of the compound having Formula (A) to matrix former is in a concentration such that the ratio of the compound having Formula (A):matrix former is 1:999 to 1:1 (w/w); wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight; and wherein the dose of the compound having Formula (A) includes from 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2)) and 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma). The person of ordinary skill in the art would have been motivated to make those modification in order to obtain powder for inhalation that is stable by formulating compound having Formula (A) as powder containing the compound having Formula (A) as the active and mannitol as a matrix former and obtain a dry powder that inhibits agglomeration by including L-leucine which is believed to concentrate on the surface to inhibit agglomeration. The person of ordinary skill in the art would have reasonably expected success because Malinin a composition comprising a prostacyclin compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for including pulmonary administration to treat pulmonary hypertension (PH) (column 7, lines 10-11; 7, lines 24-28). Malinin discloses specifically a treprostinil alkyl esters Formula (A):
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl) (column 51, lines 55-58; column 52, Formula (A); column 53, compound C16-TR). Malinin discloses inhaled C16-TR (e.g., R1 is hexadecyl) at a dose of 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2) as evidenced by Sharma at Table 1 of Sharma) was well tolerated with no evidence of body weight and organ weight change after dosing for 14 consecutive days (column 82, lines 49-51). Malinin discloses dose of 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma) (column 81, lines 55-62). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]).
Thus, the claimed invention as a whole is clearly prima facie obvious over the teachings of the prior art.
Response to Arguments
Applicant’s arguments will be addressed as they pertain to the new grounds of rejection above. Applicant argues that the Weers Declaration is relevant for combination of references cited because the Weers Declaration states that formulation and manufacturing process of one API will not necessarily work for a second API because the different physical and chemical properties of the API, such as API solubility, results in different interactions with carriers and other components.
Applicant's arguments filed on 07 August 2026 and the Weers Declaration have been fully considered but they are not persuasive. In response, Malinin a composition comprising a prostacyclin compound of Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, for including pulmonary administration to treat pulmonary hypertension (PH) (column 7, lines 10-11; 7, lines 24-28). Malinin discloses specifically a treprostinil alkyl esters Formula (A):
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl) (column 51, lines 55-58; column 52, Formula (A); column 53, compound C16-TR). Weiler teaches spray-dried crystalline powders having improved properties of flowability, dispersibility, and storage and process stability (page 4, third paragraph of the English translation). Weiler teaches active ingredients are incorporated into matrix former that improves the physical stability of the spray-dried particles (page 4, fifth paragraph). Weiler teaches that matrix formers include mannitol (page 4, sixth paragraph). Weiler teaches that the powder comprises matrix formers in a concentration such that the ratio of active ingredient:matrix former is 1:999 to 1:1 (w/w) (page 13, fifth paragraph). Weiler teaches that the powders can be mixed directly as powder inhalants including single-dose system (page 14, first paragraph). Weiler teaches that the dry powder are physically stable (page 16, sixth paragraph). Weiler teaches that the inhalable powders are filled in capsules (page 16, last paragraph). Mcintosh teaches that L-leucine can be used to advantage in processes for preparing dry powders for inhalation via spray drying (paragraph [0010]). Mcintosh teaches that it is believed that L-leucine concentrates at the surface of the formed particles, due to its hydrophobicity, in such a way that the particles are stabilized and such that agglomeration is inhibited (paragraph [0014]). Mcintosh teaches that the amount of L-leucine is between 5 and 50% by weight of the dry ingredients of the formulation (paragraph [0025]). Therefore, in light of the disclosure of Malinin and the teachings of Weiler and Mcintosh, it would have been prima facie obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to produce a capsule (e.g., contains a shell) for inhalation that is filled with a dry powder for inhalation that is produced by spray drying that comprises a compound having the following formula:
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wherein R2 is including a linear C16 alkyl (e.g., R1 is hexadecyl), water-matrix former including mannitol, and L-leucine; wherein the ratio of the compound having Formula (A) to matrix former is in a concentration such that the ratio of the compound having Formula (A):matrix former is 1:999 to 1:1 (w/w); wherein the amount of the L-leucine in the dry powder is between 5 and 50% by weight; and wherein the dose of the compound having Formula (A) includes from 0.6-18 µg/kg for a rat (e.g., dose for 70 kg person is calculated to be about 6.8 µg to about 203.2 µg (human equivalent dose = dose of rat divided by 6.2)) and 6-90 µg/kg for dogs (e.g., dose for 70 kg person is calculated to be about 233.3 µg to about 3500 µg (human equivalent dose = dose of dog divided by 1.8) as evidenced by Sharma at Table 1 of Sharma).
Applicant is reminded that obviousness does not require absolute predictability, however, at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976). See MPEP 2143.02(II).
Regarding the Weers Declaration and arguments about different drugs having different properties so the formulation and manufacturing process of one API will not necessarily work for a second API, no factual evidence has been provided. The Weers Declaration and arguments are considered conclusory opinion without factual evidence that show nonobviousness. In light of the disclosure of Malinin and the teachings of Weiler and Mcintosh (described above), there is a reasonable expectation of success that the compound having Formula (A) of Malinin can be produced as a spray dried powder of Weiler which contains an active and a matrix former including mannitol and further include L-leucine to further provide inhibiting of agglomeration of the dry powder, as taught by Mcintosh.
Thus, for the reasons of record and for the reasons presented above claims 226-235 and 238-242 are rejected under 35 U.S.C. 103(a).
Conclusion and Correspondence
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOHN P NGUYEN whose telephone number is (571)270-5877. The examiner can normally be reached Monday-Friday 10am-6pm EST.
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/JOHN P NGUYEN/
Examiner, Art Unit 1619
/ANNA R FALKOWITZ/Primary Examiner, Art Unit 1600
