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 .
Status of Application, Amendments and/or Claims
The amendment, filed 31 May 2022, has been entered in full. Claims 1-17 are canceled. New claims 18-37 are added.
Applicant’s election of Group I (claims 18-31 and 35-37, drawn to a nanoparticle comprising a nanomaterial and at least a first ligand and a second ligand) in the reply filed on 07 November 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 (MPEP § 818.01(a)).
Claims 32-34 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected Group, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07 November 2025.
Claims 18-31 and 35-37 are under examination.
Foreign Priority
Acknowledgment is made of Applicant's claim for foreign priority under 35 U.S.C. 119(a)-(d). The certified copy EPO 19219424.9 (filed 12/23/2019) has been placed of record in the file.
Information Disclosure Statement
The information disclosure statement(s) (IDS) (filed 16 November 2022) was received and complies with the provisions of 37 CFR §§1.97, 1.98 and MPEP § 609. It has been placed in the application file and the information referred to therein has been considered as to the merits.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they include the following reference character(s) not mentioned in the description: The Figures teach Figure 24 (a), (b) and (c). The Brief Description of the Figures does not recite Figure 24 (c). Please see page 23.
Corrected drawing sheets in compliance with 37 CFR 1.121(d), or amendment to the specification to add the reference character(s) in the description in compliance with 37 CFR 1.121(b) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
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 18-31 and 35-37 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 18 is indefinite because of the recitation, “..first ligand is capable of mediating an attachment..” and “..second ligand is capable of mediating an internalization..”. The word “capable” means “having the ability”. However, it is unclear if the ligands actually “mediate an attachment” and “mediate an internalization”.
Claims 19-31 and 35-37 are included in this rejection insofar as they depend from claim 18 and do not resolve the issue discussed above.
Claims 19 and 24 are indefinite because they recite the acronyms “GPCR”, “PEG” and “PLA”, which have not been defined in the claims. The presence of an undefined acronym renders a claim indefinite. The Examiner notes that some of the acronyms are defined in claim 35. Nonetheless, acronyms should be defined upon their first use in a claim.
Claims 36 and 37 are indefinite because of the current recitation. The Examiner request clarification regarding Claim 36 and Claim 37. Please see wherein the instant specification teaches “In one embodiment, said first ligand is a non-agonistic agent binding to a GPCR, such as angiotensin II receptor type 1 (AT1r), human neuropeptide Y1-receptor, and C-X-C chemokine receptor type 4, and/or an agent binding to glycoprotein and/or glycolipid on a target cell surface, such as a heparan sulfate, a sialoglycoprotein, a ganglioside, and a mannose receptor, preferably is EXP3174 or telmisartan” [paragraph 0013].
Please see the instant specification which teaches “..a ligand such as Ang-II binds to a target, such as the AT1R, and, as an agonist, triggers cell uptake of particles upon receptor binding” [paragraph 0045].
Please see wherein the instant specification teaches, “In one embodiment, said second ligand is any of i) an agent binding to an integrin, such as αVβ3 integrin or αVβ5 integrin, preferably selected from RGD, a cyclic RGD-peptide having a sequence of SEQ ID NO. 1, and derivatives thereof, ii) an agonistic agent binding to a GPCR such as AT1r, preferably activated angiotensin-II, iii) an agent binding to an ectoenzyme, such as legumain, a membrane-type matrix metalloproteinase, and angiotensin converting enzyme (ACE), preferably angiotensin-I, and/or iv) an agent binding to a transferrin-receptor ” [paragraph 0014].
It appears that instant Claim 36 incorrectly states that the first ligand are the particular molecules recited, instead of a ligand/agent that binds the particular molecules recited in Claim 36.
The Examiner notes that the limitation in Claim 37, “or an agent binding to a transferrin-receptor”, appears to be correct because it is the ligand/agent that is the actual second ligand (for example transferrin) NOT the transferrin-receptor. However, the rest of Claim 37 appears to incorrectly state that the second ligand are the particular molecules recited, instead of a ligand/agent that binds the particular molecules.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
1. Claims 18-22, 25-28, 31, 35 and 37 are rejected under 35 U.S.C. 102(a1) as being anticipated by Xu et al. (Reference submitted by Applicant; Biomaterials 33:1627-1639; 2012).
Xu et al. teach a nanoparticle, comprising a nanomaterial and at least a first ligand and a second ligand, wherein said first ligand is capable of mediating an attachment of said nanoparticle to a target cell, and wherein said second ligand is capable of mediating an internalization of said nanoparticle into said target cell (abstract).
Xu et al. teach wherein said first ligand is an arginine-glycine-aspartic acid (RGD) tripeptide proved to be an efficient binding motif to assist interactions between drug delivery systems including nanoparticles and some integrins. Xu et al. teach that various peptides containing RGD sequence have been developed to be ligands for a5b3 integrin in therapeutical applications (pages 1627-1628)(i.e. RGD binds to a5B3 integrin which is a glycoprotein; applies to claims 18 and 19). Xu et al. teach wherein said second ligand is transferrin (pages 1627-1628)(i.e. an agent that binds to a transferrin-receptor)(applies to claims 18, 20 and 37). Xu et al. teach wherein said second ligand is enzymatically activated prior to said internalization of said nanoparticle into said cell (abstract, pages 1628 and 1637)(applies to claim 25). Xu et al. teach wherein the nanoparticle further comprises a therapeutic agent (i.e. paclitaxel)(abstract, pages 1627 and 1628). Xu et al. teach paclitaxel (PTX) as chemotherapeutic drug widely used to treat patients with lung, ovarian, breast cancer and advanced forms of Kaposi’s sarcoma (page 1627)(applies to claims 21 and 31). Xu et al. teach that drug-loaded nanoparticles (NPs) can be efficiently transported into the vascular endothelial cells and target tumor cells (abstract; pages 1628, 1630 and 1634)(applies to claim 26). Xu et al. teach wherein the nanomaterial comprises more than one block copolymer chain comprising polylactic acid (PLA)(abstract and page 1628)(applies to claim 35). Xu et al. teach wherein the first ligand and the second ligand are each coupled to said nanomaterial (page 1628). Xu et al. teach wherein the ratio of first ligand to second ligand is in the range of from 2:1 to 1:2 (page 1629, Figure 1)(applies to claims 22 and 28). Xu et al. teach wherein the nanoparticle size is from 5 nm to 1000 nm (page 1632, right column)(applies to claim 27).
Claim Rejections - 35 USC § 103
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.
1. Claims 18, 23, 24 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Biomaterials 33:1627-1639; 2012) in view of Liu et al. (Reference submitted by Applicant; Biomaterials 31:9145-9155; 2010).
Xu et al. teach a nanoparticle, comprising a nanomaterial and at least a first ligand and a second ligand, wherein said first ligand is capable of mediating an attachment of said nanoparticle to a target cell, and wherein said second ligand is capable of mediating an internalization of said nanoparticle into said target cell (abstract). Xu et al. teach wherein said first ligand is an arginine-glycine-aspartic acid (RGD) tripeptide proved to be an efficient binding motif to assist interactions between drug delivery systems including nanoparticles and some integrins. Xu et al. teach that various peptides containing RGD sequence have been developed to be ligands for a5b3 integrin in therapeutical applications)(i.e. RGD binds to a5B3 integrin which is a glycoprotein; applies to claim 18). Xu et al. teach wherein said second ligand is transferrin (pages 1627-1628)(i.e. an agent that binds to a transferrin-receptor; applies to claim 18). Xu et al. teach wherein the nanomaterial comprises more than one block copolymer chain comprising polylactic acid (PLA)(abstract and page 1628).
Xu et al. do teach wherein the nanomaterial comprising more than one block copolymer chain comprises polyethylene glycol (PEG). Xu et al. do teach wherein the nanoparticle has a ligand density of ligand/PEG of at least 5% or that the first ligand is coupled to a first block copolymer chain, which is longer than the second block copolymer chain which is coupled to a second ligand.
Liu et al. teach tailoring of the functional nanocarriers depends on the selection
of matrix materials as well as functionalization of surface property. Liu et al. teach that a good example is to use poly (lactide-coglycolide)(PLGA), one of the FDA approved biodegradable polymers widely applied in the drug delivery realm, as the core of the NPs and polyethylene glycol (PEG), a water soluble polymer widely used to enhance biocompatibility and circulation half-life as well as to make nanocarriers escape from being recognized and eliminated by the reticuloendothelial system (RES). Another example is to use a copolymer between poly-lactic acid (PLA) and D-alpha-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS)(page 9146, left column).
Liu et al. teach that the control of the ligand density on the nanoparticles (NPs) surface exerts the carriers in a more precise manner as well as facilitates the balance between tissue penetration and cellular uptake, resulting in optimal therapeutic efficacy. Liu et al. teach there are two strategies developed for quantitative control of the targeting
effects by adjusting the ligand density on the nanoparticle surface through varying the copolymer ratio in the nanoparticle matrix consisting of two copolymers with one of a linker molecule for ligand conjugation, which is called the pre-conjugation and the post-conjugation respectively, i.e. to conjugate the ligand to the linker molecule before or after the nanoparticle formulation. Liu et al. teach that for the post-conjugation strategy, the drug-loaded nanoparticles are firstly prepared with the two copolymer blend such as PLA-TPGS and TPGS-COOH. The nanoparticles are then functionalized by the ligand such as Herceptin or folic acid. Liu et al. teach in the present study, the feasibility of the post-conjugation strategy for quantitative control of the targeting effect by controlling the ligand density on the nanoparticle surface is demonstrated. Liu et al. teach that surface density
of the ligand molecules can be precisely controlled by adjusting the blend ratio of the two copolymers in the polymeric matrix (page 9146, right column).
Liu et al. teach ligand density on the NP surface is achieved by using various ratios of PLGA-PEG over PLGA and providing different amounts of the antibody in the Herceptin-nanoparticle conjugation (page 9147, first paragraph, left column). Liu et al. teach wherein PEG is in a range of from 1K to 20K and wherein PLA is in a range of from 5K to 40K (page 9147, left column, 2nd paragraph)(applies to claim 24). Liu et al. teach one block-copolymer chains wherein a first ligand is coupled to the first block-copolymer chain of said nanomaterial and a second ligand is coupled to a second block-copolymer chain of said nanomaterial, and wherein said first block-copolymer chain is longer than said second block-copolymer chain. Liu et al. teach nanomaterials comprising PEG and wherein said nanoparticle has a ligand density of ligand/PEG of at least 5 % (page 9149-page 9150 and Figures 2, 3 and 4 (applies to claims 23 and 30).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a nanoparticle comprising nanomaterial block copolymer chains comprising polylactic acid (PLA), an RGD ligand and a transferrin ligand, as taught by Xu et al., by using nanomaterial comprising polyethylene glycol (PEG), wherein the nanoparticle has a ligand density of ligand/PEG of at least 5%, as taught by Liu et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications for the following reasons.
Liu et al. teach polyethylene glycol (PEG) is a water soluble polymer widely used to enhance biocompatibility and circulation half-life as well as to make nanocarriers escape from being recognized and eliminated by the reticuloendothelial system (RES). Liu et al. teach examples of nanomaterial comprising a copolymer between poly-lactic acid (PLA) and D-alpha-tocopheryl polyethylene glycol 1000 succinate (PLA-TPGS). Liu et al. teach that the control of the ligand density on the nanoparticles (NPs) surface exerts the carriers in a more precise manner as well as facilitates the balance between tissue penetration and cellular uptake, resulting in optimal therapeutic efficacy. Liu et al. teach the surface density
of the Herceptin ligand on the nanoparticles (NPs) was controlled by using various ratio of
PLGA-PEG over PLGA and different initial amount of the antibody while fixing the ratio of PLGA-PEG over PLGA. Based on the teachings, it would be obvious to have a ligand density of ligand/PEG of at least 5%.
1a. Claims 29 is rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Biomaterials 33:1627-1639; 2012) in view of Liu et al. (Biomaterials 31:9145-9155; 2010), as applied to claims 18, 23, 24, and 30 above, and further in view of Henning et al. (Nanoparticle multivalency counterbalances the ligand affinity loss upon PEGylation. Journal of Controlled Release 194:20–27; 2014).
The teachings of Xu and Liu are described above. The references do not teach avidity or wherein the nanoparticle has a particle avidity for a targeted receptor of from 1 pM to 100 nM. The references do not teach wherein nanoparticles can comprise nanomaterial such as Qdots.
Henning et al. teach how PEGylation influences a ligand’s affinity and how nanoparticles are able to compensate for this loss of affinity. Henning et al. teach that nanoparticles are able to reach out to several receptors simultaneously due to the multiple
presentation of ligand molecules on the nanoparticle surface (page 20). Henning et al. teach using EXP3174, which is a ligand that binds G-protein coupled receptor angiotensin II receptor type 1 (AT1R). Henning et al. compare the receptor affinity of both the native ligand and the PEGylated ligand to the ligand's affinity when conjugated to multivalent nanoparticles. Henning et al. teach EXP3174 is coupled to PEGylated nanoparticle Quantum dots (Qdots)(page 21)(applies to claim 35). Henning et al. teach analyzing the affinity of both ligand-modified and non-modified Qdots by intracellular calcium quantifications with AT1R-expressing rat mesangial cells. Henning et al. teach in intracellular calcium measurements, the ligand-modified Qdots regained a nanomolar IC50 of 2.46 ± 0.02 nM, which is an affinity increase of a factor of 252 compared to the monovalent PEGylated ligand (Fig. 4a)(page 23, right column, last paragraph)(applies to claim 29). Henning et al. teach the enhanced affinity of the EXP3174-Qdots compared to the mPEG-EXP3174 can be explained by multivalent ligand–receptor interactions, where one nanoparticle binds several receptors simultaneously. Henning et al. teach that multivalent enhancement is described for several nanoparticle platforms including Qdots, dendrimers, polymeric or gold nanoparticles (page 24).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a nanoparticle comprising nanomaterial and ligands, wherein the nanomaterial comprises more than one block copolymer chain comprising polylactic acid (PLA) or wherein the nanomaterial comprises more than one block copolymer chain comprising polyethylene glycol (PEG), as taught by Xu and Liu, respectively, wherein the nanoparticle has a particle avidity for a targeted receptor of from 1 pm to 100 nM, as taught by Henning et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications for the following reasons.
Henning et al. discuss avidity and PEGylation on targeted nanoparticles. Henning et al. teach camouflaging nanoparticle surfaces by PEGylation or other measures is essential to avoid the uptake of nanoparticles by the mononuclear phagocyte system (MPS). However, with the introduction of polyethylene glycol (PEG) strands on its surface, the interaction between a nanoparticle and its target cell can be severely hampered. Henning et al. teach few reports address the effect of PEGylation on ligand receptor affinity. Henning et al. teach regaining ligand receptor affinity with a nanomolar IC50 that was in the range from 1.0 pM to 100 nM by multivalent ligand–receptor interactions, where one nanoparticle binds several receptors simultaneously. Henning et al. teach multivalent enhancement can be employed by several nanoparticle platforms including Qdots, dendrimers, polymeric or gold nanoparticles. Based on the teachings, it would be obvious to have nanoparticles wherein the particle avidity for a targeted receptor is in the range from 1.0 pM to 100 nM.
2. Claims 18 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Xu et al. (Biomaterials 33:1627-1639; 2012) in view of Zhang et al. (US 2010/0203142; published August 12, 2010).
Xu et al. teach a nanoparticle, comprising a nanomaterial and at least a first ligand and a second ligand, wherein said first ligand is capable of mediating an attachment of said nanoparticle to a target cell, and wherein said second ligand is capable of mediating an internalization of said nanoparticle into said target cell (abstract). Xu et al. teach wherein said first ligand is an arginine-glycine-aspartic acid (RGD) tripeptide proved to be an efficient binding motif to assist interactions between drug delivery systems including nanoparticles and some integrins. Xu et al. teach that various peptides containing RGD sequence have been developed to be ligands for a5b3 integrin in therapeutical applications (i.e. RGD binds to a5B3 integrin which is a glycoprotein; applies to claim 18). Xu et al. teach wherein said second ligand is transferrin (pages 1627-1628)(i.e. an agent that binds to a transferrin-receptor; applies to claim 18).
Xu et al. do not teach a nanoparticle comprising a nanomaterial wherein the ligand is a sialoglycoprotein.
Zhang et al. teach a nanoparticle comprising nanomaterials and targeting moieties/ligands (abstract). Zhang et al. teach that the nanoparticle can comprise nanomaterials polyethylene glycol (PEG) and (poly(lactic-co-glycolic acid)(PLGA)(para 0011). Zhang et al. teach that the nanoparticle can have any variety of targeting moieties, such as nucleic acid aptamers, growth factors, hormones, cytokines, interleukins, antibodies, integrins, fibronectin receptors, p-glycoprotein receptors, peptides and cell binding sequences (para 0014 and claim 30) (i.e. fibronectin receptors are sialoglycoproteins; applies to claim 36).
It would have been obvious for one of ordinary skill in the art before the effective filling date to modify a nanoparticle comprising nanomaterial block copolymer chains comprising polylactic acid (PLA), an RGD ligand and an transferrin ligand, as taught by Xu et al., by using a sialoglycoprotein, such as a fibronectin receptor, as a ligand, as taught by Zhang et al. One of ordinary skill in the art before the effective filing date, would have been motivated to make such modifications for the following reasons.
Xu et al. teach the RGD peptide binds to a5b3 integrin. Xu et al. teach that histological analysis of breast cancer biopsy tissue shows that a5b3 integrin is an important marker of blood vessels in the most malignant tumors, making it an attractive target for anti-angiogenesis strategy. Xu et al. teach that transferrin (Tf) is transported into cells through a receptor-mediated endocytosis via the transferrin receptor (TfR). Xu et al. teach that many studies have indicated that the expression level of TfR on tumor cells is much higher than that on normal cells, which has been widely utilized for targeting drug delivery systems as a novel potential approach. Fibronectin receptors, as taught by Zhang et al., are another type of integrin receptor that may be important in targeting tumors by binding to upregulated, tumor-specific isoforms of fibronectin.
Conclusion
No claims are allowed.
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/R.M.D/Examiner, Art Unit 1647 1/28/2026
/BRIDGET E BUNNER/Primary Examiner, Art Unit 1647