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 Claims
Amendment filed on 12/16/2025 is acknowledged.
Claims 1-96 remain cancelled. Claims 98-99, 101 and 108 are now canceled.
Claims 97, 100, 102-107 and 109-116 are amened. Claim 117 is new.
Claims 97, 100, 102-107, and 109-117 are pending and being examined herein on merits.
Priority
This instant application 18027346, filed on 03/20/2023, is a 371 of PCT/US2021051298, filed on 09/21/2021, which claims domestic benefit of 63081729, filed on 09/22/2020.
The Sequence Rules Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR §§ 1.821 through 1.825 for the reason(s) below:
The instant disclosure recites lists of sequences in the drawings, see for example, Figure 27 (last page), which are not identified by their corresponding SEQ ID Nos in the “BRIEF DESCRIPTION OF THE FIGURES AND TABLES” of the instant specification. Applicants are requested to amend the instant specification and/or claims accordingly.
Withdrawn Objections/Rejections
All previous claim Objection(s) / Rejection(s) as set forth in the previous Office action (mailed 6/16/2025) that are not repeated and/or maintained in the instant Office action are withdrawn, in light of applicant’s amendment and remark filed on 12/16/2025.
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.
Claim 97, 100, 102-107, and 109-117 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 97, the definition parentheses of “( )” is not clear, as the difference among “bonded directly”, “indirectly as a side chain”, or “as part of a side chain group to the adjacent S or H” is not clear. Does “bonded directly” mean that the drug forms part of the polymer backbone? The phrase “bonded indirectly as a side chain” indicates that additional moieties are present beyond the drug for this embodiment as otherwise the drug side chain would be directly connected to an adjacent S or H. The phrase “as part of a side chain group to the adjacent S or H” is also unclear, because if the side chain belongs to the S or H, and D is bonded as part of the side chain, the side chain with D is part of S or H, and it cannot be “to the adjacent S or H”. Therefore, the possible arrangement of elements when the “(D)” is used to define the claimed compounds is unclear.
Claim 117 recites “preferably”, this renders the claim indefinite, because it is unclear whether the limitation following such phrase is required feature or is merely exemplary. For the purpose of compact prosecution, the limitation led by “preferably” is interpreted as optional and it is not required feature.
The dependent claims 100, 102-107, and 109-116 are rejected coordinately for depending on a rejected claim, because each dependent claim does not clarify the issue in claim 97 as addressed above.
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.
Claims 97 and 109-116 are rejected under 35 U.S.C. 103 as being unpatentable over Fuks et al. (Chem Soc Rev, 2011, in record of 06/16/2025), in view of Hennink et al. (US20170231908, 08/17/2017) and Komatsu et al. (Polymer, 10/04/2017, in record of 06/16/2025).
Fuks directs to a review of micelles and vesicles made from block copolymers that are widely used as nanocarriers for drug delivery purposes (Pg. 2476), and lists numerous amphiphilic block copolymers (e.g., Abstract; Table 1, Pg. 2477), including those that comprise hydrophilic block such as PEG (polyethylene glycol), or PEO (polyethylene oxide) (Column 2 hydrophilic block, Table 1), and hydrophobic block such as poly(phenylalanine)<12, PBLG such as PBLG23 (which stands for poly(γ-benzyl-L-glutamate), or PZLL as poly(benzyloxycarbonyl L-lysine) (Column 1 hydrophobic block, Table 1).
Fuks shows many amphiphilic block copolymers comprising a hydrophilic block comprising a first hydrophilic monomer (corresponding to S in instant claim 97) and a hydrophobic block comprising a first hydrophobic monomer (e.g., glutamate or lysine) with second hydrophobic monomer constituting aromatic groups (e.g., benzyl or benzyloxycarbonyl groups) (e.g., Table 1) (corresponding to H in instant claim 97), exemplifying many hybrid micelles and triblock, such as PZLL-PEO-PEZLL (e.g., Pg. 2482, left column bottom), PZLL-DGBE-PZLL (DGBE = poly[diethyleneglycol-bis(3-aminopropyl)ether]) (Pg. 2484, right column top), each triblock constitutes a hydrophilic block (e.g., PEO or DGBE), and two hydrophobic monomers ZLL containing phenyl aromatic groups (corresponding to second hydrophobic monomer comprising phenyl aromatic group).
Fuks indicates that hydrophobic drug to be encapsulated can be dissolved into the cosolvent which provides an easy access to a satisfactory encapsulation ratio (Pg. 2482, left bottom), while the obvious advantage of using poly(amino acids) in micelle forming block copolymers is the presence of free functional groups (mostly amine or carboxylic acids) available for attachment of drugs and block copolymer-drug conjugates are especially desirable for the safe administration of highly cytotoxic drugs (e.g., Pg. 2488, left bottom), corresponding to D and its connection to S and H in instant claim 97, forming a compound, e.g., D-S-H, S(D)-H, S-H(D), D-S-H-S, D-S-H-S-D, S(D)-H-S, S(D)-H-S(D) or S-H(D)-S as in instant claim 97.
Fuks shows that thermoresponsive block copolymers can include poly(N-isopropylacrylamide) (same as PNIPAM), which is hydrophilic when temperature is at 25 °C (Table 1) and hydrophobic when temperature at 45 °C (Table 1). PNIPAM monomer N-isopropylacrylamide (NIPAM) has the structure of CH2=CH- C(O)-NHCH(CH3)2. Since PNIPAM can be used either as hydrophilic polymer or hydrophobic block in the copolymer (Table 1), the structure of PNIPAM corresponding to CH2=CH-C(O)-NHCH(CH3)2 of formula I wherein R2 is H, R1 is NHR3 and R3 is CH(CH3)2 instead of the claimed CH3 or CH2CH3; and corresponding to formula IV wherein R12 is H, R11 is NHR13 and R13 is CH(CH3)2 as recited in instant claim 97. Fuks shows PBLG (hydrophobic polybenzyl L-glutamate)-PNIPAM/PEO (hydrophilic) (Table 1), and teaches that at higher temperature, PNIPAM undergoes reversible self-association forming micelles or vesicles because PNIPAM has low LCST (Pg. 2487, left Col. 2nd paragraph), and it is hydrophobic at higher temperature (Table 1). Thus, Fuks teaches a triblock polymer at higher temperature comprising one hydrophilic block PEO, NIPAM monomer as the first hydrophobic polymer with the acrylamide of Formula IV, and BLG as the second hydrophobic monomer having phenyl aromatic group, corresponding to instant claim 97.
Fuks indicates that the combination of thermo-responsive synthetic block copolymers can form unimers or micelles (corresponding to particles) depending on temperature below or above transition temperature (Pg. 2487, left Col., 2nd paragraphs) (corresponding to instant claim 113). Fuks teaches that poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) copolymers conformation changes at low temperature 25 °C from a micelles with a PLGA (poly-L-glutamic acid, as hydrophilic polymer) core, in other words, a unimer status as hydrophilic micelles, to spontaneously revert to a PNIPAM core micelles (a hydrophobic particle status) at high temperature 45 °C (Pg. 2487, left Col. Bottom paragraph), with transition temperature range overlapping with 20 °C to 34 °C in instant claim 114. Fuks indicates that block copolymer micelles can solubilize hydrophobic drugs in their inner core and the micelles typical size range is 10-100 nm, sufficiently large to avoid renal excretion, yet small enough to bypass filtration by the spleen (Pg. 2488, top left) and the copolypeptide deblocks form stable vesicles of controllable diameter upon extrusion down to 50 nm (Pg. 2488, Right Col. 2nd paragraph) (overlapping with 30 nm to 80 nm particle diameter in instant claim 115).
Fuks provides anti-cancer drug delivery example using PLGA-PPO-PLGA and PEG-PPO hybrid block copolymers (Pg. 2486) and NK-12 or SN-38 using hydrophobic poly(glutamate) conjugated to PEG (Pg. 2488), and mentions that various drugs such as indomethacin (nonsteroidal anti-inflammatory drug), doxorubicin (DOX) (chemotherapy agent), clonazepam (seizure treatment) or norfloxacin (an antibiotic) were physically entrapped into the core of PEO-PBLA or of di- and tri-blocks of PEO and PBLG micelles (Pg. 2488) (corresponding to instant claim 116).
Fuks does not teach explicitly first hydrophobic monomer has to comprise methacrylates or methacrylamides or combinations thereof, and the second hydrophobic monomer has to comprise phenyl, fused phenyl, or heterocyclic aromatic groups, or combinations thereof, or the exact formula I of first hydrophilic monomer in instant claim 97, or the first hydrophilic monomer as 2-hydroxyethyl acrylate (HEA) as recited in instant claim 109, the degree of polymerization block ratio of hydrophilic block to hydrophobic block as 0.5:1 to 4:1 as recited in instant claim 110, the amphiphilic bock copolymer molecular weight as 5 kDa to 60 kDa as recited in instant claim 111, and Fuks also fails to teach the amphiphilic block copolymer exists as unimers at concentrations greater than 50 mg/mL in aqueous solutions while as particles at concentrations of less than or equal to 50 mg/mL as recited in instant claim 112.
Hennink throughout the reference teaches amphiphilic block copolymers for drug delivery (e.g., chemotherapy drug paclitaxel [0010]) comprising at least one hydrophilic block and at least one hydrophobic block, wherein the hydrophobic block is selected from the group consisting of acrylates, methacrylates, acrylamides, methacrylamides, and others and at least one hydrophobic block contains an acryl group (e.g., Abstract; Claim 1; Claims 16-17; [0008]), following the criteria, Hennink exemplifies polymer including mPEG-b-p(HPMAm-Bz30-co-HPMAm-Lac70) (e.g., Fig. 3; [0067]) and others [0068-0070] (corresponding to hydrophobic block first monomer and second monomer general features as recited in instant claim 97).
Hennink teaches hydrophilic block can be any suitable polymer, e.g., polyalkylene glycol such as PEG (e.g., [0038]), the micelles have a size 20-100 nm (e.g., [0046]; [0087] Table 1), delivering many drug molecules including antibiotics, peptides/proteins, and many categories of drugs (e.g., [0049]), for instance, dexamethasone (steroidal anti-inflammatory) (e.g., [0087] Table 1), overlapping with particle size in instant claim 115 and drug delivery profiles in instant claim 116. Hennink exemplifies polymer molecular weight as 22 kDa with hydrophilic 5 kDa and hydrophobic block 17 kDa [0057] or 48 kDa, 59 kDa and 32 kDa [0086] (reading into molecular weight of 5 kDa to 60 kDa in instant claim 111).
Hennink teaches that in Example 2, the empty micelles at a concentration of 27mg/ml [0059] in ~70-100 nm size [0063] processed to drug loading, results showing that drug feed concentration of 10 mg/ml has encapsulation efficiency at >80% [0064], which translates into >80% * 10 mg/ml = >8 mg/ml drug is loaded into the 27 mg/ml empty micelles, in other words, the particles are present at the concentration of >35 mg/ml (overlapping with less than or equal to 50 mg/ml in instant claim 112).
Komatsu throughout the reference teaches facile preparation of degradable thermoresponsive polymers as biomaterials: thermoresponsive polymers prepared by radical polymerization degrade to water-soluble oligomers (Title), indicating that the copolymer is valuable for use in functional biomedical materials, such as base of drug delivery carrier (Abstract).
Komatasu presents a novel thermoresponsive and biodegradable polymer, poly(MDO-co-HEA) prepared by radical copolymerization of 2-methylene-1,3,-dioxepane (MDO) and a hydrophilic vinyl monomer, 2-hydroxyethyl acrylate (HEA) (corresponding to instant claim 109, and corresponding to CH2=CH-C(O)-O-CH2-CH2-OH wherein R1 is OR3 while R3 is (CH2CH2O)iH when i is 1, as formula I in instant claim 97.
Komatsu teaches the synthesis of the amphiphilic block polymer MDO-co-HEA using feed molar ratio hydrophilic HEA to hydrophobic MDO when both are present as 85:15 ( 5.7 :1) , 80:20 (= 4:1), 70:30 (= 2.3 :1) , 60:40 (= 1.5:1), and the resulting in copolymer molecular weight of 50 kDa to 54 kDa (e.g., Table 1; Pg. 70, left Col. bottom paragraph), overlapping with the hydrophilic block to hydrophobic block ratio range of 0.5 :1 to 4:1 as recited in instant claim 110, and overlapping with molecular weight as 5 kDa to 60 kDa in instant claim 111.
It would have been prima facie obvious for one with ordinary skills in the art prior to filing date to incorporate the teaching from Hennink and Komatasu into the amphiphilic copolymers for drug delivery taught by Fuks to arrive at current invention. Because Fuks reviews various amphiphilic polymers that can be suitable for drug delivery systems, including hydrophobic block containing different functional monomers such as temperature-responsive monomers (Fuks indicates it can be advantageous in self-assembly into vesicles) and hydrophobic monomers comprising acrylate or acrylamide structure and aromatic group, combined with hydrophilic block polymers to be amphiphilic block copolymer as drug delivery carriers; meanwhile, Hennink teaches hydrophilic block can be any kind, emphasizing the hydrophobic block in the amphiphilic copolymer should be acrylate or acrylamide hydrophobic polymers with at least one hydrophobic block having aromatic group is advantageous for drug delivery, e.g., controlled release for active agents [0001], capturing hydrophobic drug in the micelles core in an aqueous environment [0002] with high stability of the loaded micelle and good retention of the drug [0003] avoiding disadvantages of covalent entrapment of the drug [0007]; in addition, Komatasu teaches HEA as hydrophilic block paired with MDO showing same thermos-responsive behavior as poly(N-isopropyl-acrylamide) (PNIPAAM, an acrylamide polymer) (Pg. 70, left-right Col.), it would flow logically to combine the teaching of these references to create the amphiphilic compound comprising the specific hydrophobic blocks as Hennink introduces and select hydrophilic HEA to remain the heat responsive behavior of the drug delivery compound. With all the advantages based upon prior art’s teaching, it would have provided reasonable expectation of success. It is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985). It is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use (MPEP §2144.07). See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). For this instance, the transition temperature, particle diameter, block ratios, molecular weight, and particle concentration overlap with those in prior art. Furthermore, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than “routine experimentation,” because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition (MPEP §2144.05 (II)). See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claims 97, 100, 102-104, 107, and 109-117 are rejected under 35 U.S.C. 103 as being unpatentable over Fuks et al. (Chem Soc Rev, 2011, in record of 06/16/2025), in view of Hennink et al. (US20170231908, 08/17/2017) and Komatsu et al. (Polymer, 10/04/2017, in record of 06/16/2025), as applied to claims 97 and 109-116 above, further in view of Kim et al. (US20130144023, 06/06/2013).
Fuks, Hennink and Komatsu teaches amphiphilic block copolymer compound comprising hydrophobic block and hydrophilic block for delivering directly- or indirectly bonded drugs, wherein the hydrophilic monomer can comprise acrylates or acrylamides of the formula I as defined in instant claim 97, e.g., HEA, hydrophobic block comprising a first hydrophobic monomer comprising acrylates or acrylamides of the formula IV as defined in instant claim 97, e.g., NIPAM, and second hydrophobic block monomer comprises aromatic groups, e.g., aryl, benzyl, as discussed and applied to claims 97 and 109-116 above and incorporated herein.
Fuks, Hennink and Komatsu does not expressly teach NIPMAM (N-isopropyl methacrylamide) as hydrophobic monomer in the copolymer compound as recited in instant claim 100 although teaching the closely related hydrophobic monomer NIPAM (N-isopropyl acrylamide), and prior art does not teach the second hydrophobic monomer can be benzyl methacrylamide (BnMAM) as recited in instant claim 102, Fuks, Hennink and Komatsu does not teach hydrophobic block comprising 70-85 mol% (or 80-99 mol%) of the first hydrophobic monomer and of 15 to 30 mol% (or 1 to 20 mol%) of the second hydrophobic monomer as recited in instant claim 104 (or instant claim 107, respectively), or the first hydrophobic monomer is NIPMAM and the second hydrophobic monomer is BnMAM as recited in instant claim 103, or the hydrophobic block comprising NIPMAM, NANPP, NVIBA, BEEP, or TEGMA, or combinations thereof, and preferably the first hydrophobic monomer is NIPAMAM, NANPP, NVIBA, BEEP or TEGMA as recited in instant claim 117.
Kim throughout the reference teaches an acrylic copolymer for optical films in which alkyl (meth)acrylate monomers; (meth)acrylate monomers comprising aromatic rings and/or aliphatic rings; and (meth) acrylamide-monomers are included and polymerized (Abstract).
Kim discloses that the acrylic copolymer comprises 50-98.9% by weight of alkyl (meth)acrylate monomers, 1 to 49.9% by weight of (meth)acrylate monomers comprising aromatic rings and/or aliphatic rings (Claim 8). If taking examples of first hydrophobic monomer as methyl methacrylate (MW 100 g/mol) when alkyl group has 1 carbon [0020] and second hydrophobic monomer as phenyl methacrylate (MW 162 g/mol) [0024], in a total amount 100 g hydrophobic block, the above weight percentage results in 0.5 – 0.985 mol of methyl methacrylate monomer and 0.006- 0.308 mol of phenyl methacrylate. So the first monomer can be 0.985/ (0.985+0.308) = 76.1 mol%, and second aromatic monomer can be 0.308/(0.985+0.308) = 23.8 mol%; or the first monomer can be 0.5/(0.5+0.006) = 99.8 mol%, second monomer can be at 0.006/(0.5+0.006) = 1.2 mol%, since both weight amounts are in a range, any numbers in between these mol% become possible. In other words, first monomer can be between 76.1 mol% to 99.8 mol%, and second aromatic monomer can be between 1.2 mol% to 23.8 mol% (overlapping to first and second hydrophobic monomer mol% ranges in instant claims 104 and 107).
Kim teaches many (meth)acrylamide monomers comprising aromatic rings and /or aliphatic rings are suitable for the copolymer composition [0024] and include N-substituted methacrylamide, and methacrylamide, examples of substituents may include ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl, and phenyl groups ([0026]; Claim 7). Therefore, Kim teaches N-isopropyl-methacrylamide (NIPMAM) (corresponding to instant claims 100, 103 and 107) when isopropyl is the substituent, which can be the first hydrophobic monomer in the copolymer; and also teaches benzyl methacryl-amide (BnMAM) when benzyl is the substituent, which can be the second hydrophobic monomer comprising a phenyl (corresponding to instant claims 102 and 103).
It would have been prima facie obvious for one with ordinary skill in the art prior to the filling date to incorporate the acrylic hydrophobic polymers taught by Kim into the block copolymer compound for drug delivery taught by Fuks, Hennink and Komatsu to arrive at instant invention. Because Fuks, Hennink and Komatsu establishes that the acrylic hydrophobic monomers with one of the hydrophobic monomer containing an aromatic ring is preferred, and Kim teaches both NIPMAM, benzyl meth-acrylamide, and many other methacrylate or methacrylamide comprising aromatic and/or aliphatic rings are suitable for the optical film that result in excellence in formability, adhesion, retardation properties, and durability, and with improved heat resistance while maintaining transparency (e.g., Abstract), it would have provided reasonable expectation of success for an artisan in the field to implement these polymer species for intended application of drug delivery using polymers as drug carrier, especially for applications like transdermal drug delivery system, which is one of the administration form indicated in instant specification. It is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). MPEP §2144.05(I) states that “A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). For this instance, first and second hydrophobic block molar amount overlaps with those disclosed in prior art. Furthermore, “[i]t would have been prima facie obvious for one of ordinary skill in the art to optimize additive amount through nothing more than “routine experimentation,” because of a reasonable expectation of success resulting from the optimization for desirable features of intended use of the composition (MPEP §2144.05 (II)). See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969).
Claims 97, 100, 102-107 and 109-117 are rejected under 35 U.S.C. 103 as being unpatentable over Fuks et al. (Chem Soc Rev, 2011, in record of 06/16/2025), in view of Hennink et al. (US20170231908, 08/17/2017) and Komatsu et al. (Polymer, 10/04/2017, in record of 06/16/2025), Kim et al. (US20130144023, 06/06/2013), as applied to claims 97, 100, 102-104, 107 and 109-117 above, further in view of Wakefield et al. (US20090048410, 02/19/2009).
Fuks, Hennink, Komatsu and Kim teaches amphiphilic block copolymer compound comprising hydrophobic block and hydrophilic block for delivering directly- or indirectly bonded drugs, wherein the hydrophilic monomer can comprise acrylates or acrylamides of the formula I as defined in instant claim 97, e.g., HEA, hydrophobic block comprising a first hydrophobic monomer comprising acrylates or acrylamides of the formula IV as defined in instant claim 97, e.g., NIPAM, NIPMAM, and second hydrophobic block monomer comprises aromatic groups, e.g., BnMAM (having benzyl aromatic group), as discussed and applied to claims 97, 100, 102-104, 107 and 109-117 above and incorporated herein.
Kim indicates that examples of substituents of the N-substituted methacrylamide may include ethyl, isopropyl, tert-butyl, cyclohexyl, benzyl, and phenyl groups. However, the substituents of the N-substituted methacrylamide are not limited thereto [0026].
Combined teaching of Fuks, Hennink, Komatsu and Kim fails to teach the second hydrophobic monomer comprising a fluorinated aromatic ring, or a fused aromatic ring, or combinations thereof as recited in instant claim 105, or the second hydrophobic monomer as N-3,4,5-trifluorobenzyl methacrlyamide, N-2,3,4,5,6 pentafluorobenzyl methacrlyamide, N-trifluoromethylbenzyl methacrylamide or N-bitrifluoromethyl-benzyl methacrlyamide as recited in instant claim 106.
Wakefield directs to membrane active heteropolymers useful for cellular delivery of compounds (Abstract) such as polynucleotides, proteins, antibodies, and membranes impermeable drugs [0012], comprising a plurality of amine-containing monomers, a plurality of first hydrophobic monomers, and a plurality of second hydrophobic monomers wherein the first hydrophobic monomer is different from the second hydrophobic monomer ([0005], Claim 1).
Wakefield describes the conjugate delivery system with the general structure N-L1-P-(L2-M)y, wherein N is a polynucleotide or other cell impermeable molecule, L 1 is a reversible linkage, P is a polymer, L 2 is a second reversible linkage, and M is a masking agent [0040]. Wakefield teaches that the polymers can be copolymers alternating with two or more different monomers, random, block and graft [0042], and can be created using step polymerization by using monomers that have two reactive groups A and B [0049] and group B can be acryloyl derivative, fluorobenzene derivatives, and disulfide derivative and others when group A is an amine (e.g., amine-containing NIPMAM) [0051]. Wakefield further teaches that groups A or B can be a photoreactive group such as aryl azide including halogenated acryl azide, diazo, benzophenone, or diazirine derivative [0057] (corresponding to the second hydrophobic monomer species recited in instant claims 105 and 106).
It would have been prima facie obvious for one with ordinary skills in the art to combine teachings from Wakefield with the teaching from Fuks, Hennink, Komatsu and Kim to use NIPMAM with second hydrophobic polymer as halogen substituted benzyl methacrylamide, such as N-trifluoromethylbenzyl methacrylamide, N-pentafluorobenzyl methacrylamide, N-trifluoromethylbenzyl methacrylamide or N-bitrifluoromethyl-benzyl methacrlyamide to arrive at instant invention. Because as Fuks points out various drugs such as indomethacin, doxorubicin (DOX), clonazepam or norfloxacin are physically entrapped into the amphiphilic block copolymer core, and stabilizing interactions between the aromatic rings of the drugs and the benzyl moiety of the amino-acid residues are believed to be an important factor for an efficient physical entrapment (Pg. 2488, left column), so did Hennink emphasizing the aromatic groups on the second hydrophobic polymer being beneficial for many advantages in drug delivery and release, it provides motivation for an artisan in the field to implement polymer monomer containing aromatic rings, while Kim teaches methacrylamide monomer can contain many various substituents and Wakefield teaches that halogenated substituents are proper for the polymer monomers in the conjugate delivery system. One would have reasonable expectation of success that such modification would result in improved drug entrapment or binding within the polymer. This renders obviousness as “use of known technique to improve similar devices (methods, or products) in the same way” or as “applying a known technique to a known device (method, or product) ready for improvement to yield predictable results”. See MPEP §2143. (I)(C) and (I)(D).
Response to Arguments
Applicant’s Remarks/Arguments filed on 12/16/2025 have been fully considered.
35 U.S.C. 112b Rejections
Claim 97, the amendment hasn’t successfully overcome all the issues from previous rejection mailed on 06/16/2025.
Art Rejections
Applicant alleges that no reference teaches or suggests the claimed feature of the claimed compounds exhibiting unique temperature-dependent assembly behavior-present as unimers at room temperature while forming particles at body temperature, citing specification paragraphs as evidence.
In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., unique temperature-dependent assembly behavior-present as unimers at room temperature while forming particles at body temperature) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The feature in claim 113, somehow different from what applicant asserts, of the compound existing as unimers in aqueous solution below transition temperature, and wherein the compound existing as particles in aqueous solutions above the transition temperature has been addressed in the office action. The most relevant paragraph is copied for reference below:
Fuks indicates that the combination of thermo-responsive synthetic block copolymers can form unimers or micelles (corresponding to particles) depending on temperature below or above transition temperature (Pg. 2487, left Col., 2nd paragraphs) (corresponding to instant claim 113). Fuks teaches that poly(N-isopropylacrylamide)-b-poly(L-glutamic acid) copolymers conformation changes at low temperature 25 °C from a micelles with a PLGA (poly-L-glutamic acid, as hydrophilic polymer) core, in other words, a unimer status as hydrophilic micelles, to spontaneously revert to a PNIPAM core micelles (a hydrophobic particle status) at high temperature 45 °C (Pg. 2487, left Col. Bottom paragraph), with transition temperature range overlapping with 20 °C to 34 °C in instant claim 114. Fuks indicates that block copolymer micelles can solubilize hydrophobic drugs in their inner core and the micelles typical size range is 10-100 nm, sufficiently large to avoid renal excretion, yet small enough to bypass filtration by the spleen (Pg. 2488, top left) and the copolypeptide deblocks form stable vesicles of controllable diameter upon extrusion down to 50 nm (Pg. 2488, Right Col. 2nd paragraph) (overlapping with 30 nm to 80 nm particle diameter in instant claim 115).
In addition, the temperature-dependent assembly behavior is interpreted as property of the copolymer compound comprising drug. Prior art teaches the copolymer compound, the property would necessarily be present, since it is inherent property of the compound.
Applicant asserts that Fuks does not teach or suggest compounds comprising a hydrophilic block comprising monomers of Formula I, hydrophobic blocks comprising a first hydrophobic monomer of Formula IV, or hydrophobic blocks further comprising a second hydrophobic monomer as required by amended claims.
In light of the claim amendment, most limitation scopes from previous claims 99, 101 and 108 are now integrated into independent claim 97, therefore, this argument is persuasive since it is based upon the amended claim 97. New grounds of rejection with additional references have been presented in this office action, Previous art rejections have been withdrawn, and new grounds of rejections are presented in this office action in light of the amendment, Formula I now is taught by prior art, as well as the required features of polymer monomers.
Applicant argues that Kim does not teach or suggest compounds having the claimed structural features. Kim does not provide suggestion or teaching to combine its optical-film polymer with the copolymers in Fuks, nor to incorporate the Formula I or Formula IV monomer architectures and thus Kim does not cure the deficiencies of Fuks.
New grounds of rejections have addressed the amended claims, and the deficiencies of Fuks have been cured by additional references, Hennink, Komatsu, teaching the specific features of hydrophilic monomer Formula I as well as hydrophobic monomer required features. Kim is combined to teach the species of NIPMAM and BnMAM. Kim’s optical film is still a copolymer, especially references Fuks, Hennink, Komatsu already suggests the suitability of this kind of polymers. “The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983). The teaching from all the references makes it obvious to combine Kim’s teaching of specific monomers. The reasoning presented in office action is copied below for reference:
It would have been prima facie obvious for one with ordinary skill in the art prior to the filling date to incorporate the acrylic hydrophobic polymers taught by Kim into the block copolymer compound for drug delivery taught by Fuks, Hennink and Komatsu to arrive at instant invention. Because Fuks, Hennink and Komatsu establishes that the acrylic hydrophobic monomers with one of the hydrophobic monomer containing an aromatic ring is preferred, and Kim teaches both NIPMAM, benzyl meth-acrylamide, and many other methacrylate or methacrylamide comprising aromatic and/or aliphatic rings are suitable for the optical film that result in excellence in formability, adhesion, retardation properties, and durability, and with improved heat resistance while maintaining transparency (e.g., Abstract), it would have provided reasonable expectation of success for an artisan in the field to implement these polymer species for intended application of drug delivery using polymers as drug carrier, especially for applications like transdermal drug delivery system, which is one of the administration form indicated in instant specification. It is well settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).
D. Applicant also alleges that Komatsu and Wakefield do not cure deficiencies of Fuks, and they do not teach the claimed invention.
In light of claim amendment, new grounds of rejections have cured deficiencies of Fuks. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Please refer to the entire office action as complete response to the remarks and arguments.
Conclusion
No claim is allowed.
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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/DX.Z./Examiner, Art Unit 1616
/SUE X LIU/Supervisory Patent Examiner, Art Unit 1616