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 invention group I, claims 1-4, 6-12 and 15, in the reply filed on 02/27/2026 is acknowledged.
Claims 16-19, 22-24, 30, 33-35 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 02/27/2026.
Applicants further elect specific polymer matrix from example 6 of specification (20% of triethylene glycol di[ethyl-1-methacryloyloxy poly(ethylene glycol) acetal cross linker and 4% of butyl methacrylate monomer), which is free of art. The examiner moves to next species at the examiner’s choice Microgels comprising acrylamides crosslinked with bisacryloyl acetal crosslinker. Claims 1-2, 8-12 and 15 read in the examined species and are under examination. Claims 3-4 and 6-7 read on the elected species and are withdrawn from consideration.
Claims 1-4, 6-12,15-19, 22-24, 30 and 33-35 are pending, claims 1-2, 8-12 and 15 are under examination.
Priority
Acknowledge is made that this application is national stage of international patent application PCT/US2022/018738, filed on 03/03/2022; which claims priority from US provisional application 63/156,177, filed on 03/03/2021.
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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
Claims 1-2, 8-12 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Hascicek et al. (“Fulvestrant-loaded polymer-based nanoparticles for local drug delivery: Preparation and in vitro characterization”, Journal of Drug Delivery Science and Technology 40 (2017), 73-82) and Frechet et al. (US20060223776).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Hascicek et al. teaches optimizing Fulvestrant (FLV)-loaded nanoparticulate formulations to overcome side effects caused by the intramuscular injection of FLV, and to prolong local intra tumoral action at high drug concentration. Novel poly(ethylene glycol) (PEG) conjugated poly(ethylene glycol)-block-poly(lactide-co-glycolide) (PEG-b-PLGA), and poly(ethylene glycol)-block-poly(ε-capro lactone) (PEG-b-PCL) nanoparticles were used as the drug-loading vehicles. The influence of hydro phobicity of the two different polymeric materials based nanoparticles was investigated with respect to in vitro properties, cytotoxic capacity and cell uptake potency. The sphere-shaped nanoparticles ranged between 84.56 and 220.20 nm, had negative surface charges, and exhibited sustained release profiles. In vitro cytotoxicity results demonstrated that nanoparticles prepared with the higher hydrophilic form of PEG-b-PCL, a diblock copolymer composition, exerted the highest inhibitory effect on the proliferation of MCF-7 cells and significantly increased the intracellular uptake, compared to free FLV and the other tested polymer-based formulations. The final data of this research indicated that polymer hydrophobicity was a key to improving the major characteristics, especially anti-proliferative activity of the developed polymer-based nanoparticles. The drug delivery systems formulated here are promising nanocarriers for FLV delivery and have potential for the treatment of hormone-dependent breast cancers (abstract). All DSC analyses indicated that FLV was still crystalline in the PEG conjugated PCL nanoparticles but amorphous in the PEG-b-PLGA nanoparticle formulation (page 80, left column, 1st paragraph).
Frechet et al. teaches Novel microgels, microparticles and related polymeric materials capable of delivering bioactive materials to cells for use as vaccines or therapeutic agents. The materials are made using a crosslinker molecule that contains a linkage cleavable under mild acidic conditions. The crosslinker molecule is exemplified by a bisacryloyl acetal crosslinker. The new materials have the common characteristic of being able to degrade by acid hydrolysis under conditions commonly found within the endosomal or lysosomal compartments of cells thereby releasing their payload within the cell. The materials can also be used for the delivery of therapeutics to the acidic regions of tumors and sites of inflammation (abstract). The present invention is directed to microgels for application in the delivery of proteins, vaccines, drugs (such as the anticancer drugs cisplatin, paclitaxel or taxitere), and other bioactive materials. The microgels comprise crosslinked polymer hydrogels of microparticle size, that contain or incorporate bioactive materials. The hydrogel compositions are made using an inverse microemulsion technique (aqueous droplets in an oil or aliphatic phase) that results in microgels of a predetermined size, typically 0.1-10 microns in diameter. A size range between 200 nm and 500 nm is optimal for phagocytosis by immune cells ([0013]). The term “acrylic polymer” herein refers to a polymer made from polymerizing units (monomers) that yield a polymer having a cross linkable side chain, wherein said monomers are acrylic acid, acrylamide, or various monomers and mixtures thereof having hydrogen substitutions such as NH2 at the CH group. The term “loading efficiency” herein refers to the percentage of the starting amount of bioactive material that is encapsulated per milligram of the microgels (μg material/mg microgel) on average, based on the starting bioactive material/monomers ratio ([0044-0045]). FIG. 1 shows a schematic diagram illustrating the overall composition and use of the present microgels. The microgels 10 of the current invention are loaded with bioactive material 40 including but not limited to, antigens, proteins, polynucleotides, polypeptides, and other bioactive material 50. The microgels 10 of the current invention should be synthesized with polymerizable groups 30 and a bisacryloyl acetal crosslinker 20 that hydrolyzes under acidic conditions and releases the encapsulated contents 40 in response to mildly acidic conditions. The mild acidic conditions found in the body such as in tumors, inflammatory tissues and in cellular compartments such as lysosomes and phagolysosomes 50 of antigen presenting cells 60 should cause the acetal group of the bisacryloyl acetal crosslinker 20 to be hydrolysed thereby degrading the microgel and releasing its contents. In a preferred embodiment, the microgels are delivered to antigen presenting cells and then phagocytosed and trafficked to the lysosome or phagolysosome of the cells. The mild acidic conditions found in lysosomes and phagolysosomes of APCs should cause the acetal group of the bisacryloyl acetal crosslinker to be hydrolysed thereby degrading the microgels ([0050-0051]). Microgels made with the bisacryloyl acetal crosslinker should efficiently entrap bioactive material with a comparable loading efficiency. In a preferred embodiment, the microgel particle size may vary between 0.1-10 μm and exhibit a loading efficiency of at least 40% bioactive material encapsulation, more preferably at least 50% loading efficiency and even more preferably at least 54% loading efficiency ([0082]). Appropriate polymerizable groups that can be used for the microgels of this invention include acrylic polymers such as, acrylamides, methacrylamides, methacrylates, and acrylates ([0084]). Appropriate biocompatible polymerizable groups that can be used for the microgels of this invention include biocompatible polymers including but not limited to, dextrans, saccharides, mannoses, sugars, carbohydrates, nucleic acids, oligonucleotides, amino acids, polypeptides, lipids and combinations thereof ([0087]). In a preferred embodiment, the invention contemplates entrapping such bioactive materials including but not limited to, nucleotides, polynucleotides, ribonucleotides, amino acids, peptides, proteins, antigens, plasmid DNA, growth factors and hormones, interleukins, immunostimulatory agents, drugs, vaccines, neuromodulatory agents such as neurotransmitters, stimulatory and adrenergic agents, enzymes, proteases, anticancer and antitumor agents, imaging agents, diagnostic agents, antiviral agents and antibacterial agents ([0089]). The loaded microgels of the invention can be administered by various suitable means to a patient, including but not limited to parenterally, by intramuscular, intravenous, intraperitoneal, or subcutaneous injection, or by inhalation ([0140]). In one embodiment, the encapsulated Albumin is 44.3 to 154.5 ug in 1 mg of microgel ([0195]).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Hascicek et al. is that Hascicek et al. do not expressly teach Microgels comprising acrylamides crosslinked with bisacryloyl acetal crosslinker. This deficiency in Hascicek et al. is cured by the teachings of Frechet et al.
Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Hascicek et al., as suggested by Frechet et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to replace Microgels comprising acrylamides crosslinked with bisacryloyl acetal crosslinker for PEG conjugated PCL nanoparticles or PEG-b-PLGA nanoparticle to encapsulate fulvestrant because this is simple substitution of one known polymer matrix for another for encapsulation of fulvestrant to obtain predictable results. MPEP 2143, it is prima facie obviousness for simple substitution of one known element for another to obtain predictable results. Under guidance from Frechet et al. teaching Microgels comprising acrylamides crosslinked with bisacryloyl acetal crosslinker for encapsulation of anticancer drug and release drug under mild acidic condition due to hydrolytically cleavage of bisacryloyl acetal crosslinker, since it is advantage to do so, it is obvious for one of ordinary skill in the art to replace Microgels comprising acrylamides crosslinked with bisacryloyl acetal crosslinker for PEG conjugated PCL nanoparticles or PEG-b-PLGA nanoparticle to encapsulate fulvestrant and produce instant claimed invention with reasonable expectation of success.
Regarding claims 1-2, prior art teaches a microgel comprising acrylamides crosslinked with bisacryloyl acetal crosslinker encapsulating fulvestrant. Since microgel comprising acrylamides crosslinked with bisacryloyl acetal crosslinker is hydrolytically cleaved under mild acidic condition, it is considered dissociating polymer matrix. Since fulvestrant is encapsulated in microgel comprising acrylamides crosslinked with bisacryloyl acetal crosslinker, the crosslinked acrylamide chain defining pore within microgel that fulvestrant is encapsulated within.
Regarding claims 8-9, Hascicek et al. teaches encapsulated fulvestrant is solid, either crystalline or amorphous.
Regarding claim 10, Frechet et al. teaches microgel size of 200 nm and 500 nm, and size of encapsulated crystalline fulvestrant is adjustable and need to be smaller than 500nm or 200nm through routing experimentation to have size such as 10nm to 200nm and produce instant claimed invention with reasonable expectation of success. MPEP 2144.05. Especially in the absence of showing criticality of claimed range.
Regarding claims 11-12, one artisan in the art would have been motivated to optimize the encapsulated range of active ingredient fulvestrant through routing experimentation or under prior art condition. Since Frechet et al. teaching Albumin of 44.3 to 154.5 ug in 1 mg of microgel (4.4% to 15.5%), it is obvious to have active ingredient fulvestrant at 5-50% and produce instant claimed invention with reasonable expectation of success.
Regarding claim 15, this is regarded as inherency of prior art condition. Since prior art teaches the same composition, this same composition must have the same properties. MPEP 2112, "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977). Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-2, 8-12 and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4,9-10, 23-31, 33—34, 37, 52-68 of copending Application No. 17007966 in view of Hascicek et al. (“Fulvestrant-loaded polymer-based nanoparticles for local drug delivery: Preparation and in vitro characterization”, Journal of Drug Delivery Science and Technology 40 (2017), 73-82) and Frechet et al. (US20060223776). The reference application teaches encapsulation of active ingredient by acrylate polymer crosslinked with hydrolytically degradable linker but silent about fulvestrant, under guidance from Hascicek et al. teaching fulvestrant encapsulated by PEG conjugated PCL nanoparticles or PEG-b-PLGA nanoparticle, Frechet et al. teaching Microgels with polymer crosslinked with hydrolytically degradable linker in mild acidic condition which is advantage, it is obvious for one of ordinary skill in the art to encapsulate active ingredient fulvestrant by acrylate polymer crosslinked with hydrolytically degradable linker and produce instant claimed invention with reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JIANFENG SONG. Ph.D. whose telephone number is (571)270-1978. The examiner can normally be reached M-F 8-5.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian-Yong Kwon can be reached at (571)272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JIANFENG SONG/Primary Examiner, Art Unit 1613
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