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.
Previous Rejections
Applicant’s arguments, filed May 13, 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1-21 are pending.
Claims 16-21 are withdrawn.
Claims 1-15 are examined on the merits in this prosecution.
CLAIM REJECTIONS
Indefiniteness Rejection (Maintained)
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.
Claim 4 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 pre-AIA the applicant regards as the invention.
The term “HKP” in claim 4 appears to have alternative definitions in the life sciences, including “housekeeping proteins” and “hunter-killer peptide.” As such, the term is indefinite.
The examiner suggests adding the term “(HKP)” after “histidine-lysine copolymer” in the second line of claim 1 to overcome this rejection.
Obviousness Rejections
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 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.
1) Claims 1-4, 7, and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (WO 2021/133931 A1; of record), in view of Andreozzi (“Exploring the pH Sensitivity of Poly(allylamine) Phosphate Supramolecular Nanocarriers for Intracellular siRNA Delivery,* ACS Appl. Mater. Interfaces 2017, 9, 38242-38254; of record).
MIxson teaches compositions and methods for improved delivery of mRNA into eukaryotic cells using histidine-lysine (HK) peptide polymers. The polymers comprising four short peptide branches linked to a three-lysine amino acid core. The peptide branches consist of histidine and lysine amino acids, in different configurations, and they can vary in their location on the lysine core (Abstract).
For claim 1, Mixson teaches that the ratio of the nucleic acid molecule to the HK polymer is from 2:1 to 1:12 (wt:wt) (pg 7, [0022]), overlapping the claimed range. Because the claimed range overlaps with the range disclosed by the prior art, a prima facie case of obviousness exists. Mixson teaches that peptide H3K4b is an effective carrier of siRNA (pg 11, [0040]). This teaching also reads on claim 4.
For claims 2 and 3, Mixson teaches the pH of the medium or buffer in which the HK polyplexes are made can range from pH 4 to 8 (pg 17, [0056]), overlapping each of the claimed ranges.
The examiner acknowledges that some picking and choosing was used to arrive at the instantly claimed methods in view of Mixson. However, the claimed combination of components, including the nucleic acid and the HKP, is taught as known and taught as a method of making the complex. It would have therefore been prima facie obvious to a person having ordinary skill in the art to prepare the claimed formulation comprising the claimed ingredients, in the claimed ratio with a reasonable expectation of success that the process of making would be efficacious, as taught by Mixson.
Mixson does not teach the method of addition of phosphate anion in an amount of about 1 to about 2 mM to the reaction solution.
Andreozzi teaches the missing elements of Mixson.
Andreozzi teaches a nanocarrier (NC) for siRNAs that is stable at physiological pH and releases siRNAs in acidic endosomal pH, fulfilling siRNA delivery only inside cells. Andreozzi teaches application of polyarnine phosphate are able to load negatively charged nucleic acids and the complexes are pH stable. The polyamine-siRNA complexes are fabricated by complexation of phosphate anions from phosphate buffer solution with the amine groups of polyamine. It is noted that the polyamine example taught by Andreozzi is poly(allylamine) (Abstract). Andreozzi teaches a concentration of phosphate of 1-10 mM (pg 38243, Fig 2), and further teaches that the particle size of the polyamine siRNA particle may be controlled by manipulating the concentration of phosphate during the formation step.
The skilled artisan would have expected success in adding phosphate anion to the mixing method of Mixson sans phosphate anion since Andreozzi teaches a concentration of phosphate of 1-10 mM, and further teaches that particle size may be manipulated by optimizing the amount of phosphate present, wherein the lower the concentration of phosphate, the smaller the particle produced from the reaction of the polyamine with siRNA (pg 38244, left column). While Andreozzi does not specifically teach a histidine-lysine copolymer, it appears from the teachings of Andreozzi (pg 38243) that the advantages of a millimolar phosphate solution are generally applicable to polyamines, and such an effect would be obvious to skilled practitioners of drug formulation and utilized for control of particle size with a reasonable expectation of success.
2) Claims 5, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (cited above), in view of Andreozzi (cited above) and Leaver (“NANOPARTICLES - A Revolution in the Development of Drug Delivery Vehicles,” Drug Development and Delivery, June 2017; of record).
The teachings of Mixson and Andreozzi are discussed above.
The combination of Mixson and Andreozzi does not teach microfluidic mixing or the mixing flow rates recited in claims 8 and 9. It is noted that Mixson teaches a method for preparing a nucleic acid molecule with an HK polymer under conditions permitting binding between the nucleic acid molecule and the HK polymer to form a HK polyplex (pg 38, claim 9). It is further noted that Mixson teaches the nucleic acid to histidine-lysine peptide recited in claims 5
Leaver teaches the missing elements of the combination of Mixson and Andreozzi.
Leaver teaches a method of synthesizing polymeric nanoparticles by mixing in a microfluidic device (pg 4, first paragraph), further reading on claim 5.
For claims 8 and 9, Leaver teaches that the drug concentrations, flow rates, and mixing ratios can be manipulated and optimized by one of skill in the art to obtain nanoparticular products having a desired average particle diameter, polydispersity (inhomogeneity) and drug encapsulation efficiency (pg 4, third paragraph). Leaver teaches flow rates up to 18 mL/min are useful and the nanoparticle products are typically completed in just 15 to 20 seconds, enabling over 40 formulations to be prepared in 1 day (page 5, second paragraph).
The skilled artisan would have expected success in substituting Leaver's microfluidic mixing method for the mixing method of the combination of Mixson and Andreozzi since Mixson teaches a microfluidic mixer can utilize flow rates of up to 18 mL/min and such flow rates are useful for preparing nanoparticle products in large scale since each synthesis typically requires only 15 to 20 seconds to complete at a high flow rate. The person of ordinary skill in the art would have found it obvious to make the substitution because ordinarily skilled artisans would have predicted that the microfluidic system would also be effective in making nanoparticles having a desired average particle diameter and polydispersity (inhomogeneity).
Nonstatutory Double Patenting Rejection
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. See 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); and 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) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the conflicting application or patent is shown to be commonly owned with this application. See 37 CFR 1.130(b).
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based Terminal Disclaimer may be filled out completely online using web-screens. An e-Terminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
1) Claims 1-4, 6-7, and 10-15 are provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 7-12 and 19-21 of copending Application No. 17/935,022.
Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims in the reference application recite a method of making a pharmaceutical nanoparticle composition comprising mixing a nucleic acid composition in a solution of pH 4.0-6.9 with a solution comprising a histidine-lysine copolymer at pH 5.5-6.0, wherein the ratio of histidine-lysine copolymer is between about 2.5:1 to about 3:1. This method reads on claims 1-3 and 15 of the instant application.
The copending claims also recite the histidine-lysine copolymer, reading on claim 4 of the instant claims; the amount of acetate and/or phosphate in the composition, reading on instant claims 6-7 and 10-12 of the instant application; and nanoparticles, reading on claim 13 of the instant application. Claim 14, being prepared by the same process as claim 12, would be expected to have the same physical properties. See MPEP
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Examiner’s Reply to Attorney Arguments dated 5/13/2026
1. Rejection of claim 1 under 35 USC 112(b).
The applicant argues:
It is axiomatic that an applicant may be their own lexicographer, and that the claims must be construed in light of the specification. The specification makes clear that, in the context of the instantly claimed methods, "HKP" refers to histidine lysine copolymers. Moreover, the structures of the various HKP molecules recited in claim 4 are clearly shown, inter alia, in Figure 1 and paragraph 104 of the specification.
The Examiner acknowledges the arguments presented, but does not consider them persuasive. While the applicant has provided the structures and sequences of H3K4b and H3K8b, as shown in Figure 1, the disclosure does not provide limiting definitions, sequences, or structures of HKP or HKP(+H). As such, the rejection stands.
2. Rejection of claims 1-4 under 35 USC §103 over Mixson.
The applicant argues that Mixson is directed to compositions for delivering mRNA, whereas the instant claims are directed to delivery of siRNA. The applicant argues that Mixson mentions once in passing the notion of delivering siRNA, but all of the description and, in particular, all of the described nucleic acid:HKP ratios, relate to mRNA and not siRNA, and Mixson fails to teach or suggest any ratio of siRNA:HKP. The applicant further argues “mRNA molecules are much larger than siRNA molecules and, therefore, while the weight ratios described by Mixson might superficially resemble those recited in the instant claims, the actual molar ratios of nucleic acid and HKP differ enormously.”
The Examiner acknowledges the arguments presented, but does not consider them persuasive. As acknowledged by the applicant, Mixson, in fact, teaches the method of preparing a pharmaceutical composition comprising siRNA and the histidine-lysine copolymers. Mixon states:
two histidine-rich peptides analogs of H2K4b, namely H3K4b and H3K(+H)4b, were effective carriers of siRNA, although H3K(+H)4b appeared to be modestly more effective. Moreover, the H3K4b carrier of siRNA induced cytokines to a significantly greater degree in vitro and in vivo than the H3K(+H)4b siRNA polyplexes.
([0040]; references deleted by the Examiner)
As such, Mixson teaches the claimed histidine-lysine copolymer complexed with an siRNA, as presently claimed.
Regarding the ratio of copolymer to siRNA nucleic acid, since Mixson teaches siRNA as a nucleic acid, complexed with a histidine-leucine copolymer, the teaching of Mixson regarding the ratio of the nucleic acid molecule to the HK polymer is from 2:1 to 1:12 (wt:wt) (pg 7, [0022]), overlapping the claimed range, is sufficient for a prima facie obviousness rejection.
3. Rejection of claims 5 and 8-9 under 35 USC §103 over Mixson and Leaver.
The applicant argues that Mixson is deficient and no prima facie case of obviousness exists.
The Examiner acknowledges the argument presented, but does not consider it persuasive. As discussed above, it is the position of the Examiner that the invention of instant claim 1 is prima facie obvious in view of the teachings of Mixson, as modified by the prior art of Andreozzi.
4. Rejection of claims 7 and 11 under 35 USC §103 over Mixson and Andreozzi.
The applicant argues that Andreozzi is cited merely as teaching use of phosphate buffer in the context of a polyamine/siRNA complex where the polyamine has a structure that is completely unrelated to that of HKP.
The Examiner acknowledges the argument presented, but does not consider it persuasive. Andreozzi is cited for it’s teaching of the addition of phosphate ion to form the complex of siRNA and the basic carrier, in the teaching of Andreozzi’s poly(allylamine). Andreozzi teaches the basic nanocarriers “are very easy to prepare requiring just the mixing in a proper molar ratio of polyamines and phosphate ions, usually from sodium phosphate dibasic solution (Na2HPO4)” (pg 38243, left column). Andreozzi teaches polyamines act as a proton sponge, complexing with protons present in the acidic endosomal environment, swelling the endosome and leading to endosomic rupture and transfer a cargo such as an siRNA into the cytoplasm (pg 38243, right column). While poly(allylamine) is structurally different than a histidine-lysine copolymer, the teaching of Andreozzi suggests that polyamines other than poly(allylamine) would serve the same function of cargo release in the acidic endosomal environment.
4. Rejection of claims 1-4, 6-7, and 10-15 for obviousness-type double patenting over claims 7-12 and 19-21 of copending Application No. 17/935,022.
The applicant requests that the rejection over copending Application No. 17/935,022 be held in abeyance pending an indication of allowable subject matter.
The applicant requests that the rejection be held in abeyance until an allowable claim is identified.
Applicant requested that the Non-Statutory Double Patenting (NSDP) rejections be held in abeyance. In response to applicant’s request to hold In abeyance a response, such as a terminal disclaimer (TD) to the pending NSDP rejection, it is noted that the filing of a TD cannot be held in abeyance since that filing “is necessary for further consideration of the rejection of the claims,” as set forth in MPEP 804(I)(B)(1) quoted below:
As filing a terminal disclaimer, or filing a showing that the claims subject to the rejection are patentably distinct from the reference application's claims, is necessary for further consideration of the rejection of the claims, such a filing should not be held In abeyance. Only objections or requirements as to form not necessary for further consideration of the claims may be held In abeyance until allowable subject matter is indicated.
As such applicants’ request to hold the rejection in abeyance is considered to be non-responsive and the rejection is maintained.
CONCLUSION
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL P COHEN whose telephone number is (571)270-7402. The examiner can normally be reached on M-Th 8:30-5:30; F 9-4.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana S. Kaup, can be reached on (571)272-0580. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL P COHEN/Primary Examiner, Art Unit 1612
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