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 .
Status of the Claims
Claims 1, 20-26, and 31-39 are pending in this application. Claims 2-19 and 27-30 have been cancelled by applicant.
Claim Interpretation
“Crystalline particles,” as stated in amended claim 1, will be interpreted as encompassing “microcrystalline particles.”
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.
Claims 1, 20-26, and 31-39 are rejected under 35 U.S.C. 103 as being unpatentable over Guarneri et al. (US 20190321290 – cited in IDS – previously cited) (“Guarneri”); in view of Stenzler et al. (US 20160198758 A1 – cited in IDS – previously cited) (“Stenzler”); and Kelly et al. (WO 2022/072864 – cited in IDS – previously cited) (“Kelly”).
Regarding claim 1, Guarneri teaches a method of making inhalable dry powder composition comprising combining 2,5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine (FDKP; instant diketopiperazine compound) and a solution of acetic acid and homogenizing in a high shear mixer to form a precipitate; washing the precipitate in suspension with deionized water; concentrating the suspension and drying the suspension in a spray drying apparatus (Example 1; and para. [0056], [0058]). FDKP microcrystallites (reading on crystalline particles – see claim interpretation) are obtained by preparing a suspension of FDKP in an aqueous ammonia solution and combining an acetic acid solution in a high shear mixture at a temperature of about 25°C ± 5°C (i.e encompassing about 20°C); FDKP microcrystallites suspension can optionally be washed using deionized water; FDKP microcrystallites can be optionally be isolated by spray drying or lyophilization. It is also taught that after washing in water, the resulting particle suspension is lyophilized to remove water and re-suspended in an alcohol solution, including ethanol, prior to adding the active agent as a solid or in a suspension or solution (para. [0059]). Preparation of dry powder composition comprising microcrystalline FDKP particles and Treprostinil is obtained by adding a solution of 0.2-1.0 wt% treprostinil in ethyl alcohol to a suspension of FDKP microcrystallites; the mixture was spray dried (Example 2). Guarneri teaches a composition comprising 2.5-6.25 wt% of FDKP (reading on resuspending the microcrystalline particles forming a resuspension comprising at least 0.2% solid) (Table 1, page 8, col. 1).
Regarding claims 20-21, Guarneri teaches that the FDKP microcrystalline particles have a pore size ranging from about 23.8 nm to 26.2 nm (para. [0072]).
Regarding claims 22-25, Guarneri teaches a composition of aqueous ammonium mixed with 2.5-6.25 wt% of FDKP (reading on resuspension of microcrystallites consisting essentially of FDKP in at least about 0.2% solid) (Table 2, page 8, col. 2).
Regarding claim 26, Guarneri teaches concentrating the suspension and drying the suspension in a spray drying apparatus (para. [0056], [0058]).
Regarding claims 31-33, Guarneri teaches the weight % concentration of treprostinil in the resultant powder was 0.5-10% ([0073] – Example 2) and up to 20 wt% ([0062]).
Regarding claims 34-38, Guarneri teaches doses of their dry powder composition administered comprising 30-180 µg of treprositinil ([0074]) and up to 1-200 µg ([0062]).
Regarding claim 39, Guarneri teaches their microcrystalline particles have surface areas ranging from 59-63 m2/g (Table 2a and [0072]).
Regarding the instantly claimed ranges of: (i) temperature ranging from 13-20 °C (claim 1); (ii) resuspension comprising about 0.2-10% solid (claims 1, 22-25); (iii) pore sizes of 23-30 nm (claims 20-21); (iv) about 0.25-20 wt% treprostinil (claims 31-33); (v) 1-200 µg of treprositinil (claims 34-38); and (vi) 59-63 m2/g surface areas (claim 39); Applicant is advised that Guaneri’s disclosure of: (i) 25°C ± 5°C; (ii) 2.5-6.25 wt% of FDKP; (iii) 23.8 nm to 26.2 nm; (iv) 0.5-20 wt% treprostinil; (v) 1-200 µg of treprositinil; and (vi) surface areas ranging from 59-63 m2/g; respectively, read on the instant claims. The courts have stated where the claimed ranges overlap or lie inside the ranges disclosed by the prior art and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. See In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985) (see MPEP 2144.05.01). The courts have also found that 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 In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05-II.
Therefore, the claimed ranges merely represent an obvious variant and/or routine optimization of the values of the cited prior art.
While Guarneri does not specifically teach: (i) pelletizing the suspension in a cryo-granulator prior to lyophilizing (claim 1); or (ii) resuspension in water and ethanol (claim 1); the teachings of Stenzler and Kelly are relied upon for these disclosures.
Stenzler teaches a method of making nicotine-FDKP microparticle formulations (abstract). It is taught that FDKP microparticles/nicotine suspension can be pelletized (cryogranulated) by flash freezing in liquid nitrogen, and the ice pellets can then be lyophilized, (para. [0046]; claim 12).
Kelly teaches dry powder inhalable composition comprising FDKP and a hydrophobic cannabinoid (abstract; para. [0076], [0102], [0103], and [0166]). It is taught that utilizing the spray-drying approach, cannabinoids are mixed into a solvent such as ethanol, ethanol and water; then mixed with a phospholipid to form cannabinoid/phospholipid solution. FDKP is added to solvent which includes ethanol and water to obtain FDKP suspension. FDKP suspension is added to cannabinoid suspension, mixed; and the resulting suspension is spray dried (page 25, para. [0079]; claims 1, 2).
Therefore, regarding washing with water and palletizing the suspension comprising FDKP in a cryogranulator and drying in a lyophilizer to collect the FDKP particles, as recited in claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention in view of Guarneri in view of Stenzler and Kelly. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Guarneri discloses FDKP microcrystallites suspension can optionally be washed using deionized water and optionally isolated by spray drying or lyophilization, and that after washing in water, and lyophilizing, FDKP particles can be re-suspended in an alcohol solution, including ethanol, prior to adding the active agent as a solid or in a suspension or solution; further because Stenzler teaches a process wherein similar FDKP microparticles (with nicotine) are pelletized (cryogranulated) prior to being lyophilized. Thus, one of ordinary skill would have been motivated to isolate the FDKP particles after washing with deionized water by pelletizing, then lyophilizing. Applicant is advised that a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR, 550 U.S. at 421, 82 USPQ2d at 1397.
Regarding resuspending the crystalline particles in water and ethanol, forming a resuspension, then adding Treprostinil in dry powder form to the resuspension, and drying, as recited in claim 1, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention in view of Guarneri in view of Stenzler and Kelly. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Guarneri discloses re-suspension in an ethanol prior to adding the active agent as a solid or in a suspension or solution, and also preparing the dry powder composition comprising microcrystalline FDKP particles and Treprostinil a solution of 0.2-1.0 wt% Treprostinil in ethanol to a suspension of FDKP microcrystallites, followed spray drying (reading on “drying the suspension”); further because Kelly teaches that, for a spray drying approach, FDKP is added to solvent which includes ethanol and water (and cannabinoids) to obtain FDKP water and ethanol suspension. Thus, it would have been obvious to one of ordinary skill to resuspend Guarneri’s FDKP in an ethanol and water mixture (as taught by Kelly), then add the Treprostinil active ingredient, followed by spray drying, as taught by Guarneri in view of Kelly. Applicant is reminded that a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
Response to Arguments
Claims/ Claim Objections
Claim amendments are acknowledged and have been entered. No new matter has been introduced.
In view of claim amendments, all claim objections have been withdrawn.
Claim Rejections - 35 USC § 112(b)
In view of claim amendments, all 35 USC § 112(b) rejections of the claims have been withdrawn.
Claim Rejections - 35 USC § 103
Applicant's arguments filed 04/21/2026 have been fully considered but they are not persuasive.
Applicant argues that Guarneri does not teach resuspending FDKP particles in water and ethanol or pelletizing the FDKP suspensions in a cryogranulator. Applicant asserts that Stenzler and Kelly fail to remedy the deficiencies of Guarneri. Applicant argues that Kelly does not teach or suggest cryogranulation or any manipulation of FDKP, or any preparation or purification method relating to FDKP. Applicant argues Stenzler does not teach cryogranulation of FDKP alone, but with nicotine. Applicant states the order of steps in the instant claim is essential and non-obvious, citing the declaration filed 04/21/2026 (see discussion about declaration below). Applicant states Stenzler’s use of cryogranulation is strictly limited to nicotine coated particles. Applicant asserts that a person of ordinary skill would understand that the presence of the active agent is essential in Stenzler’s disclosure, and that therefore, a skilled artisan would not use cryogranulation for FDKP alone. Applicant states there’s no reason to combine the cited references, and that one of ordinary skill would not look to Stenzler, since they teach nicotine coated FDKP, which is a different active ingredient.
As an initial matter, Applicant is advised, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
In this case, Guarneri teaches a method of making inhalable dry powder composition comprising FDKP microcrystallites, which are obtained by preparing a suspension of FDKP in an aqueous ammonia solution and combining an acetic acid solution in a high shear mixture at a temperature of about 25°C ± 5°C (i.e encompassing about 20°C); FDKP microcrystallites suspension can optionally be washed using deionized water; FDKP microcrystallites can be optionally be isolated by spray drying or lyophilization. It is also taught that after washing in water, the resulting particle suspension is lyophilized to remove water and re-suspended in an alcohol solution, including ethanol, prior to adding the active agent as a solid or in a suspension or solution (para. [0059]).
Stenzler teaches a method of making nicotine-FDKP microparticle formulations (abstract). It is taught that FDKP microparticles/nicotine suspension can be pelletized (cryogranulated) by flash freezing in liquid nitrogen, and the ice pellets can then be lyophilized, (para. [0046]; claim 12). Thus, Stenzler is only relied upon for their teaching of cryo-granulation as a known technique in the art, and thus routinely available to the skilled artisan.
Kelly teaches dry powder inhalable composition comprising FDKP and a hydrophobic cannabinoid (abstract; para. [0076], [0102], [0103], and [0166]). It is taught that utilizing the spray-drying approach, cannabinoids are mixed into a solvent such as ethanol, ethanol and water; then mixed with a phospholipid to form cannabinoid/phospholipid solution. FDKP is added to cannabinoids solution ethanol and water to obtain FDKP suspension. FDKP suspension is added to cannabinoid suspension, mixed; and the resulting suspension is spray dried (page 25, para. [0079]; claims 1, 2). Thus, Kelly is only relied upon for their teaching that FDKP can be in a water/ethanol medium prior to the final spray drying to obtain the final product.
Therefore, regarding washing with water and palletizing the suspension comprising FDKP in a cryo-granulator and drying in a lyophilizer to collect the diketopiperazine, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention in view of Guarneri in view of Stenzler and Kelly. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Guarneri discloses their FDKP microcrystallite suspension can optionally be washed using deionized water and optionally isolated by spray drying or lyophilization. It is also taught that after washing in water, the resulting particle suspension is lyophilized to remove water and re-suspended in an alcohol solution, including ethanol, prior to adding the active agent as a solid or in a suspension or solution; further because Stenzler teaches a process wherein similar FDKP microparticles (with nicotine) are pelletized (cryo-granulated) prior to being lyophilized. Applicant is advised that a person with ordinary skill has good reason to pursue known options within his or her technical grasp. Note: MPEP 2143(E) KSR, 550 U.S. at 421, 82 USPQ2d at 1397. Thus, one of ordinary skill would have been motivated to prepare, with a reasonable expectation of success, Guarneri’s FDKP microcrystallines and pelletize followed by lyophilization, as taught by Stenzler.
Regarding resuspending the crystalline FDKP particles in water and ethanol, forming a resuspension, then adding Treprostinil in dry powder form to the resuspension, and drying, it would have been prima facie obvious to one of ordinary skill prior to the effective filing date of the claimed invention in view of Guarneri in view of Stenzler and Kelly. One of ordinary skill would have been motivated to do so with a reasonable expectation of success because Guarneri discloses re-suspension in ethanol prior to adding the active agent as a solid or in a suspension or solution, followed by spray drying (reading on “drying the suspension”); further because Kelly teaches that, for a spray drying approach, FDKP is added to solvent which includes ethanol and water to obtain FDKP suspension. Thus, it would have been obvious to one of ordinary skill to resuspend the FDKP in an ethanol and water mixture (as taught by Kelly), then add the Treprostinil active ingredient, followed by spray drying, as taught by Guarneri in view of Kelly. Applicant is reminded that a person with ordinary skill has good reason to pursue known options within his or her technical grasp.
In response to Applicant’s arguments that Stenzler’s use of cryogranulation is strictly limited to nicotine coated particles and that “Stenzler’s use of cryogranulation is to ensure that ‘the nicotine in solution will be deposited on the surface of the FDKP…” – nowhere in Stenzler does it say that the purpose of cryogranulation (by itself) in to ensure nicotine deposition. See [0046] below, which states that pelletizing (by cryogranulation) followed by lyophilizing, is what ensures nicotine deposits – not the pelletizing alone.
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In regards to Applicant’s arguments that the presence of an active agent with the FDKP is essential in Stenzler (see statement above about attacking references individually) – Guarneri teaches FDKP microcrystallites can be optionally be isolated (without any active ingredient present) – thus, one of ordinary skill would have been motivated to pelletize, then lyophilize the FDKP particles alone, in view of the art of record.
Applicant is advised, in order to overcome the obviousness rejections of record, Applicant needs to demonstrate an advantageous property of the FDKP-Treprostinil composition prepared using the instantly claimed method, which incorporates an intermediate step of pelletizing the initial suspension in a cryogranulator and lyophilizing to isolate crystalline FDKP, prior to resuspending in water and ethanol for introduction of the Treprostinil, followed by drying, versus Guarneri’s composition made without the intermediate pelletizing (cryogranulation) step and resuspension in water and ethanol. Applicants who allege the inventor discovered the source of a problem must provide evidence substantiating the allegation, either by way of affidavits or declarations, or by way of a clear and persuasive assertion in the specification. In re Wiseman, 596 F.2d 1019, 201 USPQ 658 (CCPA 1979) (unsubstantiated statement of counsel was insufficient to show appellants discovered source of the problem); In re Kaslow, 707 F.2d 1366, 217 USPQ 1089 (Fed. Cir. 1983). See MPEP 2141.02 (IV).
It is noted that the response above should not be construed as an invitation to file an after final declaration. See MPEP 715.09.
Declaration filed 04/21/2026:
The declaration filed merely states: “our process group developed a commercial scale method for preparing crystalline particles of …(FDKP) in large quantities…” and recites the limitations of claim 1. Applicant states that at this point, the process can be halted and the crystalline FDKP can be stored for later use or moved to a second processing area or physical location. *Applicant is advised that this point (point 6 of the declaration) is not commensurate with the scope of the claims, which requires the process to go through to completion by resuspending the FDKP and adding the TIP active ingredient*. In point 7, Applicant finishes restating the limitations of claim 1. Applicant states their procedure was developed over 4-5 years and has been the commercial process to make TIP since FDA approval for 6 years.
If Applicant intends to say that their inventive step is the ability to halt the process midway and isolate crystalline FDKP for later use, this limitation (which, again is not commensurate with the scope of claim 1) is clearly taught by Guarneri, who teaches that FDKP microcrystallites can optionally be isolated by spray drying or lyophilization (Example 1, [0070]). Therefore, it would have been obvious to one of ordinary skill to halt the process prior to introduction of the Treprostinil.
The declaration under 37 CFR 1.132 filed 04/21/2026 is insufficient to overcome the rejection of the instant claims, as set forth in the last Office action because: Applicant’s declaration amount to no more than reinstating the limitations of claim 1 and a statement that the claimed process has been employed for the last 6 years for the preparation of FDKP-TIP inhalable dry powder composition.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JACKSON J HERNANDEZ whose telephone number is (571)272-5382. The examiner can normally be reached Mon - Thurs 7:30 to 5.
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/JACKSON J HERNANDEZ/Examiner, Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627
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