DETAILED CORRESPONDENCE
Application Status
1. The present application is being examined under the pre-AIA first to invent provisions.
2. Applicant’s amendment to the claims filed on 01/12/2026 in response to the Non-Final Rejection mailed on 10/10/2025 is acknowledged. This listing of claims replaces all prior listings of claims in the application.
3. Claims 1-16 are pending.
4. Claims 1-11 stand withdrawn pursuant to 37 CFR 1.142(b).
5. Applicant’s remarks filed on 01/12/2026 in response to the Non-Final Rejection mailed on 10/10/2025 have been fully considered and are deemed not persuasive to overcome 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)
6. 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.
7. Claims 12-16 are newly 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. This new grounds of rejection is necessitated by applicants’ amendment to the claims to recite the limitation “within the interior volume of the microparticles”.
Regarding claim 12, there is insufficient antecedent basis for the limitation “the interior volume”, and further it is unclear what the metes and bounds of the term “interior volume” is intended to encompass. The examiner has reviewed the specification and found no such disclosure of what is intended to be encompassed by the interior volume of the microparticle. It is suggested that applicants clarify the meaning of the claims.
Claim Rejections - 35 USC § 112(a)
8. 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.
9. Claims 12-16 are newly 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 new grounds of rejection is necessitated by applicants’ amendment to the claims to recite the limitation “within the interior volume of the microparticles”.
MPEP § 2163.11.A.3.(b) states, "when filing an amendment an applicant shouldshow support in the original disclosure for new or amended claims" and "[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description". According to MPEP § 2163.I.B, "While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure" and "The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as nowclaimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117".
In the instant case, claim 12 (claims 13-16 dependent therefrom) recite the limitation “said active agent is entrapped within the interior volume of the microparticles”. The examiner has reviewed the specification and found no such disclosure of “within the interior volume of the microparticles” in view of the 112(b) rejection above. As such, the new limitation constitutes new matter.
Claim Rejections - 35 USC § 103
10. 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.
11. 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 volume 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.
12. 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].
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: Applicants’ remarks filed on 01/12/2026 have been fully considered by the examiner. Applicants’ remarks repeat prior arguments of record, and as such, the remarks are found to be not persuasive for the reasons already of record and the reasons set forth below. The amendment to the claims does not further change the scope of the claims from what has already been presented by prior amendments and the teachings of the prior art and reasons for combining the prior art of record is still applicable to the amended claims [see above].
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). The claims require that the active agent comprise prostaglandin, which the rejection already states that Oberg et al. does not teach wherein the active agent is prostaglandin (not an antibody or insulin); however, this limitation is met by the teachings of Malakhov et al. [see rejection above]. The recitation of “wherein said active agent is prone to rapid degradation as a result of exposure to peripheral tissue, vascular venous tissue or liver metabolism” merely recites a correlation between the structure of the active agent, in this case prostaglandin, and its susceptibility to rapid degradation. Nevertheless, Oberg et al. does teach other active agents prone to rapid degradation such as GLP-1 that is not an antibody or insulin.
Applicants further contend that the person of ordinary skill in the art would not combine the references in the manner claimed without using improper hindsight reasoning and the cited references do not teach or suggest the instant claims. Applicants’ allege that Malakhov teaches away from the instant claims in that Malakhov stresses the advantage of providing microparticles that are predominantly composed of the active agent itself. Additionally, applicants contend that Malakhov appears to provide no data regarding the effectiveness of its prostaglandins compositions and that forming a prostaglandin particle differs from developing an effective prostaglandin pharmaceutical composition because Malakhov describes particles predominantly composed of the active agent that do not provide protection to active agents susceptible to rapid degradation.
These arguments are found to be not persuasive because it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning but so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Furthermore, 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). Also, the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). To this end, diketopiperazine has been well documented as a microparticle drug delivery system through oral inhalation as evidenced by the teachings of Oberg et al., Hokenson et al., and Leone-Bay et al. Given that Malakhov et al. teach oral inhalation delivery of microsphere containing prostaglandins, one of ordinary skill in the art would have a reasonable level of predictability that prostaglandins could also be combined with diketopiperazine delivery systems. This analysis is consistent with MPEP 2143, which states, “[t]he Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.... Examples of rationales that may support a conclusion of obviousness include: (A) Combining prior art elements according to known methods to yield predictable results; (B) Simple substitution of one known element for another to obtain predictable results”. In the instant case, combining the prior art elements of Oberg et al., Hokenson et al., and Leone-Bay et al. with Malakhov et al. and/or simple substitution of one known element with another would yield predictable results. Additionally, Hokenson et al. in paragraph 0095 teach that various methodologies may be employed wherein diketopiperazines can be formed into particles that incorporate GLP-1 molecules or particles onto which GLP-1 molecules can be adsorbed, which may involve mixing of the diketopiperazine solutions with solutions or suspensions of GLP-1 molecules followed by precipitation. Hokenson et al. clearly makes a distinction between GLP-1 molecules embedded in diketopiperazine and adsorbed to the surface and contemplates both types of embodiments.
Regarding applicants’ remarks that Malakhov teaches away from the claimed microparticles because Malakhov stresses the advantage of providing microparticles that are predominantly (if not entirely) composed of the active agent itself, this argument is found to be not persuasive because as stated above, 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). Hokenson et al. disclose the desire of high concentration of the active agent in the FDKP particles at 15% concentration of active agent [see paragraphs 0065, 0095, 0152-0156 of Hokenson et al.].
Regarding applicants’ remarks that Malakhov does not provide any teaching as to the effectiveness of the prostaglandin pharmaceutical composition in providing protection to rapid degradation, this argument is found to be not persuasive because as stated above, diketopiperazine has been well documented as a microparticle drug delivery system through oral inhalation as evidenced by the teachings of Oberg et al., Hokenson et al., and Leone-Bay et al. Given that Malakhov et al. teach oral inhalation delivery of microsphere containing prostaglandins, one of ordinary skill in the art would have a reasonable level of predictability that prostaglandins could also be combined with diketopiperazine delivery systems. In the instant case, combining the prior art elements of Oberg et al., Hokenson et al., and Leone-Bay et al. with Malakhov et al. and/or simple substitution of one known element with another would yield predictable results. Hokenson et al. disclose that diketopiperazine particles provide improved stability [see paragraphs 0015-0016].
Double Patenting
13. 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
14. 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.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 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