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 . 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 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.
Election/Restrictions
Applicant’s election without traverse of group I (method of making particles) with polyethyleneimine attached to a sequence of 5 to about 320 repeating units of VPGXG, crosslinked with glutaraldehyde, raised above LCST, crosslinked, then cooled in the presence of salt in the reply filed on 23 Dec, 2025 is acknowledged.
Applicants have elected making particles. A search was conducted for this invention, and references rendering it obvious were found. As a result, claims 1-14 and 17 were examined and claims 15, 16, and 18-20 were withdrawn from consideration. Applicants have stated that they believe claim 16 reads on the elected process, but that claim requires an additional method step that applicants have not elected.
Claims Status
Claims 1-20 are pending.
Claims 15, 16, and 18-10 have been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 23 dec, 2025.
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.
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.
first rejection
Claims 1-5, 9-12, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Weeks et al (ACS Biomatter. Sci. Eng. (2016) 2 p2196-2206, cited by applicants) in view of Singh et al (Exp. Mol. Pathol. (2009) 86(3) p215-223, cited by applicants), Streletzky et al (APS March Meeting, 2016, abstract ID M1.203, cited by applicants), and Kim et al (Biomacromol. (2012) 13 p814-825, cited by applicants).
Weeks et al discuss the conjugation of elastin like polypeptides (ELPs) with various polyelectrolyte compounds (title) for such applications such as drug delivery (p2196, 1st column, 1st paragraph). These are amphiphilic compounds, i.e., both hydrophobic and hydrophilic (p2196, 2nd column, 2nd paragraph). An ELP with (VPGVG)40 was made (p2198, 1st column, 1st paragraph), then conjugated to polyethylenimine (applicant’s elected species) (PEI) using EDC/NHS chemistry, using 10x polyethyleneimine vs ELP on a molar basis (p2198, 1st column, 2nd paragraph, continues to 2nd column). Multiple coacervate steps with NaCl concentrations between 0.2 and 1 M, at varying temperatures was conducted to purify the material (p2198, 2nd column, 2nd paragraph). Particle size vs temperature for various NaCl concentrations was determined for unlabeled ELPs (fig 7, p2203, top of page) showing that the salt concentration makes a difference in the particle size and coacervation temperature – with data points within the range claimed by applicants.
The difference between this reference and the instant claim is that this reference does not discuss crosslinking the ELP constructs.
Singh et al discuss nanoparticle based drug delivery (title); the same sort of compounds and utility as described by Weeks et al. Particle size and size distribution are the most important characteristics of these nanoparticles, as they determine in vivo distribution, biological fate, toxicity, and targeting ability (3d page, 4th paragraph). Drug release rate (3d page, 5th paragraph) and stability (4th page, 1st paragraph) are also affected by particle size. This reference shows that particle size is a critical variable in application described by Weeks et al, affecting many important parameters (i.e. is a result oriented variable).
Streletzky et al discuss controlling the size and shape of elastin like polypeptide micelles (title). The reference discusses three elastin like polypeptides attached by a foldon (1st line and 6th line of abstract) which form micelles of varied size and shape depending on the length of the polypeptide chain, the pH, and salt concentration (3d line of abstract). This reference describes ELPs as the hydrophobic portion of a surfactant system that forms micelles, and how varying the conditions will affect those micelles.
Kim et al discuss the effect of crosslinking in micelles as drug delivery carriers (title). Crosslinking micelles increased stability in cell culture media and greatly prolonged the rate of drug release (abstract). At concentrations below the CMC, such as would be used in vivo, the differences were profound (p824, 1st column, 3d paragraph). This reference teaches the advantages of crosslinking micelles in the context of drug delivery.
Streletzky et al teach that the ELP can be the hydrophobic portion of a surfactant system, and Weeks et al teaches that the materials they made are amphiphilic (i.e. surfactants) which form micelles. Therefore, it would be obvious to crosslink these micelles, as discussed by Kim et al, to increase the stability of the assembly structures and to modulate the release rate of any drug. As the chemistry of micelle formation and dissolution are relatively well known, an artisan in this field would attempt this modification with a reasonable expectation of success.
Weeks et al discusses ELP-PEI constructs in the context of drug delivery, which Streletzky et al teach form micelles. Kim et al teaches advantages of crosslinking micelles in drug delivery. As the crosslinking has to be while they are micelles (i.e. while coacervated), the reaction must have been run at or above the LCST. Thus, the combination of references renders obvious claim 1.
Singh et al teach that the size of the particles affects many parameters in drug delivery, suggesting that this is a parameter that can be varied to optimize the features of the final product. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”) (MPEP2144.05.II). Thus, the combination of references renders obvious claims 2 and 12.
PEI comprises amine groups, rendering obvious claims 3-5.
Weeks et al teaches a molar ratio of PEI and ELP of 10:1, rendering obvious claim 9.
Weeks et al teaches the ELP to be 40 repeating units of VPGVG, rendering obvious claims 10 and 11.
The chemistry used to attach the ELP to the PEI will attach a carboxylic acid of the ELP (i.e. the C-terminus) to an amine of the PEI, rendering obvious claim 17.
second rejection
Claims 1-14 and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Weeks et al (ACS Biomatter. Sci. Eng. (2016) 2 p2196-2206, cited by applicants) in view of Singh et al (Exp. Mol. Pathol. (2009) 86(3) p215-223 cited by applicants), Streletzky et al (APS March Meeting, 2016, abstract ID M1.203, cited by applicants), Kim et al (Biomacromol. (2012) 13 p814-825, cited by applicants), and Virgen-Ortiz et al (J. Mater. Chem. B (2017) 5 p7461-7490, cited by applicants), with evidentiary support from Uzun et al (Coll. Surf. B: Biointerfaces (2013) 112 p74-80).
The teachings of Weeks et al, Singh et al, Streletzky et al, and Kim et al were given above, and will not be repeated here. Please note that these references render obvious claims 1-5, 9-12, and 17.
The difference between these references and the remaining claims is that these references do not discuss the crosslinker.
Virgen-Ortiz et al discuss PEI as useful in designing immobilized enzyme biocatalysts (title). Gluteraldehyde (applicant’s elected crosslinking agent) can be used to covalently immobilize polypeptides to the PEI, which will crosslink the polymer at the same time (p7468, 1st column, 1st paragraph, continues to 2nd column, 1st paragraph). This reference discusses attaching polypeptides to PEI and crosslinking the polymer with glutaraldehyde.
Therefore, it would be obvious to use glutaraldehyde to crosslink the micelles of Weeks et al and to attach a therapeutic, as a simple substitution of one known element (the crosslinking agent of Kim et al) for another (the crosslinking agent of Virgen-Ortiz et al), which will also conjugate the therapeutic, yielding expected results (crosslinked micelles). As Virgen-Ortiz et al teach that glutaraldehyde will perform these functions on a component of the polymer of Weeks et al, an artisan in this field would attempt this process with a reasonable expectation of success.
As evidenced by Uzun et al, glutaraldehyde reacts with amines to form imines (p75, 1st column, 2nd paragraph). As there are no amine groups except for the N-terminus of the ELP, this means that portions of the conjugate are not crosslinked, rendering obvious claims 6, 7, and 13.
Gluteraldehyde is an aldehyde, rendering obvious claim 14.
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
first rejection
Claims 1-3, 10, 12, and 17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, and 16 of copending Application No. 16/835,041(US 20200362016) in view of Singh et al (Exp. Mol. Pathol. (2009) 86(3) p215-223), Streletzky et al (APS March Meeting, 2016, abstract ID M1.203), and Kim et al (Biomacromol. (2012) 13 p814-825).
Competing claim 1 describes an ELP with between 5 and 671 repeating units of the sequence VPGXG that targets a placental region. Competing claim 15 allows for attachment of a cell penetrating peptide (i.e. polymer) and/or a therapeutic agent. Competing claim 16 explicitly states that the utility is drug delivery.
The difference between the competing claims and the instant claims is that the competing claims do not discuss crosslinking the ELP construct or controlling its size.
Singh et al discuss nanoparticle based drug delivery; the same sort of compounds and utility as described by Weeks et al. Particle size and size distribution are the most important characteristics of these nanoparticles, as they determine in vivo distribution, biological fate, toxicity, and targeting ability (3d page, 4th paragraph). Drug release rate (3d page, 5th paragraph) and stability (4th page, 1st paragraph) are also affected by particle size. This reference shows that particle size is a critical variable in this application, affecting many important parameters (i.e. is a result oriented variable).
Streletzky et al discuss controlling the size and shape of elastin like polypeptide micelles (title). The reference discusses three elastin like polypeptides attached by a foldon (1st line and 6th line of abstract) which form micelles of varied size and shape depending on the length of the polypeptide chain, the pH, and salt concentration (3d line of abstract). This reference describes ELPs as the hydrophobic portion of a surfactant system that forms micelles.
Kim et al discuss the effect of crosslinking in micelles as drug delivery carriers (title). Crosslinking micelles increased stability in cell culture media and greatly prolonged the rate of drug release (abstract). At concentrations below the CMC, such as would be used in vivo, the differences were profound (p824, 1st column, 3d paragraph). This reference teaches the advantages of crosslinking micelles in the context of drug delivery.
Streletzky et al teach that the ELP can be the hydrophobic portion of a surfactant system. Therefore, it would be obvious to crosslink these micelles, as discussed by Kim et al, to increase the stability of the assembly structures and to modulate the release rate of any drug. As the chemistry of micelle formation and dissolution are relatively well known, an artisan in this field would attempt this modification with a reasonable expectation of success.
In addition, as Singh et al teach that the size of the particle formed has an effect on the drug delivery, it would be obvious to optimize the size of the particle, using the pH, salt concentration, and ELP length, as discussed by Streletzky et al. As the reference clearly states that these parameters will affect the size of the resulting particles, an artisan in this field would attempt this optimization with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
second rejection
Claims 1-3, 10, 12, and 17 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of US patent 8,841,414 in view of Singh et al (Exp. Mol. Pathol. (2009) 86(3) p215-223), Streletzky et al (APS March Meeting, 2016, abstract ID M1.203), and Kim et al (Biomacromol. (2012) 13 p814-825).
Competing claim 1 describes an ELP with between 30 and 350 repeating units of the sequence VPGXG bound to a cell penetrating peptide (i.e. polymer) and a therapeutic peptide. In other words, this is a drug delivery agent.
The difference between the competing claims and the instant claims is that the competing claims do not discuss crosslinking the ELP construct.
Singh et al discuss nanoparticle based drug delivery; the same sort of compounds and utility as described by Weeks et al. Particle size and size distribution are the most important characteristics of these nanoparticles, as they determine in vivo distribution, biological fate, toxicity, and targeting ability (3d page, 4th paragraph). Drug release rate (3d page, 5th paragraph) and stability (4th page, 1st paragraph) are also affected by particle size. This reference shows that particle size is a critical variable in this application, affecting many important parameters (i.e. is a result oriented variable).
Streletzky et al discuss controlling the size and shape of elastin like polypeptide micelles (title). The reference discusses three elastin like polypeptides attached by a foldon (1st line and 6th line of abstract) which form micelles of varied size and shape depending on the length of the polypeptide chain, the pH, and salt concentration (3d line of abstract). This reference describes ELPs as the hydrophobic portion of a surfactant system that forms micelles.
Kim et al discuss the effect of crosslinking in micelles as drug delivery carriers (title). Crosslinking micelles increased stability in cell culture media and greatly prolonged the rate of drug release (abstract). At concentrations below the CMC, such as would be used in vivo, the differences were profound (p824, 1st column, 3d paragraph). This reference teaches the advantages of crosslinking micelles in the context of drug delivery.
Streletzky et al teach that the ELP can be the hydrophobic portion of a surfactant system. Therefore, it would be obvious to crosslink these micelles, as discussed by Kim et al, to increase the stability of the assembly structures and to modulate the release rate of any drug. As the chemistry of micelle formation and dissolution are relatively well known, an artisan in this field would attempt this modification with a reasonable expectation of success.
In addition, as Singh et al teach that the size of the particle formed has an effect on the drug delivery, it would be obvious to optimize the size of the particle, using the pH, salt concentration, and ELP length, as discussed by Streletzky et al. As the reference clearly states that these parameters will affect the size of the resulting particles, an artisan in this field would attempt this optimization with a reasonable expectation of success.
Conclusion
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658