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 .
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/21/2026 has been entered.
Applicants' arguments, filed 04/21/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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, 2, 6, 9-15, and 20-28, are pending.
Claims 1, 2, 6, 9-11, 13, and 14, are withdrawn.
Amendments to the Claims
Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered). All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of “currently amended,” and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of “currently amended,” or “withdrawn” if also being amended, shall include markings. If a withdrawn claim is currently amended, its status in the claim listing may be identified as “withdrawn— currently amended.” See MPEP 714(c) and (c)(2). In the present instance, claims 13 and 14 are withdrawn, however, the claims comprise the identifiers “(previously presented).”
Specification
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
The abstract of the disclosure is objected to because “and” is missing after “treatment;” and before “a pharmaceutical composition” in the last line. Also, a period is missing at the end of the abstract. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Claim Objections
Claim 15 is objected to because of the following informalities: “A method of medical treatment which method includes…” should read “A method of medical treatment, wherein the method includes” for purposes of grammatical clarity and claim structure. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b) or pre-AIA 2nd ¶
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.
Claims 12, 15, and 20-28, are 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c).
In the present instance, claim 12 recites the broad recitation “R1 represents a hydrogen atom or a straight or branched chain alkyl group”, and the claim also recites " preferably a branched chain alkyl group comprising from 1 to 6 carbon atoms" which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 12, as newly amended, recites the formulation comprises “an anionic polymer consisting of a repetitive unit of formula (I),” and later recites “said repetitive unit of formula (I) comprises N,N dimethyl amino ethyl methacrylate.” It is unclear how the repetitive unit of formula (I) can comprise N,N dimethyl amino ethyl methacrylate (open language), when the claim previously limits the ionic polymer to a (singular) repetitive unit of formula (I). Here, the comprising language suggests other repetitive units of formula (I) can be included, but at the same time, the claim limits the ionic polymer to a single repetitive unit of formula (I).
Further, it appears claim 12 is attempting to limit the ionic polymer to repetitive units consisting of N,N dimethyl amino ethyl methacrylate, and if so, it is unclear why the broader formula (I) precedes the recitation of N,N dimethyl amino ethyl methacrylate.
Claim 12 also recites a “proteinaceous agent,” and while it appears Applicants define the term as “a peptide or a polypeptide or a hormone,” claim 12 recites the proteinaceous agent is selected from a Markush group, where not all appear to be exclusively proteinaceous, as defined by the instant specification. For example, it does not appear that all hormones, enzymes, clotting factors, antigenic agents, etc., are proteinaceous. Adding to the lack of clarity is the instant specification, where in multiple instances, the proteinaceous agent is recited as heparin, which is a polysaccharide, and not a peptide, a polypeptide, or a hormone (see for example page 3 of the instant specification). For purposes of examination, the proteinaceous agent is being interpreted as a peptide, a polypeptide, or a hormone, and the Markush group requiring all to be proteinaceous (i.e., a peptide, a polypeptide, or a hormone).
Claim 12 also recites “a molar ratio of N,N dimethyl amino ethyl methacrylate to a different repetitive unit of formula (I) present in the said complex is greater than 75%,” and it is unclear how the molar ratio of N,N dimethyl amnio ethyl methacrylate can be anything other than 100%, where the claims, as newly amended, consists of (closed language) a single repetitive unit, the repetitive unit appearing to be N,N dimethyl amino ethyl methacrylate.
Claims 15, and 20-28, are rejected for the same reasons for depending upon, or otherwise including all limitations of rejected claim 12.
Claim 15 recites “an ionic polymer comprising a repetitive unit of formula (I) as defined in claim 12,” and it is unclear if the repetitive unit of formula (I) as defined in claim 12 is referring to the broader structure formula (I) or the N,N dimethyl amino ethyl methacrylate. For purposes of examination, the limitation is interpreted to refer to the N,N dimethyl amino ethyl methacrylate.
Claims 15 and 20 also recite the limitation of a “proteinaceous agent,” which is unclear for the same reasons discussed above.
Claim 24 recites “wherein said ionic polymer is present in said formulation in a greater weight percentage than each other components of said formulation,” and as claimed, it is unclear if the ionic polymer is in a greater weight percentage than each other component individually, or the total sum of the other components compared the weight percentage of the ionic polymer.
Claim 26 recites “wherein the complex encapsulation comprises alginate,” and the limitation is unclear where “complex encapsulation” is a step, rather than a component, and it is unclear how a step comprises alginate. For purposes of examination, the claim is interpreted as wherein the complex is encapsulated with alginate to protect from gastric environment.
Claims 27 and 28 recite “administering the complex,” and where newly amended claim 12 recites a formulation comprising a complex, it is unclear if it just the complex or the formulation comprising the complex is being administered.
Claim Interpretation
Claim 12 has been amended to newly recite “the method comprising administering… a formulation comprising an effective amount of a poly amphiphilic electrolyte complex.” The examiner notes that in the reply dated 06/18/2025, Applicants elected Group II, which was drawn to a method of administering a complex, rather than a method of administering a formulation comprising a complex. For purposes of examination, claim 12 and its dependents are interpreted as a method of administering an effective amount of a poly amphiphilic electrolyte complex, which is consistent with Applicant’s original election. Accordingly, as used throughout the claims, the formulation is interpreted as being the complex.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 12 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Foster et al (Bioconjugate Chem., 2010, 21(12): 2153-2362, cited on IDS dated 04/09/2023), as evidenced by Cymit (Poly[2-dimethylamino)ethyl methacrylate), Zanata et al (Eur. Poly. Jour., 2022, 162, pp. 1-13), and Pereira et al (Process Biochem, 2016, 51(6): 781-791).
Foster et al disclose an ionic polydimethylamionethyl methacrylate (PDMAEMA) polymer complexed to anionic PAA ovalbumin (proteinaceous antigen) conjugates, wherein cationic PDMAEMA was synthesized for nanoparticle formation by ionic complexation with anionic PPAA ovalbumin conjugates (abs, pg. 2206 1st col 2nd ¶). PDMAEMA was added at pH 7.4 where it was charged (pg. 2206 1st col last ¶). As evidenced by Cymit, polydimethylamionethyl methacrylate (PDMAEMA) is also known as N,N-dimethylaminoethyl methacrylate polymer. As evidenced by Zanata et al, PDMAEMA has a pKa between 7 and 7.5 (pg. 1 2nd col). As evidenced by Pereira et al, ovalbumin is negatively charged at neutral pH (pg 9 1st ¶). The complexes were used as vaccines and were administered to treat mice (pg. 2208 1st col last ¶).
Regarding the poly amphiphilic electrolyte complex of claim 12, where the PDMAEMA polymer disclosed by Foster et al is made up of DMAEMA monomers, and is the only polymer used to complex the ovalbumin conjugates, the limitation of a homopolymer of repeating units of DMAEMA (i.e., the PDMAEMA) is met. Further, the examiner notes that the molar ratio of claim 12 is in relation to a different repetitive unit of formula (I). Accordingly, where no other repetitive units of formula (I) are present, DMAEMA makes up the entirety of the molar ratio. In other words, the molar ratio of DMAEMA in the ionic polymer compared to a different repetitive unit of formula (I) (none appear to be present) is necessarily greater than 75%.
Further, it appears that PDMAEMA would be expected to complex with ovalbumin, where PDMAEMA is cationic and ovalbumin is negatively charged, thereby appearing to form a polyelectrolyte complex as instantly claimed. Additionally, where the complex of Foster et al comprises PDMAEMA and ovalbumin, the same components as instantly claimed, it appears that the limitation of a poly amphiphilic electrolyte complex is met.
Regarding the method of claim 12, the complexes were administered to mice as vaccines, thereby reading on administering to an animal in need of treatment, as instantly claimed.
Regarding the mean pKa of claim 12, PDMAEMA has a pKa between 7 and 7.5, as evidenced by Zanata et al above, thereby meeting the claimed limitation.
Regarding the proteinaceous agents of claim 12, where the complexes of Foster et al comprise ovalbumin (proteinaceous agent and antigen), and are used as an active agent for vaccines, the limitations are met.
Response to Arguments
Applicants assert Foster et al relies on a dual-polymer system including PPAA in additional to PDMAEMA, whereas amended claim 12 is now confined to a single ionic polymer system and excludes formulations containing PPAA. Applicants assert Foster et al does not disclose PPAA as optional, and the skilled artisan would have no reason to omit PPAA.
Respectfully, this argument is not persuasive. Claim 12, as newly amended, recites “a formulation comprising… a poly amphiphilic electrolyte complex comprising at least one… proteinaceous agent, and an ionic polymer consisting of a repetitive unit of formula (I).” Contrary to Applicants’ assertion, claim 12 allows for additional polymers as long as an ionic polymer consisting of a repetitive unit of formula (I) is present, where the complex “comprises” (open language) a polymer consisting of formula (I). Accordingly, where Foster et al discloses a complex comprising PDMAEMA (polyelectrolyte) and ovalbumin (proteinaceous agent), and where the PDMAEMA would be expected to complex with the ovalbumin, it appears the limitation of a poly amphiphilic electrolyte complex comprising at least one proteinaceous agent and an ionic polymer consisting of formula (I) is met.
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.
Claims 15 and 22-24, are rejected under 35 U.S.C. 103 as being unpatentable over Foster et al (Bioconjugate Chem., 2010, 21(12): 2153-2362, cited on IDS dated 04/09/2023), as applied to claims 12 and 19 above, and further in view of Kabanov et al (US 20190111109 A1).
Foster et al are discussed above and further contemplates the use of this compositions against true therapeutic targets, including human tumor xenografts, etc. (pg. 2210 2nd col 1st ¶).
Foster et al do not specifically disclose the further inclusion of a surfactant, wherein the complex has been submitted to a drying process, wherein the treatment is administered to a human, nor wherein the weight percent of the polymer is the majority component.
Kabanov et al teach polyelectrolyte complexes for delivery of agents to a subject, wherein the agents are therapeutic agents such as polypeptides and proteins (abs, ¶ 5). The complexes comprise a synthetic polymer and the therapeutic agent, wherein the polymer may be a homopolymer, etc. (¶ 5, ¶ 74). The homopolymer may have a net positive charge (¶ 74). Suitable polymers with a net positive charge include N,N-dimethylaminoethyl methacrylate (¶ 76). As evidenced by Zanata et al, poly(N,N-dimethylaminoethyl methacrylate) has a pKa between 7 and 7.5 (pg. 1 2nd col). The complexes may contain any suitable agent, e.g., a polypeptide, including, but not limited to, enzymes, antibodies or antibody fragments, hormones, cytokines (¶¶ 88, 89). The complexes provide improved delivery and/or retention of the therapeutic agents (¶ 5). Administration of the polyelectrolyte complexes of the present invention to a human subject or an animal in need thereof can be by any means known in the art for administering compounds for medical and veterinary applications (¶¶ 102, 119). Emulsifiers can be included for poorly soluble compounds, including phosphatidylcholines and lecithin (¶ 116). The formulations can comprise dispersing agents, adjuvants, etc. (¶ 100). The complexes can be freeze-dried (lyophilized) (¶ 105). In some embodiments, the proteinaceous agent is included at 1 mg/ml and the polymer at 2 mg/ml (¶ 96). The complexes can be encapsulated, enteric-coated for selective disintegration in the gastrointestinal tract, etc. (¶ 108). The compositions can be administered intranasally, to the lungs, topically, etc. (¶¶ 103, 107).
Regarding claim 15, it would have been obvious to further include an emulsifier or dispersing agent, such as phosphatidylcholine, to the complex of Foster et al, where these emulsifiers were known to be include into complexes that can comprise PDMAEMA and a proteinaceous agent, as taught by Kabanov et al, where the skilled artisan would recognize that emulsifiers or dispersing agents can be used in order to optimize the surface properties of the proteinaceous agents for stability, compatibility, etc. Further, it appears the emulsifying agents and dispersing agents taught by Kabanov et al read on surfactants, where the instant specification defines surfactants as any compound that is capable of altering surface properties of a given phase towards another phase, and phosphocholine derivatives (i.e., phosphatidylcholine) are disclosed as suitable surfactants (see ¶ 13 of the instant specification).
Regarding claim 22, it would have been obvious to modify the complex in the method made obvious above, by formulating a freeze-dried complex, a known storage method for polymeric complexes comprising proteinaceous agents, as taught by Kabanov et al.
Regarding claim 23, while Foster et al do not each delivering the complexes comprising proteinaceous agents to a human, and instead teaches administration to mice, Foster et al contemplates future studies for treating human tissues. The skilled artisan would recognize that the goal from administration of the complexes to mice, would be to extend those treatments to human subjects. Accordingly, where complexes comprising N,N-dimethyl amino ethyl methacrylate with a proteinaceous agent were known to be suitable for administration to humans, it would have been obvious for the skilled artisan to administer the complexes of Foster et al to a human for medical treatment, where both are directed to complexes comprising N,N-dimethyl amino ethyl methacrylate with a proteinaceous agent for medical treatments.
Regarding claim 24, it would have obvious to modify the complex of Foster et al with known ratios suitable for polymer complexes comprising proteinaceous agents, such as 2:1 (2 mg/ml polymer to 1 mg/ml proteinaceous agent), as taught by Kabanov et al, thereby appearing to read on the limitation of wherein the polymer by weight percent is the majority component.
Response to Arguments
Applicants have not provided arguments with respect to Foster et al in view of Kabanov et al. Accordingly, the claims stand rejected for the same reasons above and of record.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Foster et al (Bioconjugate Chem., 2010, 21(12): 2153-2362, cited on IDS dated 04/09/2023), as applied to claim 12 above, and further in view of Wilson et al (ACS Nano, 2013, 7, 5, pp. 3912-3925, cited on IDS dated 04/09/2023).
Foster et al are discussed above but do not teach wherein the proteinaceous agent is an antigenic peptide specifically nor wherein the complex further comprises an adjuvant of instant claims 20 and 21.
Wilson et al teach pH responsive nanoparticle vaccines where it was known to formulate polymeric complexes comprising DMAEMA (i.e., N,N-dimethyl amino ethyl methacrylate) for the co-delivery of proteinaceous antigens and immunostimulatory oligonucleotides (abs). Dual delivery of proteinaceous antigens and immunostimulatory oligonucleotides from the polymer complexes were known to significantly increase immune response (abs). In a particular embodiment, DMAEMA as the primary component (97%) (pg. 3913).
Regarding claims 20 and 21, it would have been obvious to modify the complex in the method made obvious above, by selecting from other known protein based therapeutic agents that are suitable for polymeric complexes for administering to a subject for medical treatment, such as proteinaceous antigens, as taught by Wilson et al. Additionally, it would have been obvious to further include an oligonucleotide adjuvant, where the dual delivery of proteinaceous antigens and oligonucleotide adjuvant from polymeric complexes comprising N,N-dimethyl amino ethyl methacrylate were known to significantly increase immune response, as contemplated by Foster et al and taught by Wilson et al.
Response to Arguments
Applicants assert amended claim 12 no longer reads on the Foster et al system for the reasons discussed above. Applicants further assert Wilson et al do not cure the deficiencies of Foster et al, where it is argued that Wilson et al do not disclose or suggest the presently claimed PAEC formulation, nor disclose or suggest the now-claimed single ionic polymer system that excludes Foster et al’s PPAA-containing complexes. Applicants assert the proposed combination is based on hindsight as Wilson et al do not teach or suggest modifying Foster to remove or exclude PPAA.
Respectfully, this argument is not persuasive. The examiner disagrees with Applicants that Foster et al does not disclose the method of claim 12, for the same reasons discussed above and of record.
Claims 12, 15, 22-25, 27, and 28, are rejected under 35 U.S.C. 103 as being unpatentable over Kabanov et al (US 20190111109 A1), in view of Horn et al (Polymers, 2019, 11, 578, pp. 1-26, hereinafter “Horn”), as evidenced by Zanata et al (Eur. Poly. Jour., 2022, 162, pp. 1-13).
Kabanov et al teach polyelectrolyte complexes for delivery of agents to a subject, wherein the agents are therapeutic agents such as polypeptides and proteins (abs, ¶ 5). The complexes comprise a synthetic polymer and the therapeutic agent, wherein the polymer may be any type of polymer that is suitable for the complex, including a homopolymer, a random copolymer, or a block or graft copolymer (¶¶ 5, 74, claim 10). The homopolymer may have a net positive charge (¶ 74). Suitable polymers with a net positive charge include N,N-dimethylaminoethyl methacrylate (¶ 76). As evidenced by Zanata et al, poly(N,N-dimethylaminoethyl methacrylate) has a pKa between 7 and 7.5 (pg. 1 2nd col). The complexes may contain any suitable agent, e.g., a polypeptide, including, but not limited to, enzymes, antibodies or antibody fragments, hormones, cytokines (¶¶ 88, 89). The complexes provide improved delivery and/or retention of the therapeutic agents (¶ 5). Administration of the polyelectrolyte complexes of the present invention to a human subject or an animal in need thereof can be by any means known in the art for administering compounds for medical and veterinary applications (¶¶ 102, 119). Emulsifiers can be included for poorly soluble compounds, including phosphatidylcholines and lecithin (¶ 116). The formulations can comprise dispersing agents, adjuvants, etc. (¶ 100). The complexes can be freeze-dried (lyophilized) (¶ 105). In some embodiments, the proteinaceous agent is included at 1 mg/ml and the polymer at 2 mg/ml (¶ 96). The complexes can be encapsulated, enteric-coated for selective disintegration in the gastrointestinal tract, etc. (¶ 108). The compositions can be administered intranasally, to the lungs, topically, etc. (¶¶ 103, 107).
Kabanov et al do not specifically teach poly(N,N-dimethylaminoethyl methacrylate) as a homopolymer.
Horn teaches it was known to formulate protein-polyelectrolyte complexes with homopolymers, suitable common synthetic polycations include PDMAEMA (fig 1, table 1, pg 6 1st ¶). Proteins can participate in macrophase separation by directly phase separating with an oppositely charged polymer (pg 2 last ¶).
Regarding the complex of claim 12, where Kabanov et al teach the complexes can be formulated with any type of polymer suitable for complexing, and include cationic homopolymers, it would have been obvious for the skilled artisan to modify Kabanov et al by selecting from known polycationic homopolymers suitable for formulating polyelectrolyte complexes with proteinaceous agents, such as PDMAEMA, as taught by Horn, and where Kabanov et al teaches N,N-dimethylaminoethyl methacrylate as a suitable polymer for polyelectrolyte complexes. Where the polymer made obvious above is a homopolymer, the homopolymer consists of repeating units of N,N-dimethylaminoethyl methacrylate, thereby meeting the claimed limitation.
Regarding the mean pKa of claim 12, poly(N,N-dimethylaminoethyl methacrylate) has a pKa between 7 and 7.5, as evidenced by Zanata et al above.
Regarding the molar ratio, where the polymer is a homopolymer, the N,N-dimethylaminoethyl methacrylate repeating monomers necessarily have a molar ratio relative to a different repetitive unit of formula (I) of greater than 75%.
Regarding the proteinaceous agent of claim 12, it would have been obvious to select from suitable proteinaceous agents, such as cytokines, hormones, enzymes, etc., as taught by Kabanov et al.
Regarding the method of claim 12, it would have been obvious administer the complex made obvious above to a human or animal in need thereof for medical treatment, as taught by Kabanov et al.
Regarding claim 15, it would have been obvious to include an emulsifier or dispersing agent, such as phosphatidylcholine, to the complexes of Kabanov et al, in order to emulsify the desired proteinaceous agent, as taught by Kabanov et al, where a skilled artisan would recognize that the inclusion of emulsifiers or dispersing agents are a way to include various proteinaceous agents with varying surface properties for compatibility with the complex made obvious above. Further, it appears the emulsifying agents and dispersing agents taught by Kabanov et al read on surfactants, where the instant specification defines surfactants as any compound that is capable of altering surface properties of a given phase towards another phase, and phosphocholine derivatives (i.e., phosphatidylcholine) are disclosed as suitable surfactants (see ¶ 13 of the instant specification).
Regarding claim 22, where the claims are directed to a method of treating a subject comprising the complex made obvious above, the process of formulating the complex are simply product by process limitations or intended use limitations. Here, where the method made obvious above comprises a complex that can be in the form of a dry powder, it appears the product by process or intended use limitations are met where the drying process is simply a method of drying the composition to be used in the treatment methods. Nevertheless, were Kabanov et al teaches the complexes can be freeze-dried, it would have been obvious for the skilled artisan to freeze dry the complexes made obvious above.
Regarding claim 23, it would have been obvious to administer the complex in the method made obvious above to a human, as taught by Kabanov et al.
Regarding claim 24, where Kabanov et al disclose working embodiments comprising a 2:1 weight ratio of polymer to proteinaceous agent (2 mg/ml to 1 mg/ml), when formulating the complex made obvious above, it would have been obvious to start with those ratios from the working examples and adjust from there in order to achieve desired optimal structure and properties. Accordingly, the limitation of wherein the polymer by weight percentage is the majority component appears to be met.
Regarding claim 25, it would have been obvious to encapsulate or coat the complex in an enteric coating for selective disintegration in the gastrointestinal tract, as taught by Kabanov et al.
Regarding claim 27, it would have been obvious to administer the complex in the method made obvious above by nasal administration or pulmonary administration, as taught by Kabanov et al.
Regarding claim 28, it would have been obvious to administer the complex in the method made obvious above by topical administration, as taught by Kabanov et al.
Response to Arguments
First, Applicants assert Kabanov et al’s core disclosure is not directed to the presently claimed formulation, and is instead configured around a required charge-ratio framework that does not point toward, and teaches away from, the presently claimed formulation based on a single ionic polymer consisting of the recited repetitive unit.
Second, Applicants assert the Examiner’s reliance on paragraph [0074] of Kabanov et al is misplaced when divorced from the context of the document as a whole. Applicants assert that although Kabanov et al refers generally to a homopolymer or a random copolymer and to net positive or negative charge, Kabanov et al do not actually disclose or exemplify a homopolymer, much less the claimed formulation based on DMAEMA. Applicants assert paragraph [0076] merely lists DMAEMA among many possible monomers for a polyion segment of a block or graft copolymer. Applicants assert that absent the present disclosure, the Examiner’s path from Kabanov to the formulation using a DMAEMA-based ionic polymer as presently claimed can be reached only through impermissible hindsight.
Third, Applicants assert, with regards to claim 24, that the polymer used in the protein polymer ratio was a PEG-PGA block copolymer, not a DMAEMA ionic polymer. Applicants assert these teachings cannot be extrapolated to a homopolymer or a single ionic polymer based on DMAEMA. Further, Applicants assert paragraph [0097] of Kabanov et al teaches that excess unreacted polyion can be removed, so there is no clear teaching of the final relative amount of polymer to proteinaceous agent.
Fourth, Applicants assert Kabanov refers to emulsifiers in paragraph [0116], however, the paragraph expressly addresses water-insoluble compounds. Applicants assert this teaching cannot be reasonably applied to the presently claimed complexes, because the complexation with the ionic polymer of the present invention confers water-soluble properties.
First, respectfully, this argument is not persuasive. The charge ratio of Kabanov et al appears to be discussing the difference in charges for the peptide and polymer used in the polyelectrolyte complexes. It is not clear to the examiner how a recitation on charge ratio teaches away from a single ionic polymer consisting of the recited repetitive units, where the reference explicitly teaches the polymer can be an ionic homopolymer, as discussed above. It would have been obvious for the skilled artisan to modify polyelectrolyte complex of Kabanov et al, with other known homopolymers suitable for polyelectrolyte complexes, such as PDMAEMA, as taught by Horn for the same reasons discussed above.
Second, respectfully, this argument is not persuasive. Paragraph [0074] of Kabanov et al explicitly teaches the polymer in the polyelectrolyte complex may be any type of polymer that is suitable for the complex, including ionic homopolymers (including polymers with a net positive charge), random copolymers, or a block or craft copolymer. While the examiner does recognize that DMAEMA is listed among suitable cationic polymers as part of a polyion segment of a copolymer, Kabanov et al teaches DMAEMA was a suitable cationic polymer for the polyelectrolyte complexes. From there, the skilled artisan can look to Horn, where Horn teaches that protein polyelectrolyte complexes were known to be formulated with homopolymers, and common suitable homopolymers include PDMAEMA. Therefore, it would have been obvious to modify Kabanov et al by formulating the polyelectrolyte complexes with PDMAEMA homopolymer, for the same reasons discussed above. In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Third, respectfully, this argument is not persuasive. While Kabanov et al do disclose a PEG-PGA block copolymer embodiment and do not appear to disclose a working embodiment with PDMAEMA homopolymer, where Kabanov et al teach homopolymers, copolymers, etc., are suitable as the polymer component, it would have been obvious for the skilled artisan to turn to the examples for guidance as to the amounts of polymer and proteinaceous agent. The skilled artisan could reasonably start with those from the examples (1 mg/ml protein, 2 mg/ml polymer), and adjust from there in order to achieve desired and optimal complex properties, thereby resulting in a polymer content that is greater in weight percentage than the other components of the complex. Regarding the argument of the final relative amounts, Kabanov et al teaches excess unreacted polyion may be removed (i.e., not required), and further teaches that the polyion complexes contain less than 10% free polyion not incorporated in the complex, e.g., less than 2% free polyion, e.g., the complex is essentially free of the polyion (see ¶ 97 of Kabanov et al). So at worst, the complex comprises less than 10% of free polyion that is not complexed, which would appear to still result in a greater weight percentage of polymer than proteinaceous agent. There appears to be no requirement in Kabanov et al that the removal of excess polyion must take place in order for less than 10% free polyion to be achieved.
Fourth, respectfully, this argument is not persuasive. As recited in the last Office Action, while Kabanov et al do disclose embodiments with dispersing agents (i.e., surfactants) for poorly water-soluble compounds, the reference more broadly teaches the formulations can optionally comprise additional agents including medicinal agents, pharmaceutical agents, carriers, adjuvants, dispersing agents, diluents, and the like (¶ 100). It would have been obvious to include an emulsifier or dispersing agent, to the complexes of Foster et al, in order to emulsify the desired proteinaceous agent, as taught by Kabanov et al, where a skilled artisan would recognize that the inclusion of emulsifiers or dispersing agents are a way to include various proteinaceous agents with varying surface properties for compatibility with the complex made obvious above.
Claims 20 and 21 are rejected under 35 U.S.C. 103 as being unpatentable over Kabanov et al (US 20190111109 A1) and of Horn et al (Polymers, 2019, 11, 578, pp. 1-26, hereinafter “Horn”), as applied to claims 12, 15, 22-25, 27, and 28 above, and further in view of Wilson et al (ACS Nano, 2013, 7, 5, pp. 3912-3925, cited on IDS dated 04/09/2023).
The references are discussed above but do not teach wherein the proteinaceous agent is an antigenic peptide for vaccination, nor wherein the complex further comprises an adjuvant to enhance the immune response towards the antigenic peptide.
Wilson et al are discussed above and are repeated here for convenience. Wilson et al teach pH responsive nanoparticle vaccines where it was known to formulate polymeric complexes comprising DMAEMA (i.e., N,N-dimethyl amino ethyl methacrylate) for the co-delivery of proteinaceous antigens and immunostimulatory oligonucleotides (abs). Dual delivery of proteinaceous antigens and immunostimulatory oligonucleotides from the polymer complexes were known to significantly increase immune response (abs). In a particular embodiment, DMAEMA as the primary component (97%) (pg. 3913).
Regarding claims 20 and 21, the examiner notes that while the working embodiments are directed to delivering agents to the central nervous system, the reference more broadly teaches administering an active agent, in particular a proteinaceous active agent, from polymeric complexes for medical treatments. Accordingly, it would have been obvious to modify the complex in the method made obvious above, by selecting from other known protein based therapeutic agent that are suitable for polymeric complexes for administering to a subject for medical treatment, such as proteinaceous antigens, as taught by Wilson et al. Additionally, it would have been obvious to further include an oligonucleotide adjuvant, where the dual delivery of proteinaceous antigens and oligonucleotide adjuvant from polymeric complexes comprising N,N-dimethyl amino ethyl methacrylate were known to significantly increase immune response.
Response to Arguments
Applicants assert Kabanov et al, as evidenced by Zanata, do not teach the presently claimed formulation of claim 12 for the same reasons discussed above. Applicants assert Wilson et al do not cure the deficiencies of Kabanov et al and assert that before Wilson et al can be considered, a proper basis in view of Kabanov et al must be established.
Respectfully, this argument is not persuasive. The claims stand rejected for the same reasons above and of record. The examiner notes that Horn et al is newly cited above for teaching homopolymers of PDMAEMA were known to be used in polyelectrolyte protein complexes.
Claim 26 is rejected under 35 U.S.C. 103 as being unpatentable over Kabanov et al (US 20190111109 A1) of Horn et al (Polymers, 2019, 11, 578, pp. 1-26, hereinafter “Horn”), as applied to claims 12, 15, 22-25, 27, and 28 above, and further in view of Pippa et al (J Polym Res, 2018, 25: 117, pp. 1-9, cited on IDS dated 04/09/2023).
The references are discussed above but do not specifically teach alginate as the encapsulant.
Pippa et al teach it was known to encapsulate PDMAEMA polymers in alginate beads for use in gastric fluid (abs).
It would have been to encapsulate the complex in the method made obvious by Kabanov et al with other known encapsulating agents suitable for PDMAEMA polymers in gastric environments, such as alginate, as taught by Pippa et al.
Response to Arguments
Applicants assert Kabanov et al, as evidenced by Zanata, do not teach the presently claimed formulation of claim 12 for the same reasons discussed above. Applicants assert the examiner has not established that Kabanov et al teaches or suggests the underlying formulation and the additional reference to Pippa et al does not render claim 26 obvious.
Respectfully, this argument is not persuasive. The claims stand rejected for the same reasons above and of record. The examiner notes that Horn et al is newly cited above for teaching homopolymers of PDMAEMA were known to be used in polyelectrolyte protein complexes.
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 12, 15, and 20-28, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/566,679 (reference application), hereinafter ‘679, in view of Kabanov et al (US 20190111109 A1), Wilson et al (ACS Nano, 2013, 7, 5, pp. 3912-3925, cited on IDS dated 04/09/2023), and Pippa et al (J Polym Res, 2018, 25: 117, pp. 1-9, cited on IDS dated 04/09/2023). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘679 disclose a method of medical treatment which includes a step of administering to a human or animal a complex comprising at least one medically active hydrophobic active agent, an ionic polymer comprising a repetitive unit of formula (I) (appearing to be substantially the same polymer as instantly claimed), and optionally a surfactant.
The claims of ‘679 do not disclose a proteinaceous agent specifically, wherein the active agent is an antigenic peptide, the further inclusion of an oligonucleotide adjuvant, wherein the complex has been submitted to a drying process, wherein the complex is encapsulated to protect from gastric environment, wherein the ionic polymer is greater in weight percentage than the other components, nor the administration routes of instant claims 27 and 28.
Kabanov et al, Wilson et al, and Pippa et al, are discussed above.
It would have been obvious to modify the claims of ‘679 by including a proteinaceous agent, which were known to be suitable for complexing with polymers for active agent delivery, as taught by Kabanov et al. Further, the skilled artisan would recognize that many proteinaceous agents are hydrophobic, and could reasonably select from hydrophobic proteinaceous agents. Further, where the method made obvious above comprises a proteinaceous agent and a polymer as instantly claimed, and form a complex, it appears the limitation of a poly amphiphilic electrolyte complex is met.
It would have been obvious to modify the complex in the method made obvious above, by selecting from other known protein based therapeutic agents that are suitable for polymeric complexes for administering to a subject for medical treatment, such as proteinaceous antigens, as taught by Wilson et al. Additionally, it would have been obvious to further include an oligonucleotide adjuvant, where the dual delivery of proteinaceous antigens and oligonucleotide adjuvant from polymeric complexes comprising N,N-dimethyl amino ethyl methacrylate were known to significantly increase immune response.
Regarding wherein the complex has been submitted to a drying process, the process of formulating the complex are simply product by process limitations or intended use limitations. It would have been obvious to formulate the complex made obvious above in the form of a dry powder, which was known to be suitable for polyelectrolyte complexes, as taught by Kabanov et al for the same reasons discussed above. Accordingly, it appears the product by process or intended use limitations are met where the drying process is simply a method of drying the composition to be used in the treatment methods.
It would have been obvious to encapsulate or coat the complex in an enteric coating (i.e., encapsulate) for selective disintegration in the gastrointestinal tract, as taught by Kabanov et al.
It would have been obvious to encapsulate the complex in the method made obvious above with other known encapsulating agents suitable for PDMAEMA polymers in gastric environments, such as alginate, as taught by Pippa et al.
When formulating the complex made obvious above, it would have been obvious to start with known amount of polymer and proteinaceous agent that were known to be suitable for polyelectrolyte complexes, such 2 mg/ml polymer and 1 mg/ml proteinaceous agent, as taught by Kabanov et al, and adjust from there in order to achieve desired optimal structure and properties. Accordingly, the limitation of wherein the polymer by weight percentage is the majority component appears to be met.
It would have been obvious to administer the complex in the method made obvious above by nasal administration, pulmonary administration, or topical administration, all of which were known administration methods for active agent-polymer complexes for delivery of an active agent, as taught by Kabanov et al.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 12, 15, and 20-28, are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of copending Application No. 18/728,039 (reference application), hereinafter ‘039, in view of Kabanov et al (US 20190111109 A1), Horn et al (Polymers, 2019, 11, 578, pp. 1-26, hereinafter “Horn”), Wilson et al (ACS Nano, 2013, 7, 5, pp. 3912-3925, cited on IDS dated 04/09/2023), and Pippa et al (J Polym Res, 2018, 25: 117, pp. 1-9, cited on IDS dated 04/09/2023). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘039 disclose a polymer consisting of a succession of monomers according to formula I (overlapping structure with those instantly claimed), and a pharmaceutical component, wherein said pharmaceutical component is non-covalently bound to the polymer. The polymer may be administered to a mammalian patient by inhalation (nasal), topically, etc., and the polymer and pharmaceutical component are encapsulated in a stomach protecting layer. The weight ratio of polymer to pharmaceutical component ranges from 99.9:0.1 and 50:50. The pharmaceutical component is selected from the group consisting of peptides, nucleic acids, etc. Adjuvants can be included.
The claims of ‘039 do not specifically disclose the combination is a poly amphiphilic electrolyte complex, an embodiment comprising a surfactant, wherein the peptide is an antigenic peptide for vaccination, wherein the adjuvant is an oligonucleotide, wherein the complex has been submitted to a drying process, nor wherein the encapsulant comprises alginate.
The references are discussed above.
Where the claims of ‘039 comprise repetitive units of a polymer as instantly claimed, and comprise pharmaceutical proteinaceous agents as instantly claimed, it appears that the combination would form a poly amphiphilic electrolyte complex as instantly claimed. See MPEP 2112(II) and (III). Purely arguendo, even if not, it would have been obvious to modify the claims of ‘039 by forming a polyelectrolyte complex, where proteinaceous agents and polymers as instantly claimed were known to form polyelectrolyte complexes for the delivery of active agents, as taught by Kabanov et al and Horn et al, for the same reasons discussed above. Additionally, it appears the polyelectrolyte complex meets the limitation of a poly amphiphilic electrolyte complex for the same reasons discussed above. Further, it would have been obvious to use the complexes for the method of medical treatment, were Kabanov et al teaches polyelectrolyte complexes are suitable for proteinaceous active agent delivery, for the same reasons discussed above.
It would have been obvious to include an emulsifier or dispersing agent, such as phosphatidylcholine, to the complexes of made obvious above, in order to emulsify the desired proteinaceous agent, as taught by Kabanov et al, where a skilled artisan would recognize that the inclusion of emulsifiers or dispersing agents are a way to include various proteinaceous agents with varying surface properties for compatibility with the complex made obvious above. Further, it appears the emulsifying agents and dispersing agents taught by Kabanov et al read on surfactants, where the instant specification defines surfactants as any compound that is capable of altering surface properties of a given phase towards another phase, and phosphocholine derivatives (i.e., phosphatidylcholine) are disclosed as suitable surfactants (see ¶ 13 of the instant specification).
It would have been obvious to modify the complex in the method made obvious above, by selecting from other known protein based therapeutic agents that are suitable for polymeric complexes for administering to a subject for medical treatment, such as proteinaceous antigens, as taught by Wilson et al. Additionally, it would have been obvious to further include an oligonucleotide adjuvant, where the dual delivery of proteinaceous antigens and oligonucleotide adjuvant from polymeric complexes comprising N,N-dimethyl amino ethyl methacrylate were known to significantly increase immune response.
Regarding wherein the complex has been submitted to a drying process, the process of formulating the complex are simply product by process limitations or intended use limitations. It would have been obvious to formulate the complex made obvious above in the form of a dry powder, which was known to be suitable for polyelectrolyte complexes, as taught by Kabanov et al for the same reasons discussed above. Accordingly, it appears the product by process or intended use limitations are met where the drying process is simply a method of drying the composition to be used in the treatment methods.
It would have been obvious to encapsulate the complex in the method made obvious above with known encapsulating agents suitable for PDMAEMA polymers in gastric environments, such as alginate, as taught by Pippa et al.
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 JOSHUA A ATKINSON whose telephone number is (571)270-0877. The examiner can normally be reached M-F: 9:00 AM - 5:00 PM + Flex.
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/JOSHUA A ATKINSON/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
Prosecution Insights