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 of Group I, claims 1-15, in the response dated 12/1/2025, is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.03(a)).
Regarding the species elections, since the elections result in no claims being withdrawn, the species restrictions required in the 6/26/2025 Restriction Requirement are withdrawn.
Claims 16-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claim Status
Claims 1-20 are pending.
Claims 16-20 are withdrawn.
Claims 1-15 are examined on the merits in this prosecution.
CLAIM REJECTIONS
Indefiniteness Rejection
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 listing the amino acid sequence or the SEQ ID No. of each of the claimed histidine-lysine peptide.
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 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (WO 2021/133931 A1).
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.
2) Claims 5, 8, and 9 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (cited above), in view of Leaver (“NANOPARTICLES - A Revolution in the Development of Drug Delivery Vehicles,” Drug Devlopment and Delivery, June 2017).
The teachings of Mixson are discussed above.
Mixson 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 Mixson.
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 Mixson 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).
3) Claims 7 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Mixson (cited above), 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).
The teachings of Mixson are discussed above.
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.
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.
2) Claim 1 is provisionally rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claim 70 of copending Application No. 18/249,023.
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 with a histidine-lysine copolymer. While the copending claim does not recite the instantly claimed ratio of histidine-lysine copolymer is between about 4.5:1 to about 2.5:1, MPEP 2144(II)(A) states “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." As such, a skilled artist would have the ability to determine a workable range by routine experimentation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
CONCLUSION
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) 272-6897. 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