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 .
Priority
This application, filed 01/13/2023 is a National Stage entry of PCT/US2021/042097, International Filing Date: 07/16/2021. PCT/US2021/042097 Claims Priority from Provisional Application 63053228, filed 07/17/2020.
Status of Claims
Claims 42 and 60-77 are pending as of the response filed on 12/24/25. Claims 1-41 and 43-59 have been canceled.
Applicant’s election without traverse of invention I, drawn to a composition and a kit, encompassed by claims 60-71 in the reply filed on 12/24/25 is acknowledged.
Claims 42 and 72-77 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 12/24/25.
Claims 60-71 were examined and are rejected.
Claim Rejections-35 USC § 112
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.
Claims 65-67 are 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.
Claim 65 depends directly from claim 64, and recites the PPAR agonist is conjugated to the dendrimer through a linker attached to the terminal group. However, claim 64 requires the PPAR agonist to be conjugated to the dendrimer by an ether linkage formed by the terminal group of the dendrimer. The language of claim 64 doesn’t allow for an additional linker, as the PPAR agonist must be directly bonded to the dendrimer by an ether linkage to the terminal group of the dendrimer. The metes and bounds of the claim as such aren’t clear, and the claim is indefinite. Claims 66-67 are similarly rejected as these claims depend directly or indirectly from claim 64 and don’t provide further clarity.
To provide compact prosecution, the claims have been examined as if an additional linker is present between the terminal group of the dendrimer and the PPAR agonist.
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.
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.
Claim(s) 60 and 70-71 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bharatam et. al., J. of Nanosci. & Nanotechnol., vol. 6, pp. 3277-3282, publ. 2006.
Bharatam teaches glitazones as PPARγ agonists that function as insulin sensitizers in the treatment of type 2 diabetes (abstract). Bharatam teaches dendrimers as nanoparticles with notable potential for drug delivery due to characteristics of high degree of branching, multivalences, globular architecture, and well-defined molecular weight (p. 3277, 1st para). Bharatam teaches incorporation of glitazones with dendrimers can enhance the delivery of these agents (abstract), and provides examples of known PEGylated (poly ethylene glycol) PAMAM (polyamidoamine) dendrimers, including PAMAM dendrimers covalently linked to a therapeutic via an amide linker (p. 3277, 1st para). Bharatam also teaches other known dendrimers include G5 (generation 5) PAMAM, and dendrimers capped with 2,3-dihydroxypropyl groups (pp. 3277-3278, bridging para).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have arrived at the claimed composition comprising a PPAR agonist conjugated to a dendrimer via an amide linkage, wherein the dendrimer comprises a plurality of terminal hydroxyl groups in consideration of Bharatam. Bharatam teaches glitazones as PPAR agonists used in the treatment of type 2 diabetes, and that dendrimers can be used to improve delivery of these agents. Bharatam further provides examples of known dendrimers conjugated to therapeutic agents, including PEGylated (poly ethylene glycol) PAMAM (polyamidoamine) dendrimers linked to a therapeutic via an amide linker, G5 PAMAM dendrimers, and dendrimers capped with 2,3-dihydroxypropyl groups. Therefore, one of ordinary skill in the art would have been motivated to have arrived at a composition comprising a dendrimer, such as a PEGylated (poly ethylene glycol) PAMAM (polyamidoamine) dendrimer or G5 PAMAM capped with 2,3-dihydroxypropyl groups linked to a PPARγ agonist, a glitazone, with a reasonable expectation of success in order to enhance delivery of the glitazone for enhancing the sensitivity to insulin.
Claim(s) 60-61, 64-68, and 70-71 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan et. al., US 20170119899 A1, publ. 5/4/2017 (cited in an IDS).
Kannan teaches composition and methods for treating or alleviating one or more symptoms associated with axonal degeneration, wherein the composition comprises one or more poly(amidoamine) (PAMAM) dendrimers of generation 1-10 (G1-G10) complexed with a therapeutic, prophylactic, and/or diagnostic agent (title & abstract; para [0003]). Kannan teaches the compositions allow for targeted delivery of therapeutics, e.g., to affected neurons, as well as for targeted delivery of therapeutics in inflammatory disorders (abstract; para [0010-0011], [0062]). Kannan further teaches the compositions have utility for treating peroxisomal disorders (para [0012]). Peroxisomal disorders are further taught to include treatment of symptoms of these disorders, such as cystic kidneys (para [0151]). The dendrimers are preferably G4-G6, with exemplary and preferred therapeutic agents for conjugation to the dendrimer taught to include pioglitazone (para [0013], [0068]). Pioglitazone is a PPAR-γ agonist for the treatment of diabetes which has been shown to block axonal damage in mice (para [0085-0087]). Kannan teaches the PAMAM preferably has carboxylic, hydroxyl, or amine terminal groups, wherein the dendrimer is linked to a therapeutic agent via disulfide, ester, or amide bonds (para [0063]). Kannan teaches each dendrimer of the complex can be of similar or different chemical nature, e.g., one dendrimer being a PAMAM, while the other being polypropylamine, polyethyleneimine, polylysine, polyester, aliphatic poly(ether), etc. (para [0035-0036]). Kannan further teaches the therapeutic agent can be attached to the dendrimer via a PEG spacer (para [0058-0059]). Kannan teaches the compositions to further comprise a pharmaceutically acceptable carrier (para [0031], [0120]). Kannan provides an example wherein the number of terminal hydroxyl groups on the dendrimer prior to conjugation with a therapeutic is 64, and the number of terminal hydroxyl groups on the dendrimer after conjugation is 42 (pp. 5-6, see Scheme 5); therefore, conjugation with the therapeutic occurs on about 34% of total available terminal hydroxyl groups (22/64 =34.4%). Kannan teaches medical kits containing a pharmaceutical composition as described above, along with instructions for administration (para [0173]).
One of ordinary skill in the art, before the effective filing date of the claims would have found it prima facie obvious to have arrived at the composition of the instant claims comprising a dendrimer having a plurality of terminal hydroxyl groups conjugated to a PPAR agonist such as pioglitazone via an ester, ether, or amide linkage, in consideration of Kannan. Kannan teaches compositions comprising one or more poly(amidoamine) (PAMAM) dendrimers of generation 1-10 (G1-G10) complexed with a therapeutic agent, with the PPAR agonist, pioglitazone, taught as a preferred agent. Kannan further teaches dendrimers having a plurality of terminal hydroxyl groups, dendrimers containing a spacer, such as PEG (e.g., ether linkage) between the therapeutic agent and dendrimer, as well as amide and ester linkages between the dendrimer and therapeutic. Kannan teaches the compositions for treating symptoms of inflammatory and peroxisomal disorders, and kits comprising the compositions with instructions for administration. As such, one of ordinary skill in the art would have arrived at the composition of the instant claims in consideration of Kannan and have had a reasonable expectation of success.
Kannan teaches kits comprising the compositions with instructions for use and administration, as well as unit dosages containing effective amounts of the conjugate (para [0127], [0166], [0173]). As Kannan includes cystic kidneys within the group of peroxisomal disorders, it would have been prima facie obvious to have arrived at a kit of instant claim 61 comprising a dendrimer having a plurality of terminal hydroxyl groups conjugated to the PPAR agonist, pioglitazone, along with instructions for administration for the treatment of cystic kidneys.
Claim(s) 62 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan et. al., US 20170119899 A1, publ. 5/4/2017 as applied to claims 60-61, 64-68, and 70-71 as discussed above, in view of Still et. al., Calcif. Tissue Int., vol. 83, pp. 285-292, publ. 2008.
The disclosure of Kannan as discussed previously is incorporated herein. In addition, Kannan includes the therapeutic bezafibrate for conjugation with a dendrimer, in particular via an ester linkage to a hydroxyl terminated PAMAM dendrimer (para [0068], [0076-0078], [0143], [0276-0286]).
Kannan doesn’t explicitly teach a PPAR-δ agonist as recited by claim 62.
Still teaches bezafibrate as a PPARα/δ agonist (see abstract).
As Kannan further includes bezafibrate as a preferred therapeutic agent for conjugation with a PAMAM dendrimer having a plurality of hydroxyl groups via an ester linkage, it would have been prima facie obvious to have arrived at a composition comprising the PPARα/δ agonist, bezafibrate, conjugated via an ester linkage to a PAMAM dendrimer having a plurality of hydroxyl groups, and have had a reasonable expectation of success.
Claim(s) 69 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan et. al., US 20170119899 A1, publ. 5/4/2017 as applied to claims 60-61, 64-68, and 70-71 as discussed above, in view of Rangaramanujam et. al., US 20190142964 A1, publ. 5/16/2019 (cited in an IDS).
The teachings of Kannan as discussed previously are incorporated herein. Although Kannan teaches conjugation with the therapeutic, e.g., PPAR agonist occurs on about 34% of total available terminal hydroxyl groups, it is not explicitly taught or suggested that conjugation occurs on less than 20% of terminal hydroxyl groups of the dendrimer prior to conjugation.
Rangaramanujam teaches low-generation dendrimers containing a high density of surface hydroxyl groups, such as at least one hydroxyl group/nm3, and conjugation of a therapeutic to the dendrimer (title & abstract; para [0014], [0017]). Dendrimers having a plurality of surface hydroxyl groups are preferred (para [0065]). Rangaramanujam teaches the dendrimers and compositions comprising the dendrimers provide targeted delivery to the CNS with little to no toxicity (para [0013]). Examples of suitable dendrimers include PAMAM, POPAM, polyester, polylysine, aliphatic poly(ether), among others (para [0046]). Rangaramanujam teaches the conjugation of therapeutic agents to dendrimers to occur via disulfide, ester, carbamate, amide, ether, or carbonate linkages (para [0069], [0072], [0076], [0140-0141]). A wide range of therapeutic agents are suitable for conjugation to dendrimers, with preferred active agents taught to include pioglitazone (para [0075], [0083]). Furthermore, conjugation of active agents or linkers occurs via about 1%, 2%, 3%, 4%, or 5% of total available dendrimer hydroxyl groups prior to conjugation (para [0146]).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have arrived at the claimed composition comprising a dendrimer having a plurality of terminal hydroxyl groups conjugated to a PPAR agonist such as pioglitazone, wherein conjugation to pioglitazone occurs on less than 20% of total available terminal groups of the dendrimer prior to conjugation, such as about 5% of total available hydroxyl groups, thereby meeting the limitation of instant claim 69. Kannan teaches dendrimer compositions comprising a dendrimer having a plurality of terminal hydroxyl groups conjugated via an ester, amide, or ether bond to a therapeutic agent, with the PPAR agonist, pioglitazone, exemplified. Rangaramanujam teaches highly similar dendrimer compositions, wherein the therapeutic agent, with pioglitazone included as a preferred agent, is conjugated to the dendrimer. Since Rangaramanujam teaches conjugation of active agents or linkers via about 1%, 2%, 3%, 4%, or 5% of total available dendrimer hydroxyl groups prior to conjugation, and as the dendrimers disclosed in both Kannan and Rangaramanujam are highly similar, it would have been prima facie obvious to have applied this percent of conjugation of the dendrimer to the compositions taught by Kannan, and have had less than 20% of total available surface hydroxyl groups of the dendrimer conjugated to the PPAR agonist.
Claim(s) 62-63 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kannan et. al., US 20170119899 A1, publ. 5/4/2017 as applied to claims 60-61, 64-68, and 70-71 as discussed above, in view of Kobayashi et. al., WO 2010110479, publ. 9/30/2010 (English translation referred to for discussion).
The disclosure of Kannan as discussed previously is incorporated herein. However, Kannan doesn’t explicitly teach indanyl acetic acid derivatives.
Kobayashi teaches indanylacetic acid derivative compounds as PPAR activators for the treatment of PPAR-mediated diseases (abstract; para [0001], [0003]). In particular, Kobayashi teaches the compounds as PPARδ agonists, with some compounds also possessing PPARα and/or PPARγ agonist activity, and that these agents have therapeutic utility for treating a variety of conditions such as malignant tumors, diabetes, obesity, hypercholesterolemia, heart failure, cardiovascular disease, Alzheimer’s disease and other neurodegenerative diseases, and other inflammatory diseases (p. 12 of 26; p. 24 of 26, Table 13; p. 26 of 26, claim 15).
It would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claims to have arrived at the composition of the instant claims comprising a dendrimer having a plurality of terminal hydroxyl groups conjugated to a PPARδ agonist, an indanylacetic acid derivative, wherein the conjugation is via an ester or amide linkage in consideration of the combined teachings of Kannan and Kobayashi.
Kannan teaches compositions for treating inflammatory and peroxisomal disorders comprising one or more PAMAM dendrimers having a plurality of surface hydroxyl groups conjugated via an ester or amide bond to a therapeutic agent, with the PPAR agonist, pioglitazone, exemplified as an agent. Kannan further teaches the conjugation of a therapeutic agent to a dendrimer allows for targeted delivery of the therapeutic. Kobayashi teaches indanylacetic acid derivative compounds as PPAR agonists, wherein the PPAR agonists are in particular PPARδ agonists, and that these agents have utility for treating neurodegenerative and inflammatory diseases. As such, one of ordinary skill in the art would have been motivated to have conjugated the indanyl acetic acid derivatives of Kobayashi to the PAMAM dendrimers taught by Kannan, for the purpose of provided targeted delivery of the compounds as needed, and have had a reasonable expectation of success.
Information Disclosure Statements
The IDS filed on 5/18/23, 10/6/23, and 12/24/25 have been considered.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH PIHONAK whose telephone number is (571)270-7710. The examiner can normally be reached Monday-Friday 9:00-5:30 EST.
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SARAH . PIHONAK
Primary Examiner
Art Unit 1627
/SARAH PIHONAK/Primary Examiner, Art Unit 1627