DETAILED CORRESPONDENCE
Application Status
1. The present application is being examined under the pre-AIA first to invent provisions.
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/19/2026 has been entered.
3. Applicant’s amendment to the claims filed on 05/19/2026 in response to the Final Rejection and Advisory Action mailed on 02/19/2026 and 04/28/2026, respectively, is acknowledged. This listing of claims replaces all prior listings of claims in the application.
4. Claims 1-16 are pending.
5. Claims 1-11 stand withdrawn pursuant to 37 CFR 1.142(b).
6. Applicant’s remarks filed on 05/19/2026 in response to the Final Rejection and Advisory Action mailed on 02/19/2026 and 04/28/2026, respectively, have been fully considered and are deemed persuasive to overcome at least one of the rejections and/or objections as previously applied.
The text of those sections of Title 35 U.S. Code not included in the instant action can be found in the prior Office Action.
Claim Rejections - 35 USC § 112(b)
7. The rejection of claims 12-16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for lack of antecedent basis is withdrawn in view of applicants’ amendment to the claims.
Claim Rejections - 35 USC § 112(a)
8. The new matter rejection of claims 12-16 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, is withdrawn in view of applicants’ amendment to the claims.
Claim Rejections - 35 USC § 103
9. The rejection of claims 12-16 under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Oberg (US Patent No. 7,799,344, 2010; cited on PTO-892 mailed on 11/19/2024) in view of Hokenson et al. (US Patent Application Publication 2008/0260838 A1; cited on PTO-892 mailed on 11/19/2024), Leone-Bay et al. (US Patent Application Publication 2006/0040953 A1; cited on PTO-892 mailed on 11/19/2024), and Malakhov et al. (US Patent Application Publication 2009/0098207 A1; cited on PTO-892 mailed on 11/19/2024) is maintained for the reasons of record and the reasons set forth below. The rejection has been modified in order to address applicants’ amendment to the claims.
10. As amended, claims 12-16 are drawn to a method of treating a diseases or disorder in a patient in need thereof comprising administering to said patient an inhalable dry powder by oral inhalation, said administering comprising providing a drug delivery system comprising a dry powder inhaler and a single dose cartridge comprising an inhalable dry powder formulation comprising precipitated microparticles comprising assemblages of crystalline plates having irregular surfaces of 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine and internal voids, and an active agent prone to rapid degradation as a result of exposure to liver metabolism, wherein said active agent is entrapped within the interior voids of the microparticles by the precipitation process and said active agent comprises 15% by weight of the microparticles, said inhalable dry powder provided in a dose 0.01 mg to 3 mg in said single dose cartridge, wherein 35% to 75% of the microparticles of the dry powder formulation that are delivered to the pulmonary alveoli upon being administered have an aerodynamic diameter less than 5.8 m, and wherein said active agent comprises a PG-I2, and wherein said precipitation process comprises pH controlled precipitation of a 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine acid at an acidic pH, and wherein the active agent is present during precipitation and entrapped under acidic conditions.
11. With respect to claim 12, Oberg et al. teach methods for treating a disease or disorder comprising administering a drug delivery system comprising crystalline microparticles with a diameter of 0.5 – 1000 m comprising diketopiperazine such as 3,6-di(4-aminobutyl)-2,5-diketopiperazine and 3,6-bis(N-fumaryl-N-(n-butyl)amino-diketopiperazine and an active agent (pharmaceutical substance) comprising GLP-1, monoclonal antibody or insulin [see column 1; column 5, lines 32-34, 48-49, claims 13, 18, 24, 29, column 4, line 51; column 15, lines 11-12]. Per applicants’ disclosure, these are all active agents that are considered to be rapidly metabolized or degraded. Oberg further teach that the crystalline particles are acid precipitated by acetic acid at pH 3.6 and form as plates with two large, flat faces and narrow edges [see column 11, lines 11-12; column 13, bottom]. Although Oberg does not explicitly teach that the crystalline plates comprise internal voids, this feature is considered to be inherent to the microparticles of Oberg given that paragraph 0054 of the disclosure states that the microparticles can be assemblages of crystalline plates with irregular surfaces and internal voids as is typical of those made by pH controlled precipitation of DKP acids. Oberg et al. teach the method wherein the crystalline particles are acid precipitated by acetic acid at pH 3.6 and form as plates with two large, flat faces and narrow edges (interpreted as pH controlled precipitation) [see column 11, lines 11-12; column 13, bottom]. Oberg et al. teach suspending the microparticles in an acidic solution, adding the active agent and then raising the pH. Alternatively, Oberg et al. teach the pH of the suspension can be raised prior to the addition of the active agent [column 8]. It is also of note that the limitation “said precipitation process comprises pH controlled precipitation of a 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine acid and the active agent at an acidic pH, and wherein the active agent is present during precipitation and entrapped under the acidic conditions” are “product-by-process” limitations. MPEP 2113 states "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
With respect to claim 13, Oberg et al. teach the method wherein the formulation further comprises a sugar [see column 4, lines 30-35].
With respect to claims 14 and 15, Oberg et al. teach the method wherein the wherein the X is fumaryl [see column 5, lines 32-34, 48-49, claims 13, 18, 24, 29, column 4, line 51; column 15, lines 11-12].
With respect to claim 16, Oberg et al. teach the method wherein the diketopiperazine is a pharmaceutically acceptable salt [see column 5, bottom].
However, Oberg does not teach the method wherein the dry powder formulation, dry powder inhaler and a single dose cartridge for oral inhalation, wherein the pharmaceutical substance comprises a PG-I2 and said active agent comprises 15% by weight of the microparticles.
Hokenson et al. teach GLP-1 particles in combination with diketopiperazine for pulmonary delivery, wherein diketopiperazone has the formular 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine, wherein X is fumaryl, wherein the composition provides a stable formulation that is resistant to degradation for use in the treatment of diseases such as diabetes, cancers and obesity [see paragraphs abstract, 0009-0010, 0078, 0094, 0096]. Hokenson et al. teach precipitation methods wherein the diketopiperazine incorporates GLP-1 molecules (embedded) at 15% concentration [see paragraphs 0065, 0095]. Hokenson et al. further teach a dry powder inhaler in the form of single dose cartridges to deliver the particle via oral inhalation to specific area of the respiratory system at a dosage of 0.08 mg, which is within applicants’ claimed range [see paragraphs 0009, 0031, 0106, 0172, 0248 claims 13, 21].
Leone-Bay et al. teach biologically active agent delivery compositions comprising diketopiperazine [see Abstract] having greater solubility at neutral and acidic pH [see paragraph 0004] and further teach that microparticles of size 0.1 to 10 m in diameter exhibit desirable size distributions as well as good cargo tolerance wherein 44.5% of the composition is the bioactive agent [see Abstract; paragraphs 0054, 0073, 0078, 0100; Table 3].
Malakhov et al. teach microsphere compositions comprising a prostaglandin, PG I2, for oral inhalation delivery that are administered in single dosage form, and further teach that microparticle compositions further comprising sugars that play a role in increasing the stability of the dry powder microparticle formulation for use in the treatment of diseases [see paragraphs 0037, 0040, 0046, 0040, 0136, 0138, 0145, 0152, 0496, 0505, 0699; claims 16 and 28]. Per applicants’ disclosure, prostaglandin is an active agent that considered to be rapidly metabolized or degraded as a result of exposure to peripheral tissue, vascular venous tissue, or liver metabolism.
Before the effective filing date of the claimed invention, it would have been obvious for one of ordinary skill in the art to combine the teachings of Oberg et al., Hokenson et al., Leone-Bay et al. and Malakhov et al. in a method of administering a drug delivery system for oral inhalation comprising 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine and a pharmaceutical substance comprising a prostaglandin because Oberg et al., Hokenson et al., and Leone-Bay et al. all teach drug delivery compositions comprising diketopiperazine for oral inhalation delivery to be used a therapeutic that offers stability and greater solubility at neutral and acid pH. Malakhov et al. teach similar compositions that can be used for inhalation delivery of prostaglandins for therapeutic purposes. One of ordinary skill in the art would have had a reasonable expectation of success and a reasonable level of predictability to combine the teachings of Oberg et al., Hokenson et al., Leone-Bay et al. and Malakhov et al. because Oberg et al., Hokenson et al., Leone-Bay et al. all acknowledge the advantages of diketopiperazine for use in microparticles for drug delivery systems for therapeutic purposes and Malakhov et al. acknowledges that prostaglandins can be formulated into microparticles for oral inhalation delivery for therapeutic purposes. Therefore, the above invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
RESPONSE TO REMARKS: Beginning on p. 5 of applicants’ remarks, applicants in summary contend that the rejection is improper because the claim requires entrapment of the prostaglandin at an acidic pH and that Malakhov teaches away from exposing prostaglandins to acidic precipitation environments because PG-12 is unstable at acidic pH.
These arguments are found to be not persuasive in view of the modified rejection above. As stated above, limitation “said precipitation process comprises pH controlled precipitation of a 2,5-diketo-3,6-di(4-X-aminobutyl)piperazine acid and the active agent at an acidic pH, and wherein the active agent is present during precipitation and entrapped under the acidic conditions” are “product-by-process” limitations. MPEP 2113 states "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985)”.
Even so, the examiner maintains the position in the advisory action mailed on 04/28/2026 that Oberg already contemplates the situation wherein the active agent is unstable at acidic pH. Oberg et al. teach suspending the microparticles in an acidic solution, adding the active agent and then raising the pH. Alternatively, Oberg et al. teach the pH of the suspension can be raised prior to the addition of the active agent [column 8]. As stated in the Advisory Action mailed on 04/28/2026, applicants are invited to provide evidence that the prostaglandin in said microparticles is indeed stable in the precipitation at acidic pH given the instability of prostaglandin at low pH.
Double Patenting
12. The nonstatutory double patenting rejection of claims 12-16 over claims 1-21 of U.S. Patent No. 8,372,804 is maintained for the reasons already of record set forth in the Non-Final Rejection mailed on 11/19/2024.
RESPONSE TO REMARKS: Beginning on p. 15 of applicants’ remarks, applicants request that the rejections be held in abeyance until claims are allowable. Accordingly, the rejections are maintained for the reasons already of record.
Conclusion
13. Status of the claims:
Claims 1-16 are pending.
Claims 1-11 stand withdrawn pursuant to 37 CFR 1.142(b).
Claims 12-16 are rejected.
No claims are in condition for an allowance.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PAUL J HOLLAND whose telephone number is (571)270-3537. The examiner can normally be reached Monday to Friday from 8AM to 5PM.
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/PAUL J HOLLAND/Primary Examiner, Art Unit 1656
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