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 .
Current Status
This action is responsive to the amended claims of 08/05/2025. Claims 1 and 3-42 are pending. Claim 2 has been canceled. Claims 13-42 are withdrawn. Claims 1 and 3-12 have been examined on the merits.
Election/Restrictions
Recall, Applicant’s election without traverse of Group I (claims 1 and 3-12) in the reply filed on 03/31/2025.
Applicants further elected the species: generation 4-6 predominantly hydroxyl terminated PAMAM that is covalently conjugated to DPTIP.
A search for Applicants elected species returned prior art, thus the Markush search was not previously extended. The amendment and arguments of 08/05/2025 do not overcome the pending prior art rejection of the elected species. Thus, the Markush search has not been extended.
Applicants elected species reads on claims 1 and 3-12.
Claims 13-42 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 03/31/2025.
Priority
The effective filing date remains 04/24/2020.
Response to Arguments
Examiner acknowledges receipt of and has reviewed the amendments and remarks of 08/05/2025, no new matter is found.
The objection to the specification is withdrawn because Applicant has amended the specification to remove the browser-executable code.
The objections to claims 1-12 are withdrawn due to Applicants amendments: the punctuation and spelling objections in claims 1, 7, and 10 have been resolved.
The 102 rejection of claims 1 and 6-10 over KANNAN, evidenced by TARDIOLO, is withdrawn due to Applicant’s amendments. Applicant has defined the therapeutic agent of claim 1 as an agent that inhibits/reduces neutral sphingomyelinase 2; the compound of KANNAN does not have this property.
The two 103 rejections of 05/06/2025 have been modified in view of Applicant’s amendments to claims 1; in particular, the addition of the phrase “the composition is in an effective amount” for the treatment of certain diseases or associated inflammation which was not previously recited in any of the examined claims. Further, Applicant's arguments filed 08/05/2025 have been fully considered but they are not persuasive. Applicant argues that the combination of WAYNE, NANCE, and ROJAS (which form the basis of both pending rejections) does not provide a reasonable expectation of success in achieving the claimed subject matter for the following reasons.
First, Applicant argues that DPTIP, as shown in the specification Pg. 61-62, has poor oral bioavailability, limited brain penetration, and fast clearance. Despite extensive experimentation, analogs with improved bioavailability could not be identified; only upon incorporation into the dendrimer was the bioavailability and brain penetration improved. Further, the claimed invention selectively accumulates in the brain tissue.
Examiner does not find this line of reasoning persuasive for the following reasons. It seems the issue Applicant is addressing is optimizing delivery of the DPTIP/therapeutic agent to the brain. However, WAYNE teaches the same goal, an improved device for delivery of such small molecules. See Pg. 7 last para – Pg. 8 para 1 of the previous action (05/06/2025): “WAYNE teaches nanodevices comprising a dendrimer and a therapeutically active agent wherein the agent is attached or conjugated to PAMAM dendrimers (Pg. 18 Para 1)… WAYNE also teaches the nanodevice can selectively target microglia and astrocytes; after the nanodevice localizes at the microglia and astrocytes the agent is delivered near the site of localization enabling the nanodevice to locate and treat inflammation (Pg. 23 Para 2). WAYNE further teaches the nanodevices can preferentially cross the blood brain barrier only under diseased condition and are useful for targeted delivery of the therapeutics in neuro-inflammation (Pg. 18 Para 1).” Thus, WAYNE teaches a dendrimer device for improved and targeted delivery of therapeutics to the brain. With that teaching in mind, the artisan would easily recognize ROJAS’s molecule DPTIP, which while potent has relatively low brain penetration of AUCbrain/AUCplasma = 0.26 (Pg. 1 Abstract, see previous action at Pg. 8 para 3), as ripe for application within such a device as taught by WAYNE. Applicant’s statement that DPTIP has low bioavailability and poor brain penetration seems to align with such reasoning. Furthermore, the claimed compound is not an improved analog of DPTIP, but a dendrimer+small molecule device equivalent to that taught in WAYNE.
Second, Applicant argues that NANCE would not imbue the artisan with a reasonable expectation of success since NANCE teaches that in vivo dendrimer clearance is dependent on size, surface chemistry, and interior chemistry (see NANCE Pg. 606 Left col. para 2-3). Applicant argues the office action overlooks this teaching of NANCE and fails to articulate how the artisan would reasonably expect to generate the instant dendrimer+DPTIP conjugate with improved bioavailability. Applicant further cites to MPEP 2141.02(V) regarding inherency of properties under the obviousness analysis.
Examiner, respectfully, disagrees that WAYNE in view of NANCE would not provide a reasonable expectation of success. Both WAYNE and NANCE teach hydroxyl-termination of PAMAM-G4 dendrimers as preferred carriers (see Pg. 7-8 of previous action): “WAYNE teaches a series of nanodevices comprising G4-PAMAM-OH (i.e., hydroxyl-terminated) dendrimers conjugated by disulfide bond to small molecule therapeutics (Pg. 4 Para 2-7), i.e., covalently conjugated… NANCE teaches a hydroxyl-terminated G4 PAMAM dendrimer was administered to a healthy rat and readily cleared; however, when administered to a disease model rat there was significant uptake into activated microglia (Pg. 601 Left Col. Para 1).”
The artisan would understand hydroxyl-termination on the PAMAM dendrimers and the generation 4 (G4) structure to constitute size and surface/interior chemistry of the dendrimer nanodevice. Further, in view of the above teachings of WAYNE describing localization of the nanodevice at microglia/astrocytes/neuroinflammation and preferential crossing of the blood brain barrier in diseased condition (Pg. 23 Para 2 & Pg. 18 Para 1), the artisan would recognize that both WAYNE and NANCE teach hydroxyl-terminated G4 PAMAM dendrimer as a preferred carrier/device of small molecule therapeutics in microglial disease states. Furthermore, the cited portion of NANCE provides guidance as to a preferrable carrier in vivo (i.e., disease model rat). Moreover, while the instant claim 1 puts forth a use for treatment of certain diseases, in vivo administration is not required. Thus, WAYNE, supported by NANCE, points to a size and surface chemistry of PAMAM dendrimer that results in improved bioavailability via improved brain penetration/localization. Therefore, the artisan would have a reasonable expectation of success in view of the combined references.
Furthermore, Examiner notes that, at least, instant claims 1 and 3 do not structurally define the dendrimer+therapeutic agent device. Thus, these claims are drawn to a diverse array of sizes and surface/interior chemistries.
Finally, Examiner does not agree with the inherency argument put forth by Applicant because: 1) Examiner did not rely on an inherency argument within the pending rejection and 2) WAYNE and NANCE (as shown above) together teach improved and preferential blood brain barrier penetration using the hydroxyl-terminated G4 PAMAM dendrimer. Thus, the feature/property of the claimed invention is taught by the combined references.
The three obviousness-type nonstatutory double patenting rejections are withdrawn: claims 1 and 6-9 over U.S. Patent No. 10,561,673; claims 1 and 6-9 over U.S. Patent No. 10,369,124; and claims 1 and 6-9 over U.S. Patent No. 8,889,101. Claim 1 has been amended to include the limitation of now canceled claim 2. None of the patent documents are drawn to dendrimer conjugates with therapeutic agents that inhibit or reduce neutral sphingomyelinase 2. Since the independent claim now requires the therapeutic agent either inhibit or reduce neutral sphingomyelinase 2, the double patenting rejections no longer read on the claims.
Claim Rejections - 35 USC § 103 – Necessitated by Amendment
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.
Claims 1 and 3-9 are rejected under 35 U.S.C. 103 as being unpatentable over WAYNE (WO 2010/147831, cited in IDS 04/12/2023), NANCE (Nance et al., Journal of Internal Medicine, 2014, 276, 579-617, cited in IDS 04/12/2023), and ROJAS (Rojas et al., Scientific Reports, 2018, 8, 1-11, cited in IDS 04/12/2023).
Determining the Scope and Contents of the Prior Art:
WAYNE teaches nanodevices comprising a dendrimer and a therapeutically active agent wherein the agent is attached or conjugated to PAMAM dendrimers (Pg. 18 Para 1). WAYNE teaches the PAMAM dendrimer can have hydroxyl terminations and can be generation 4, 5, or 6 (Pg. 18 Last Para). WAYNE teaches a series of nanodevices comprising G4-PAMAM-OH (i.e., hydroxyl-terminated) dendrimers conjugated by disulfide bond to small molecule therapeutics (Pg. 4 Para 2-7), i.e., covalently conjugated.
WAYNE also teaches the nanodevice can selectively target microglia and astrocytes which play a key role in neurodegenerative disease; after the nanodevice localizes at the microglia and astrocytes the agent is delivered near the site of localization enabling the nanodevice to locate and treat neuroinflammation (Pg. 23 Para 2). WAYNE further teaches the nanodevices can preferentially cross the blood brain barrier only under diseased condition and are useful for targeted delivery of the therapeutics in neuro-inflammation (Pg. 18 Para 1).
NANCE teaches a hydroxyl-terminated G4 PAMAM dendrimer was administered to a healthy rat and readily cleared; however, when administered to a disease model rat there was significant uptake into activated microglia (Pg. 601 Left Col. Para 1). NANCE further teaches a clinically used small molecule was conjugated to the dendrimer producing a nanodevice with sustained drug release for up to 90 days (Pg. 601 Left Col. Para 1).
ROJAS teaches brain inflammation induces extracellular vesicles (EV) release from astrocytes and suppression of this release by neutral sphingomyelinase 2 inhibition is a new therapeutic strategy (Pg. 1 Abstract). ROJAS teaches DPTIP is a potent (IC50 30 nM), selective, metabolically stable, and brain penetrable (AUCbrain/AUCplasma = 0.26) neutral sphingomyelinase 2 inhibitor that inhibits EV release by astrocytes (Pg. 1 Abstract). ROJAS teaches limitations of previous neutral sphingomyelinase 2 inhibitors are low potency and limited brain penetration and that DPTIP overcomes these limitations (Pg. 2 Para 1). ROJAS further teaches in a mouse model of brain inflammation that recapitulates features of neurodegenerative diseases (i.e., neurological disease and inflammation associated therewith), DPTIP effectively inhibited EV release (Pg. 2 para 1).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
WAYNE does not teach the G4-6 hydroxyl-terminated PAMAM dendrimers are conjugated to DPTIP.
NANCE does not teach the composition of instant claim 1.
ROJAS does not teach the DPTIP is conjugated to a G4-6 hydroxyl-terminated PAMAM dendrimer.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a composition useful for treatment of neuroinflammation and possesses the technical knowledge necessary to make adjustments to the composition to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding decreasing secretion of EVs (exosomes) by inhibition of neutral sphingomyelinase 2 and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references WAYNE, NANCE, and ROJAS.
The artisan would be motivated to covalently conjugate G4-6 PAMAM hydroxyl-terminated dendrimers to DPTIP in order to develop a composition useful for treatment of neuroinflammation. The artisan would find it obvious to substitute one functional equivalence (therapeutics in neuro-inflammation (Pg. 18 Para 1 WAYNE)) with another (DPTIP (Pg. 1 Abstract ROJAS)), since both are taught for the same purpose/function. The artisan would be motivated, with an expectation of success, since:
1) WAYNE teaches the dendrimers localize at astrocytes (Pg. 23 Para 2) and are useful for targeted delivery of neuro-inflammation therapeutics (Pg. 18 Para 1); and
2) ROJAS teaches DPTIP overcomes limitations of previous neutral sphingomyelinase 2 inhibitors (Pg. 2 Para 1), inhibits EV release by astrocytes and penetrates the blood brain barrier as a therapy for brain inflammation (Pg. 1 Abstract).
Thus, the artisan would recognize the compatibility of ROJAS’s DPTIP with WAYNE’s PAMAM-dendrimer nanodevice. This is particularly true in view of the fact that, while DPTIP is taught as improving upon previous neutral sphingomyelinase 2 inhibitors (Pg. 2 Para 1), the brain penetration score is still relatively low (AUCbrain/AUCplasma = 0.26) (Pg. 1 Abstract). Thus, the targeted delivery of WAYNE’s device would be understood as useful for optimization/enhancement of neuroinflammation treatment by DPTIP.
The artisan would be further motivated, with an expectation of success, to utilize hydroxyl-terminated G4-PAMAM dendrimers to develop an improved composition since NANCE teaches hydroxyl-terminated G4-PAMAM is preferentially taken up in disease models of neuroinflammation (vs. healthy) and conjugation with a small molecule therapeutic produced a nanodevice with sustained drug release (Pg. 601 Left Col. Para 1). Thus, NANCE teaches a hydroxyl-terminated G4-PAMAM+small molecule therapeutic device was successfully used as a therapeutic in vivo.
Finally, the artisan would be motivated to include an effective amount of the dendrimer+DPTIP conjugate in the composition in order to effectively treat a neurological disease and/or inflammation associated therewith. The artisan would have an expectation of success in the composition being effective for such a treatment since:
1) ROJAS teaches DPTIP inhibited EV release in a mouse model of brain inflammation/neurodegenerative diseases (Pg. 2 para 1), wherein EV release is a result of brain inflammation and is a therapeutic target (Pg. 1 Abstract); and
2) WAYNE teaches the dendrimer nanodevice selectively targets microglia and astrocytes involved in neurodegenerative disease enabling the nanodevice to locate and treat neuroinflammation (Pg. 23 Para 2).
Thus, the artisan would expect the dendrimer+DPTIP conjugate from combination of WAYNE and ROJAS, particularly utilizing a hydroxyl-terminated G4-PAMAM dendrimer in view of NANCE’s teachings discussed above, to be effective for treatment of neurological disease and/or inflammation associated therewith. Thus, it would be obvious for the artisan to include an effective amount of such a device within a composition thereof.
Claims 1 and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over WAYNE (WO 2010/147831, cited in IDS 04/12/2023), NANCE (Nance et al., Journal of Internal Medicine, 2014, 276, 579-617, cited in IDS 04/12/2023), and ROJAS (Rojas et al., Scientific Reports, 2018, 8, 1-11, cited in IDS 04/12/2023) as applied to claim 1, further in view of CHAUDHARI (Chaudhari et al., IJAPBC, 2012, 1(1), 21-34, provided by Examiner 05/06/2025).
Determining the Scope and Contents of the Prior Art:
WAYNE, NANCE, and ROJAS teach the composition of instant claim 1 (see above 103 rejection).
WAYNE further teaches the nanodevices can be administered via parenteral and oral route either by itself or as a part of a formulation such as hydrogels, nanoparticle or microparticles, suspensions, powders, tablets, capsules, and solutions (Pg. 18 Lines 11-14).
CHAUDHARI teaches excipients play an important role in formulating a dosage form (Pg. 1 abstract) and are added along with active pharmaceutical ingredients to support or enhance formulation stability and increase patient acceptance (Pg. 1 Intro Left Col.). CHAUDHARI teaches excipients must be inert to the human body and nontoxic (Pg. 22 Right Col. Para 3), i.e., pharmaceutically acceptable.
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
WAYNE, NANCE, and ROJAS do not teach the composition further comprises a pharmaceutically acceptable excipient.
CHAUDHARI does not teach the composition of instant claim 1.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of a composition useful for treatment of neuroinflammation and possesses the technical knowledge necessary to make adjustments to the composition to optimize/enhance the treatment outcomes. Said artisan has also reviewed the problems in the art regarding pharmaceutical acceptability of compositions and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references WAYNE, NANCE, ROJAS, and CHAUDHARI.
Regarding claim 10, the artisan would find it obvious to include a pharmaceutically acceptable excipient within the composition comprising the nanodevice, G4-6 hydroxyl-terminated PAMAM dendrimer conjugated to DPTIP, made obvious by WAYNE, NANCE, and ROJAS (above 103). The artisan would be motivated to do so in order to support stability of the composition and/or improve patient acceptance of the composition, in view of CHAUDHARI (Pg. 1 Intro Left Col.). The artisan would have an expectation of success since WAYNE teaches the nanodevice may be administered as part of a formulation (Pg. 18 Lines 11-14), i.e., further comprising other compounds. The artisan would expect the excipients to be pharmaceutically acceptable since CHAUDHARI teaches excipients must be inert and nontoxic (Pg. 22 Right Col. Para 3).
Regarding claims 11-12, the artisan would find it obvious for the composition to be in the form of hydrogels, nanoparticle or microparticles, suspensions, powders, tablets, capsules, and solutions for parenteral or oral administration, in view of WAYNE (Pg. 18 Lines 11-14), i.e., WAYNE teaches these as acceptable forms/paths to administer the composition, thus, there is an expectation of success.
Conclusion
Claims 1 and 3-12 are rejected.
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.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625