DETAILED ACTION
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 1-7, 11 and 18, in the reply filed on 07/24/2026 is acknowledged.
Claims 44-48, 56, 76, 78 and 81-83 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.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 07/24/2026.
Claims 1-7, 11, 18, 44-48, 56, 76, 78 and 81-83 are pending, claims 1-7, 11 and 18 are under examination.
Priority
Acknowledge is made for priority claiming from US provisional application 63/459351, file don 04/14/2023 and 63/382528, filed on 11/06/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 06/26/2024 and 07/30/2024 is being considered by the examiner.
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 3 is 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 3 recites removing acid after adding at least a molar equivalent of acid relative to the block polymer, if all the acid added is removed and the block polymer is not protonated (protonated is required in claim 1). Thus, the scope and boundary of claimed is unclear. For compact prosecution purpose, removing acid is examined as removing excessive acid (which is consistent with applicant’s specification).
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 1-3, 5-7, 18 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO2021091924).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Zhao et al. teaches therapeutic pH responsive compositions comprising a block copolymer and a therapeutic agent useful for the treatment of cancer (abstract). n an aspect, provided herein is a block copolymer having the structure of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
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wherein: is an integer from 10-200; x1 is an integer from 40-300; y1is an integer from 0-6; z1 is an integer from 0-10; X1 is a halogen, -OH, or -C(0)OH; R1 and R2 are each independently an optionally substituted C1-C6 alkyl, C3-C10 cycloalkyl or aryl; or R1 and R2 are taken together with the corresponding nitrogen to which they are attached to form an optionally substituted 5 to 7-membered ring; each R3 is independently hydrogen, acyl, or ICG; L1 is a bond or -C(O)-, or optionally substituted C1-C10 alkylene linker or PEG linker; and Y is a therapeutic agent ([0008]). In another aspect, provided herein is a micelle comprising: (i) a block copolymer of Formula (III), or a pharmaceutically acceptable salt, solvate, or hydrate thereof:
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Formula (III), wherein: n3 is an integer from 10-200; X3 is an integer from 40-300; y3 is an integer from 0-6; Z3 is an integer from 0-10; X3 is a halogen, -OH, or -C(0)0H; each R10 is independently hydrogen or ICG; R8 and R9 are each independently an optionally substituted C1-C6 alkyl, C3-C10 cycloalkyl or aryl; or R8 and R9 are taken together with the corresponding nitrogen to which they are attached to form an optionally substituted 5 to 7-membered ring; and (ii) a therapeutic agent encapsulated by the block copolymer ([0016]). FIG. 4A and FIG. 4B shows encapsulation of bispecific antibodies using pH-sensitive micelles. 4A shows SEC chromatograph after bispecific antibodies encapsulation and size distribution by DLS of the micelles encapsulated bispecific antibody (three replicates) ([0028]). In some embodiments, the block copolymer is a diblock copolymer. In some embodiments, the block copolymer comprises a hydrophilic polymer segment and a hydrophobic polymer segment. In some embodiments, the hydrophilic polymer segment comprises poly(ethylene oxide) (PEO) ([0082]). In some embodiments, the hydrophobic segment comprises a dibutyl amine. In some embodiments, the hydrophobic segment comprises ([0085]).
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In some embodiments, the therapeutic agent is a cytokine or a fragment thereof, an engineered antibody fragment, or a small molecule having a molecular weight less than 900 Daltons ([0094]). In some embodiments, the therapeutic agent is a cytokine or a fragment thereof. Cytokines are a broad and loose category of small proteins that are important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents. Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5 - 16 kDa protein that regulates the activities of white blood cells that are responsible for immunity ([0095]). In some embodiments, the therapeutic agent is an engineered antibody fragment. In some embodiments, the engineered antibody fragment is a bispecific T cell engager ([0098]). One or more block copolymers described herein may be used to form a pH-sensitive micelle compositions. In some embodiments, the composition comprises a single type of micelle. In some embodiments, two or more different types of micelles may be combined to form a mixed-micelle composition. In some embodiments, the micelle comprises a block copolymer covalently conjugated to a therapeutic agent. In some embodiments, the micelle comprises one or more block copolymer that non-covalently encapsulates a therapeutic agent (00102]). ] In some embodiments, the block copolymer of Formula (I), (I-a), (I-b), or (I-c), or a pharmaceutically acceptable salt, solvate, or hydrate thereof is in the form of a micelle. In some embodiments, the block copolymer of Formula (I), or a pharmaceutically acceptable salt, solvate, or hydrate thereof is in the form of a micelle. In some embodiments, the block copolymer of Formula (I-c), or a pharmaceutically acceptable salt, solvate, or hydrate thereof is in the form of a micelle ([00103]). In some embodiments, the encapsulation is non-covalent encapsulation, wherein the therapeutic agent is physically within a micelle. In some embodiments, the therapeutic agent is non-covalently encapsulated ([00106]). In some embodiments, pharmaceutically acceptable salts are obtained by reacting a block copolymer with an acid. In some embodiments, the block copolymer disclosed herein (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. In some embodiments, a block copolymers disclosed herein are prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt ([00171-00172]). In on example, Methanol is added to the block copolymer in a glass round bottom flask and dissolved with the aid of a sonication bath. After dissolution, the resulting solution is quantitatively transferred to a HDPE bottle containing a stir bar and cooled to 0 °C with an ice-bath. Water is added dropwise while stirring, to the methanolic polymer solution in the HDPE bottle using a peristaltic pump. The HDPE bottle containing the polymer solution is maintained in the ice bath, resulting in the formation of micelles. Methanol is removed from the micelle solution using 5 cycles of tangential flow filtration (TFF) through a 100k Pellicon® 2 Mini Ultrafiltration Module. PEG-PDBA-IL-2 formulations prepared by Simple Mixing ([00195]). Polymer micelle solution in water was diluted with injectable water (WFI). 10% (w/w) of IL-2 (% of polymer) in phosphate buffer was added to make a solution of 1 mg/mL micelle and 0.1 mg/mL IL-2 by pipette mixing. The solution was incubated at room temperature for 10 minutes. Then the sample was centrifuged at high-speed in a microcentrifuge at ambient temperature (Eppendorf, 21,130 x g, 10 mins.). The solution was purified by membrane ultrafiltration (Amicon, 0.5 mL, MWCO 100kDa) to remove any unencapsulated IL-2. Then 0.5 mL of the formulation was added to an Amicon ultracentrifugation device and centrifuged at 5,000 ref for 2-3 minutes. The permeate was discarded and the retentate which contained the micelle-IL-2 formulation was diluted to 0.5 mL in water for injection ([00196]).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Zhao et al. is that Zhao et al. is not specific enough for anticipation.
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 produce the instant invention.
Regarding claims 1, 7 and 18, Zhao et al. teaches a method of encapsulation of protein such as bispecific antibody by a micelle formed from block polymer salt (protonated) with structure formula (III)
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Formula (III), wherein: n3 is an integer from 10-200; X3 is an integer from 40-300; y3 is an integer from 0-6; Z3 is an integer from 0-10; X3 is a halogen, -OH, or -C(0)0H; each R10 is independently hydrogen or ICG; R8 and R9 are each independently an optionally substituted C1-C6 alkyl, C3-C10 cycloalkyl or aryl. When Z3 is 0, the formula (III) is polymer structure in applicant’s claim 1.
Regarding claims 2-3, Zhao et al. teaches a working example of encapsulation process comprising dissolving block polymer in methanol (organic solvent) forming micelles followed by removing methanol, then adding therapeutic agent to the micelle for encapsulation. Since Zhao et al. also teaches in one embodiment block polymer is a salt (forming from reaction of block polymer and acid), the reaction of block polymer and acid can happen either before mixing with methanol or after mixing with methanol, since there is finite choice (few choice), adding acid with block polymer after mixing with methanol is obvious. Furthermore, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. Since fully protonate block polymer requires 1 equivalent molar of acid, at least 1 equivalent molar of acid is required for the reaction. It is also within skill of one artisan in the art to remove excess of acid because this ensures encapsulation process take place without interference of excessive acid, and one artisan in the art knows that only required components need be present in any physical chemical process.
Regarding claims 5-6, Zhao et al. teaches diblock polymer and hydrophobic segment is
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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.
Claims 4 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao et al. (WO2021091924), as applied for the above 103 rejections for claims 1-3, 5-7 and 18, in view of Nallani et al. (US20210251899).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Zhao et al. teaching has already been discussed in the above 103 rejection and is incorporated herein by reference.
Nallani et al. teaches encapsulation of protein comprising Polymer and or polymer lipid mixture were dissolved in ethanol or any water miscible solvent and added dropwise to a protein solution to self - assemble and the proteins are encapsulated into polymersomes during self assembly. Non-encapsulated proteins were removed by dialysis with PBS ([0442]).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02)
The difference between the instant application and Zhao et al. is that Zhao et al. do not expressly teach dialysis with neutral buffer. This deficiency in Zhao et al. is cured by the teachings of Nallani 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 Zhao et al., as suggested by Nallani et al., and produce the instant invention.
Zhao et al. teaches encapsulation of protein therapeutic agent with block polymer micelle followed by removing unencapsulated protein therapeutic agent throughmembrane ultrafiltration, but silent about dialysis against a neutral buffer.
One of ordinary skill in the art would have been motivated to replace a step of dialysis with PBS (neutral buffer) for membrane ultrafiltration to remove unencapsulated protein therapeutic agent because this is simple substitution of one known method for another to remove unencapsulated protein therapeutic agent. MPEP 2143, it is prima facie obviousness for simple substitution of one known element for another to obtain predictable results. Under guidance from Nallani et al. teaching dialysis with PBS (a neutral buffer with pH 7.4 according to applicant’s specification) as suitable step to remove Non-encapsulated proteins in the encapsulation of protein, it is obvious for one of ordinary skill in the art to replace a step of dialysis with PBS (neutral buffer) for membrane ultrafiltration to remove unencapsulated protein therapeutic agent and produce instant claimed invention with reasonable expectation of success.
Regarding claims 4 and 11, prior art teaches after encapsulation, micelle comprising block polymer and protein therapeutic agent is dialysis with PBS (neutral buffer) to unencapsulated protein therapeutic agent, and the dialysis with PBS results in neutralization with neutral buffer.
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 1-7, 11 and 18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 58 and 74 of copending Application No. 17755671 in view of Zhao et al. (WO2021091924) and Nallani et al. (US20210251899). The reference application teaches antibody encapsulated by block polymer that read on the block polymer in applicant’s instant claim 1 but silent about process to make this encapsulated antibody, in view of Zhao et al. teaches a process to encapsulate antibody with block polymer and Nallani et al. teaching dialysis with PBS to remove unencapsulated protein drug, it is obvious to produce applicant’s claimed invention with reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-7 and 11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18, 21, 37 of copending Application No. 18907886 in view of Zhao et al. (WO2021091924) and Nallani et al. (US20210251899). The reference application teaches protein (biomolecule) encapsulated by block polymer that read on the block polymer in applicant’s instant claim 1 but silent about process to make this encapsulated antibody, in view of Zhao et al. teaches a process to encapsulate antibody with block polymer and Nallani et al. teaching dialysis with PBS to remove unencapsulated protein drug, it is obvious to produce applicant’s 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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/JIANFENG SONG/Primary Examiner, Art Unit 1613
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