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 .
Election/Restrictions
Applicant’s election without traverse of:
Group II (claims 50-55), drawn to a hydroxyl-terminated dendrimer comprising a triantennary N-acetylgalactosamine and a therapeutic agent conjugated to the dendrimer; and
Species (I): a small molecule in the reply filed on August 27, 2025 is acknowledged.
Because Applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse, see MPEP § 818.01(a).
Applicant’s election of Group II encompasses claims 50-55 and 57-62 as drawn to said hydroxyl-terminated dendrimer as discussed above. Additionally, Applicant’s election of the small molecule as the therapeutic agent encompasses claims 53-55, 57-58 and 60.
Thus, the Examiner respectfully notes the elected group and species as discussed above encompass claims 50-55 and 57-62 as discussed above.
Claims 63-65 are new and are drawn to a method of treating a liver disease or disorder by administering the dendrimer of claim 50.
Claims 63-65 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 August 27, 2025.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/943,705, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior-filed application '705 as discussed above does not provide support for a hydroxyl-terminated dendrimer comprising a triantennary N-acetylgalactosamine (GalNAc) and a therapeutic agent as recited in claim 50.
Thus, the Examiner reasonably interprets that claims 50-55 and 57-62 have a priority date of August 18, 2020.
Information Disclosure Statement
The Information Disclosure Statements (IDS) filed on 03/27/2023 and 08/27/2025 have been considered by the Examiner inasmuch as foreign documents have been submitted into the file wrapper in English.
Claim Status
The claim set filed August 27, 2025 has been entered. Claims 1-49 and 56 are canceled. Claims 57-65 are new. Claims 63-65 are withdrawn from further consideration as being directed to a non-elected invention as discussed in the Election/Restrictions section above. Thus, claims 50-55 and 57-62 as presented are examined on the merits herein.
Claim Objections
Claims 55 and 62 are objected to because of the following informalities:
(I) Claim 55 recites “a death receptor 5 agonist” in lines 1-2 and then further recites “DR5 agonist”. The Examiner respectfully notes the recitation of “DR5” is an uncommon abbreviation. However, in the context of the claim the Examiner reasonably interprets the abbreviation corresponds to the recitation of the phrase “death receptor 5”.
Thus, to promote clarity the Examiner suggests replacing the recitation of “a death receptor 5 agonist” in lines 1-2 as discussed above with the phrase “a death receptor 5 (DP5) agonist”.
(II) Claim 62 recites “a structure of formula:” in lines 1-2 of the claim. However, the Examiner respectfully notes the recited phrase is grammatically incorrect when referring to the subsequent structure recited immediately after the phrase discussed above.
Thus, to promote clarity the Examiner suggests replacing the phrase “a structure of formula:” with the phrase “a structure of the following formula:”.
Appropriate correction is required.
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.
Claims 50-55 and 57-61 are rejected under 35 U.S.C. 103 as being unpatentable over El-Sayed et al. (Published 03 January 2013, US-20130004427-A1, IDS filed 03/27/2023) in view of Yang et al. (Published 10 June 2011, Cancer Chemotherapy and Pharmacology, Vol. 69, pp. 195-206, PTO-892) and Veronese et al. (Published 13 August 2012, BioDrugs, Vol. 22, Issue 5, pp. 315-329, PTO-892) as evidenced by Shin et al. (Published 22 March 1999, Bioorganic & Medicinal Chemistry Letters, Vol. 9, Issue 6, pp. 869-874, PTO-892).
Regarding claim 50, El-Sayed teaches dendrimer conjugates useful for liver specific delivery of therapeutic agents, see paragraph [0004].
El-Sayed teaches in FIG. 14, a synthetic scheme for coupling Tri-Gal-PEG chains to G5 for hepatic cell targeting, see paragraph [0077].
El-Sayed exemplifies the structure
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178
327
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, see sheet 24 of 57, Fig. 14, last recited compound. The Examiner respectfully notes the exemplified structure above is a hydroxyl-terminated dendrimer comprising a triantennary N-acetylgalactosamine (GalNAc) (e.g. the dendrimer required in claim 50, lines 1-2).
The Examiner respectfully notes the exemplified structure above contains a cis-aconityl linkage (e.g. an acid-labile linkage, as taught by El-Sayed, see Figure 33) connecting G5 which is the generation 5 PAMAM dendrimer as disclosed by El-Sayed (e.g. generation 5 poly(amidoamine) dendrimer, required in claim 61), see paragraph [0028]; with the PEG (e.g. polyethylene glycol) linker (e.g. the at least one of the first and second linkers comprise polyethylene glycol, required in claim 51), and wherein the Examiner further notes after the PEG linker there is an amide bond (e.g. the at least one of the first and second linkers comprise an amide bond, required in claim 52).
El-Sayed teaches the dendrimer conjugate comprises a PEG chain, which, optionally is associated with the dendrimer through an acid hydrolysable linkage (e.g. the cis-aconityl linkage discussed in the exemplified structure of El-Sayed above), see paragraph [0021]. El-Sayed teaches in some aspects the PEG chain comprises two ends (e.g., termini) where a first end is (directly or indirectly) attached to the dendrimer and a second end is (directly or indirectly) attached to one or more tissue-specific targeting molecules (e.g. wherein the first linker is attached to a different terminal group on the dendrimer to form an ether linkage between each linker and the dendrimer, required in claim 50, lines 4-5), see paragraph [0021].
El-Sayed exemplifies a liver-specific targeting molecule is N-acetyl-galactosamine (GalNAc), see paragraph [0020]. The Examiner respectfully notes the N-acetyl-galactosamine (GalNAc) exemplified within the structure above is the one or more tissue-specific targeting molecules as taught by El-Sayed above.
El-Sayed teaches in an exemplary embodiment the dendrimer conjugate comprises a hepatic-tumor targeting molecule; and to functionalize these dendrimer conjugates the surface NH2 groups of the dendrimer are pegylated, see paragraph [0161].
El-Sayed exemplifies a PAMAM dendrimer (Gn) comprising a trigalactose-functionalized PEG brush called Gn-(PEG-triNAcGal)M. El-Sayed further exemplifies said trigalactose-functionalized PEG brush as Gn-(PEG-triNAcGal)1-50%, see Table 1, pg. 7, right column, line 6.
The Examiner respectfully notes said dendrimer may comprise between 1-50% of triNAcGal (e.g. less than 30% of terminal groups on the dendrimer comprise a terminal carbohydrate, required in claim 59).
El-Sayed teaches the functionalized dendrimer conjugates wherein about 0% to about 25% of the polymer surface NH2 groups contain PEG chains, see paragraph [0162].
Therefore, in view of the teachings of El-Sayed discussed above, the Examiner respectfully notes the combined teachings of El-Sayed teach a dendrimer comprising a plurality of terminal (i) hydroxyl groups and (ii) carbohydrate moieties wherein at least one comprises the triantennary GalNAc as required in instant claim 58.
Although, El-Sayed does not teach a small molecule DR5 agonist is conjugated to the dendrimer through a second linker wherein the second linker is attached to a different terminal group on the dendrimer to form an ether linkage between each linker and the dendrimer, required in claim 50, lines 3-5; claims 53-55, claims 57-58 and claim 60.
However, in the same field of endeavor of liver specific delivery of therapeutic agents, Yang teaches 5,7-dimethoxyflavone sensitizes TRAIL-induced apoptosis through DR5 upregulation in hepatocellular carcinoma cells (HCC) (e.g. the small molecule DR5 agonist, required in claim 53-55 and claim 57), see pg. 195, title.
Yang teaches human hepatocellular carcinoma cell lines Hep3B, Huh-7, and Hep G2 and human embryo liver L-02 cells were tested, see pg. 195, abstract, methods, paragraph 1.
Yang teaches the results demonstrated subtoxic concentrations of DMF sensitize HCC cells to TRAIL-induced apoptosis and induce the death receptor 5 (DR5) expression level, see pg. 195, abstract, results, paragraph 1.
Additionally, Veronese teaches the impact of PEGylation on biological therapies, see pg. 315, title.
Veronese teaches the term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug, see pg. 315, abstract, paragraph 1.
Veronese teaches in order to benefit from these favorable pharmacokinetic consequences, a variety of small molecule drugs have been PEGylated (e.g. the therapeutic agent is conjugated to the dendrimer through a second linker wherein the second linker is attached to a different terminal group on the dendrimer to form an ether linkage between each linker and the dendrimer, required in claim 50, lines 3-5), see pp. 315-316, abstract, paragraph 1.
With respect to limitation (a) a plurality of terminal drug moieties, wherein at least one drug moiety comprises the therapeutic agent”, required in claim 58, lines 5-6; and limitation (b) “less than 30% of terminal groups on the dendrimer comprise a terminal drug moiety”, required in claim 60, the Examiner reasonably interprets both of these limitations as physical limitations that are well within the scope of the artisan as the combined teachings of Yang and Veronese discussed above teach a pegylated 5,7-dimethoxyflavone; and where El-Sayed teaches the functionalized dendrimer conjugate is pegylated, contains PEG chains on about 0% to about 25% of the dendrimer polymer surface NH2 groups, and wherein the dendrimer conjugate is useful for liver specific delivery of therapeutic agents as discussed above.
With respect to limitation (c), “the therapeutic agent is a small molecule having a molecular weight of less than 2,500 Daltons”, required in claim 57; Shin discloses compound 8, where the Examiner respectfully notes compound 8 corresponds to 5,7-dimethoxyflavone. Shin disclosed the molecular weight of compound 8 is 282. See pg. 870, scheme 1, compound 8 and pg. 871, Table 1, compound 8.
The Examiner further reasonably interprets the molecular weight of 5,7-dimethoxyflavone disclosed by Shin as compound 8 above includes the unit of Daltons. Therefore, the Examiner reasonably interprets the molecular weight of 5,7-dimethoxyflavone is 282 Daltons.
Thus, it would have been prima facie obvious to one of ordinary skill in the art before the invention was filed to have incorporated the teachings of Yang and Veronese as discussed above into the dendrimer-drug conjugate as taught by El-Sayed above as within the scope of the artisan as simple additions according to known methods to yield predictable results. One of ordinary skill in the art would have been motivated to provide dendrimer conjugates useful for liver specific delivery of therapeutic agents as taught by El-Sayed above.
One of ordinary skill in the art would have had a reasonable expectation of success of incorporating the teachings of Yang and Veronese as discussed above into the dendrimer-drug conjugate of El-Sayed, as Veronese teaches a variety of small molecule drugs have been PEGylated and El-Sayed teaches the functionalization of these dendrimer-drug conjugates where the NH2 groups on the surface of the dendrimer are pegylated as discussed above.
Thus, the claimed invention as a whole would have been prima facie obvious over the combined teachings of the prior art.
Allowable Subject Matter
Claim 62 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: The teachings of El-Sayed do not teach wherein the triantennary GalNAc comprises a structure of the following formula as recited in claim 62; nor would it be obvious based on the teachings of El-Sayed to restrict the dendrimer of instant claim 50 to comprise a triantennary N-acetylgalactosamine of the structure recited in instant claim 62.
As allowable subject matter has been indicated, applicant's reply must either comply with all formal requirements or specifically traverse each requirement not complied with. See 37 CFR 1.111(b) and MPEP § 707.07(a).
Conclusion
No claims are allowed in this action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARET J CREWS whose telephone number is (571)270-0962. The examiner can normally be reached Monday-Friday: 9:00am-5:30pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARET J CREWS/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691