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 .
Response to Amendment
The Amendment filed 09/22/2025 has been entered. Applicant’s amendments are in response to in the Non-Final Office Action mailed 05/22/2025. Applicant’s claims have been amended in the following manner: independent claim 1 amends in “recombinant human” MG53 (rhMG53), and replaces the general excipient limitation of the previous claim set, with a specific type of hydrogel comprising particular ingredients and properties. This required a rearrangement of the 103 rejection that still relies on the same general thrust of the previous office action. The following objections/rejections are withdrawn: the 101 rejection is withdrawn (by specifying rhMG53, as discussed in the response to arguments section below) and the 102 rejection is withdrawn (and replaced by a new 103 rejection prompted by the amendments).
The Examiner further acknowledges the following:
Claims 1-20 are pending.
Claims 12-20 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-11 are presented for examination and rejected as set forth below.
Claim Objections
Claims 3, 5-6, and 11 are objected to for containing the term “about”, which is not a precise term.
Claim 5 is objected to because of the following informalities: there are multiple temperatures and use of the term “about” that lead to an inconsistent definition of the intended temperature. The Examiner is using the least restrictive option being “at least about 18 C.” Furthermore, the semicolon placed after the last temperature leads to ambiguity regarding and “and”, “or”, or “and/or” relationship with the next partial sentence (the Examiner interprets and/or for claim 5).
Claim 6 is objected to because a line was deleted, but the “a)”, “b)”, and “c)” remain (in contrast to claim 5, where “d)” is deleted). So, the option letters seem misaligned in claim 6.
Appropriate correction is required.
New Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Ma (US 20090318348A1), and in further view of Hennink (WO2001009198A1) and Yu (International Journal of Pharmaceutics 2018).
Applicant’s claims are directed to a composition comprising recombinant human MG53 (rhMG53) and a hydrogel that comprises a liquid vehicle and a boronate-ester-based copolymer. A further limitation of independent claim 1 is that the hydrogel exhibits a lower viscosity at a lower temperature and a higher viscosity at a higher temperature. The term “cosmeceutical” is an intended use and does not affect the compositional structure.
Ma teaches MG53 pharmaceutical [0040] and cosmetic [0053] compositions, comprising ingredients for formulation (Ma – claim 12), including biocompatible polymers for sustained release in various formulation shapes, including hydrogels [0206, 0219].
Regarding claim 1, 5: Ma teaches a composition comprising MG53 protein [0008], liquid vehicles (e.g., sodium chloride solution) [0138-0145, 0209-0210], and formulations such as hydrogels that incorporate copolymers (such as lactic acid-glycolic acid copolymer [0206]) with an intent for sustained release [0206, 0219]. Ma teaches a recombinant version of the MG53 protein [0036, 0048, 0256], where also “human” MG53 is an obvious selection [0038, 0258]. Thus, Ma teaches the general elements of instant claim 1 such that the use of recombinant human MG53 (rhMG53) in a hydrogel containing a liquid vehicle and copolymer would be rendered obvious to a PHOSITA for use in drug therapy (abstract, [0008]).
Regarding claim 2: Ma teaches the composition can comprise the excipient antioxidants [0211] and the carrier water ([0140-145], Ma – claims 12 and 13).
Regarding claim 3: Ma teaches formulations with carriers such as water, saline, finger’s solution, dextrose solution, and 5% human serum albumin with no other cosolvent mixed in, demonstrating the water carrier is used in >30 wt% [0210].
Regarding claims 4: Ma teaches topical, parenteral, inhalable, etc. formulations [0138, 0211].
In summary, Ma teaches that a composition comprising recombinant human MG53 (rhMG53) in a hydrogel containing a liquid vehicle and copolymer would be rendered obvious to a PHOSITA for use in sustained release drug therapy. However, Ma does not teach the gel property limitations of claim 1, 5-6), and the specific polymers (instant claims 7-11).
Hennink teaches temperature sensitive terpolymers (based on lower critical solution temperature (LCST)) comprised of monomers such as N-isopropyl acrylamide (NIPAAm) and 2-hydroxyethyl methacrylate (HEMA) (which read on 2 of the 3 monomers of terpolymers of instant claim 11), and others (pg 5, lines 9-36 and pg 6, lines 1-2) for controlled release of protein drugs (pg 7, lines 1-7) for treatment of disease (cancer, viral, bacterial, diabetes, inflammation, etc.) (pg 1, lines 5-15, pg 2, lines 9-13, pg 8, lines 3-14). Specifically, Hennink teaches NIPAAm/HEMA/AAm (50/20/30) in Table 1 (pg 15, where NIPAAm is N-isopropyl acrylamide, HEMA is 2-hydroxyethylmethacrylate, and AAm is acrylamide), having an LCST of 42.3 °C. Hennink also teaches that the LCST (and thus solubility) in drug release systems (abstract, pg 2, lines 28-36, pg 3 lines 1-20), depend from the type and ratio (which also reads on length) of different monomers in the terpolymer (pg 5, lines 25-26, pg 9, lines 31-36, pg 10 lines 1-11), and modulation of LCST by hydrolysis of monomers containing an ester moiety (such as lactate). Thus, monomeric type and ratio are amounts that would be optimized by a person skilled in the art to affect LCST and thus, drug delivery performance. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation). Hennink also speaks to terpolymers in random or block form (pg 6, lines 14-20).
For the newly amended-in limitation of the thermogelling property of claim 1: Hennink teaches “the ABA block copolymers formed by this route will be soluble in water below the LCST. When the temperature is risen above the LCST of block A, a phase separated system will be formed, wherein as a result of the choice of block copolymer architecture, a hydrogel will be obtained” (pg 9, paragraph 3). With regard to this, Hennink teaches LCST around the physiological temperatures represented by instant claim 5 (LCST ranges from 24-65 °C in Table 1 of pg 15). Thus, when the temperature rises above the LCST that is around physiological temperatures, then a hydrogel will be obtained (this reads on “wherein the hydrogel exhibits a lower viscosity at a lower temperature and higher viscosity at a higher temperature” of instant claim 1).
Yu also teaches temperature responsive drug delivery systems, which are ROS-responsive (abstract) and have specific LCSTs (pg 11, Figure 1a). Yu accomplishes a change of LCST through oxidation of the BAPAE (“(4-(benzyl acrylate) phenylboronic acid pinacol ester”) monomer (reads on the boronate species of instant claims 6-11, especially AHPPE, which is (“(4-hydroxylmethyl)-phenylboronic acid, pinacol ester) acrylate” and is the same structure as BAPAE but in a different notation) within the polymeric system (pg 12, “synthesis of BAPAE’ and figure 1b), where BAPAE undergoes oxidative cleavage to adjust the LCST of the resulting polymeric chain. Yu also teaches adjustment of the LCST property for a polymer for drug delivery by controlling the proportion of hydrophilic/hydrophobic monomers (pg 12, paragraph 1) for the treatment of cancer (pg 12, paragraph 2).
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, from specification [021]
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the teachings of Ma with the terpolymer taught by Hennink (such as NIPAAm/HEMA/AAm (50/20/30)) as useful for controlled drug release where the oxidation-sensitive boronate monomer from Yu replaces the AAm monomer of Hennink because that would allow for a terpolymer comprising an oxidation-sensitive monomer to react to different oxidation environments in vivo that especially could target abnormal ROS conditions in cancer microenvironments, as taught by Yu (abstract; pg 12, paragraph 2)).
Additionally, the boronate monomer modification to Hennink’s terpolymer installs a monomeric unit that is activated upon oxidation, which reads on the inventive purpose of Hennink’s work that is temperature sensitive polymers for controlled release of protein drugs (pg 2, lines 14-36), which derives from an incubation period, leading to a change in water solubility characteristics of the polymer (abstract). Hennink teaches that LCST polymers have the advantage of protecting a protein from degradation at low temperatures (pg 3, lines 5-14), and LCST systems that change solubility upon incubation have the ability to target sites of interest with tailored release profiles (pg 3-4, lines 34-36 and lines 1-26). The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). In this case, the combined teachings of Ma, Hennink and Yu teach a terpolymer (temperature and ROS-responsive) that would be useful for controlled release of a rhMG53 protein for treatment of diseases such as cancer (which is targeted by Ma), where the ratio and length of the polymer would be optimized for improved drug release performance. Both Hennink and Yu teach that alteration of the monomer identity and ratios impact the LCST and controlled-release profile of the drug from the polymer.
In summary, Applicant claims a ratio of NIPAAm/HEMA/AHPPE (75-85/5-20/5-20) in instant claim 11, where Hennink teaches NIPAAm/HEMA/AAm (50/20/30) and a motivation to optimize monomeric ratios and type to optimize LCST temperature (for gel formation), and Yu teaches the AHPPE monomer with a motivation to incorporate by providing an oxidation-sensitive monomer to react to different oxidation environments in vivo that especially could target abnormal ROS conditions in cancer microenvironments (whereby LCST is demonstrably modified with this monomeric component (Figure 1)). Finally, Ma teaches rhMG53 controlled-release drug delivery [0008, 0038, 0258] using hydrogels based on copolymers [0206, 0219]. Thus, the instant invention is obvious from the literature, and the results demonstrated by the Applicant are expected by optimization of elements of the prior art.
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 1-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over Claims 1-25 of Patent US7981866B2 (cited on the IDS filed on 10/31/2022), and in further view of Hennink (WO2001009198A1) and Yu (International Journal of Pharmaceutics 2018).
Although the claims at issue are not identical, they are not patentably distinct from each other because both claim sets teach MG53 compositions to treat disease such as cancer. Patent No. US7981866B2 differs only significantly by not including the terpolymer of claims 7-11.
This is remedied by the combined teachings of Hennink and Yu, who together teach terpolymers (with a property of phase separation at temperatures near physiological temperature, that results in hydrogel formation) that can comprise oxidation-sensitive boronate esters for controlled protein drug release in the treatment of disease such as cancer (see 103 rejection above for analysis), in which controlled MG53 release for cancer is targeted also by Patent ‘866 (col 9, lines 26-67). One of ordinary skill in the art would have been motivated to modify the teachings of Patent ‘866 because this uses a terpolymer for controlled drug delivery, which was also suggested by Patent ‘866 by suggesting copolymers for sustained-release protein drug delivery with varied release times such as ethylene vinyl acrylate for drug delivery (col 38, last paragraph and col 39, 1st paragraph).
Response to Arguments
Applicants arguments, see pg 7, filed 09/22/2025 , with respect to the 101 rejection of claims 1-4 under rejection have been fully considered and are persuasive. Therefore, the 101 rejection has been withdrawn.
Applicants arguments, see pg 7-9, filed 09/22/2025, with respect to the 103 rejection of claims 1-11 have been fully considered but they are not persuasive. The 103 rejection has been modified with respect to amendments made to the claim set and maintains the same relative thrust of the previous office action.
On page 7, Applicant corrects the claim objection to claim 6, and the objection is withdrawn.
On page 7, Applicant specifies “recombinant human MG53” (which does not necessarily distinguish rhMG53 from native MG53 [086], as, for example, mutant would indicate in the Specification [088]). However, Applicant amends into independent claim 1 as part of the composition comprising rhMG53 and a hydrogel (where the specification notes a mixing of rhMG53 and the hydrogel in [031]), which provides structure to the formulation and alters the release rate of the protein. For this reason, regarding the structural property incorporated by the hydrogel, the 101 rejection is withdrawn.
On page 7, Applicant has amended the independent claim 1 such that the primary reference Ma no longer anticipates the instant claim set. Thus, the 102 rejection is withdrawn, and is reformulated to a 103 rejection in combination with the secondary references, which is prompted by the amendments of the Applicant.
On page 7, Applicant remarks that the claim scope per the ISA was found to be novel and inventive. The argument to consider the ISA opinion is irrelevant to proceedings before the USPTO: “See In re Wertheim, 541 F.2d 257, 264 (CCPA 1976) (“it is immaterial in ex parte prosecution whether the same or similar claims have been allowed to others”); see also In re Nett Designs, 236 F.3d 1339, 1342 (Fed. Cir. 2001) (“The Board must decide each case on its own merits [and] the PTO’s allowance of prior registrations does not bind the Board or this court”).
On page 7-8, Applicant amends the claim scope, and argues that the combined references of Ma, Hennink and Yu no longer render obvious the claim set. Applicants specific argument is that the cited art does not disclose or suggest a composition comprising rhMG53 and a hydrogel (comprising a liquid vehicle and boronate), with the viscosity limitations of claim 1. Note that proper motivation is provided to combine Ma with Hennink and Yu for an obviousness rejection (refer to the 103 rejection above for the rationale), wherein the elements of the instant invention are contained by the three pieces of art. Thus, Ma teaches rhMG53 controlled-release drug delivery [0008, 0038, 0258] using hydrogels based on copolymers [0206, 0219]. Furthermore, Applicant claims copolymer with a monomer ratio of NIPAAm/HEMA/AHPPE (75-85/5-20/5-20) in instant claim 11, where Hennink teaches NIPAAm/HEMA/AAm (50/20/30) and a motivation to optimize monomeric ratios and type to optimize LCST temperature (for gel formation at certain temperatures), and Yu teaches the AHPPE monomer (a boronate ester monomer that can be incorporated into copolymers formed from radical polymerization) with a motivation to incorporate by providing an oxidation-sensitive monomer to react to different oxidation environments in vivo that especially could target abnormal ROS conditions in cancer microenvironments (whereby LCST is demonstrably modified with this monomeric component (Figure 1)). Thus, the instant invention is obvious from the Prior Art (as indicated in the 103 rejection above), and the limited examples/data presented by the Applicant are expected by optimization of elements of the prior art.
On page 8-9, Applicant argues that the double patenting rejection should be withdrawn for the same reasons as stated on why the 103 rejection should be withdrawn. Thus, the Examiner does not find Applicant’s arguments persuasive because the arguments for the 103 rejection are not persuasive. See discussion above.
Correspondence
Applicant's amendment necessitated the new ground 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 extension fee 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 date of this final action.
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/R.P./Examiner, Art Unit 1614 10/31/25
/SEAN M BASQUILL/Primary Examiner, Art Unit 1614