DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Replacement Drawings sheets, Amendments to the Claims and Arguments/Remarks filed 04 March 2026, in response to the Office Correspondence dated 29 October 2025, are acknowledged.
The listing of Claims filed 04 March 2026, have been examined. Claims 1-13, and 15 are pending. Claims 5, 9, and 15 are amended and are supported by the originally-filed disclosure. Claim 14 is canceled and no new claims have been added.
Response to Amendment
Corrected replacement drawing sheets in compliance with 37 CFR § 1.121(d) have been provided and are accepted. The applicant has addressed the deficiencies regarding resolution, legibility in the replacement Drawings sheets. Specifically, the chemical structures in FIG. 1 contain subscript text (e.g., NH₂) that are now sufficiently legible. Additionally, the graph legend in FIG. 4 has replaced the color/pattern indicators that were not distinctly discernible with discernable indicators. Accordingly, the objection to the drawings (Figs. 1, 4, and 12) is withdrawn.
The specification objection under 37 CFR § 1.75(d)(1) for lack of proper antecedent basis for claim 15 is withdrawn, as the amendment to claim 15 now recites wording consistent with the disclosure. The applicant’s amendment of claims 5 and 9 to correct grammatical errors and the metal alloy/ceramic misstatement is accepted. The objections to claims 5 and 9 are withdrawn. The applicant’s cancellation of claim 14 is acknowledged. The objection under 37 CFR 1.75(d)(1) regarding antecedent basis is moot as to claim 14. The rejection under 35 U.S.C. § 112(a) and (b) as to claim 14 is also moot. However, a new ground of rejection under 35 U.S.C. § 112(b) is set forth below for amended claims 15.
The applicant’s remarks have been fully considered. Notwithstanding the applicant’s arguments and amendments, the rejection of claim 15 under 35 U.S.C. § 112(a) is maintained for the reasons set forth below in the Response to Arguments. The rejection of claims 1-15 under 35 U.S.C. § 103 over Molchanova, Kirshenbaum, Jablokov, and Nyström is also maintained and is further supported by the rebuttal in the Response to Arguments below.
The applicant’s decision to defer response to the provisional nonstatutory double patenting rejection is noted, however, the provisional nonstatutory double patenting rejection is maintained.
Maintained Rejections
The following rejections are maintained from the previous Office Correspondence dated 29 October 2025, since the art which was previously cited continues to read on the amended/newly cited limitations.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. § 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. § 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 15 is rejected under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the peptoids of claim 10 and 11 for bacteria possessing anionic hydrophobic surface properties, does not reasonably provide enablement for all peptoids and all bacteria, fungi, viruses. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims.
The claim recites a function (i.e., peptoid “configured to release” or release from a polyionic gel in the presence of a number of bacteria) covering a wide range of pathogens without disclosing a conceivable means for achieving the stated function for any medical device having a surface that is metal, ceramic, or polymeric, coated with any polyanionic microgel containing any peptoid. The specification only covers those means known to the inventor using a poly(acrylic acid) microgel with an antimicrobial peptoid encompassed within claims 10 and 11 (i.e., TM1 antimicrobial peptide) for the bacteria Methicillin-susceptible Staphylococcus aureus (MSSA) and S. epidermidis. Further, the specification merely describes a mechanism for release of a cationic antimicrobial peptoid from a polyanionic microgel in the presence of a high local anionic hydrophobic concentration (¶[0046]). Accordingly, the disclosure is not commensurate with the scope of the claim. The scope of the claims is not commensurate with the enablement of the disclosure, because practice of the claimed invention would require undue experimentation by an artisan of ordinary skill in the art.
The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The court in Wands states: "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue,' not 'experimentation.' " (Wands, 8 USPQ2d 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.
In this case:
(1) The quantity of experimentation necessary is large to determine which embodiments across the entire scope of the claim are encompassed by the invention and are effective for their intended purpose. The specification provides insufficient guidance or working examples to direct the skilled artisan to the full range of claimed embodiments without resorting to a research project. Merely the use of a single poly(acrylic acid) microgel, the TM1 peptoid, and a polydimethylsiloxane gasket, a titanium rod and glass are used as surfaces in the guidance and working examples. The working examples only show reduce bacterial colonization of MSSA and S. epidermidis using the TM1 peptoid which does not represent the full scope of the claims including all claimed pathogens which can have different surface properties and all peptoids. Further, the specification provides no guidance on how to “configure” release or release of any peptiod from any polyionic microgel in the presence of any pathogen that does not have anionic hydrophobic surface properties.
(2) The amount or direction or guidance presented is lacking. The specification lacks sufficient direction or guidance, such as working examples, identifying critical parameters, or providing an enabling methodology, to practice the invention across the entire scope without undue experimentation. More specifically, the specification lacks experimental data or modeling sufficient to establish all of the claimed peptoids. The claim is broader than the supporting disclosure because it appears to provide a "laundry list" of possibilities without adequate guidance, working examples or experimental data for all the peptoid sequences encompassed in claim 11 and all pathogens encompassed in claim 15 that shows the full range of what is claimed.
In addition, claim 15 claims, wherein the polyanionic microgel releases the peptoid in the presence of a pathogen. The specification does not teach any method or process specifically used to “configure release” of the peptoid in the presence of a pathogen. A contact transfer mechanism of release is hypothesized in the specification ¶[0046], however evidence has not been presented in the context of the claimed fungi and viruses as well. The hypothesized mechanism of action is also not pathogen-specific, rather is specific to exposure of the polyanionic microgel containing cationic peptoid to a significant concentration of anionic hydrophobic surfaces, wherein the surface properties of all bacteria, fungi and viruses or even all of the specific species listed in claim 15 do not necessarily possess and anionic hydrophobic surface properties are not a specific and exclusive property of pathogens (i.e., other things can possess anionic hydrophobic surface properties that are not pathogens and trigger antimicrobial peptide release). In fact, the specification ¶[0041] teaches that simply a [Na+] threshold of about 0.35 M at pH 7.4 is needed to enable rapid release of the complexed TM1 from the microgel, which is not tantamount to the presence of a pathogen.
Anionic hydrophobic surface properties that seem to be required for polyanionic microgel peptoid release of claim 15 is a generally common property for bacteria but would vary by species, strain, environmental conditions, and life cycle stage (e.g., biofilm polysaccharide capsule hydrophyllic strains). Of the listed species in claim 15, Clostridium difficile is hydrophobic but may have a net positive surface charge, Salmonella has variable hydrophobicity but generally has a negative surface, it is unclear if these claimed species will elicit the claimed polyanionic microgel releases the peptoid in the presence of a pathogen. The working examples only show reduce bacterial colonization of MSSA and S. epidermidis.
(3) The working examples only include poly(acrylic acid) microgel fabrication steps (¶[0029]), a process for coating a polydimethylsiloxane gasket, titanium rods or glass with the poly(acrylic acid) microgel by depositing it after positive charge priming (¶[0030]), followed by placing the microgel-coated surface in a buffer containing the synthesized TM1 antimicrobial peptoid for complexation with the microgel (¶[0031]). The working examples only include poly(acrylic acid) microgel TM1 peptoid activity towards the anionic hydrophobic enveloped bacterial strains MSSA and S. epidermidis.
(4) The nature of the invention resides in an unpredictable biotechnology art, where the properties of all the claimed surfaces and structures are not identical and interchangeable the claimed interactions and function is not routine.
(5) The state of the prior art of peptide engineering (e.g., peptoids), microgel coating release properties and interactions with different medical device surfaces, pathogens and the human body in a variety of wide-ranging biologically relevant conditions is unpredictable, and the relationship between structure and function is not well-established. Therefore, one could not predict which embodiments falling within the claim's scope would be effective based on the limited disclosure.
(6) The relative skill of those in the art is high, likely possessing and advanced degree in science or biotechnology and having expertise in peptides or macromolecular materials however, however a person skilled in the art would not be able to practice the full scope of the claimed invention based on the specification's disclosure without undue experimentation because the nature of the invention resides in an unpredictable biotechnology art, with complex interactions and a wide variety of surface properties that are not identical and interchangeable and would require extensive experimental screening.
(7) The art is unpredictable. Peptoid interactions can be unpredictable. Small, non-conservative changes sequences, surface properties of interacting materials and environmental conditions can drastically alter interaction dynamics, kinetics and stability. Therefore, one could not predict the interactions based on the disclosure.
(8) The breadth of the claims is wide. The specification provides only a single species of microgel, a single peptoid, and two bacterial strains (no fungal or viral pathogens), which fails to provide a representative number of species or a common characteristic that would enable prediction of which combinations would meet the claim limitation.
Thus, based on the analysis above the conclusion that the instant claims are not enabled is inescapable.
Claim Rejections - 35 USC § 103
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 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 1-15 are rejected under 35 U.S.C. § 103 as being unpatentable over Molchanova et al. (WO2020223581A1; published 05 November 2020, hereinafter referred to as “Molchanova”) in view of Kirshenbaum and Shin (US8828413B2; published 09 September 2014, hereinafter referred to as “Kirshenbaum”) and Jablokov and Freese (US9593395B2; published 14 March 2017, hereinafter referred to as “Jablokov”), and in further view of Nyström et al. (Peptide-Loaded Microgels as Antimicrobial and Anti-Inflammatory Surface Coatings. Biomacromolecules. 2018 Aug 13;19(8):3456-3466; electronically published 18 July 2018, hereinafter referred to as “Nyström”).
Molchanova teaches halogenated antimicrobial peptoids including Peptoid 1 [H-(NLys- Nspe-Nspe)4-NH2] variants and analogues, comprising brominated variants (¶[0076]; Figures 1, 2, 5, 7-16), oligomers of poly-N-substituted glycines (¶[0087]) and cyclic peptoids (¶[0097]), wherein the composition may be disposed in a gel for antibacterial, antifungal, and antiviral purposes (¶[0091]) having demonstrated Staphylococcus aureus [anionic and hydrophobic outer surface bacterial strain] inhibitory activity (¶[0045]; Table 1). Further, the instant specification identifies that the claimed peptiods have previously been disclosed in the referenced prior art (¶[0053]-[0071]).
Molchanova does not explicitly teach a polyanionic microgel containing the specified peptoids disposed of on a biomedical device.
Kirshenbaum teaches at least one peptoid oligomer that may be cyclic or linear (Abstract) bound to or incorporated into a substrate (claim 22) including medical devices (claim 23), wherein the device may include orthopedic fixtures, hip implants, knee implants, pacemaker components, ENT implants, ear canal shunts, vascular stents, gauze, sutures, artificial skin, and artificial hearts (column 36, line 35-50) and suitable substrates include conventional polymers including polyethylene, fluoropolymers, and functionlized polymer ketones (column 33, line 57-column 34, line 6), “…ceramics, glass, metal, metal oxides, and composites comprised of ceramics, glass, metal or metal oxides plus polymers as described above. Suitable metals include steel, stainless steel, aluminum, copper, titanium, alloys thereof, and combinations thereof.” (column 34, lines 12-17).
Jablokov teaches specific biomedical alloys used in the art to manufacture implantable medical and surgical devices including α+β titanium alloys Ti-6Al-7Nb and Ti-6Al-4V, as titanium-base metallic biomaterial references for comparative oxygen content to the metastable β titanium alloy Ti-12Mo-6Zr-2Fe (column 7, line 11- column 8, line 24; Table 5).
Nyström teaches the motivation to develop antimicrobial surface biomaterials for biomedical implant coatings (page 1, paragraph 1) and the motivation to use microgels to do so (page 2, paragraph 1). Nyström further teaches antimicrobial peptide incorporation into surface-bound ethyl poly(acrylate/methacrylic acid/1,4-butandiol diacrylate) microgels (pH 5.1; polyanionic at pH 5.1 due to the 33% or 60% methacrylic acid component of the polymer) with peptide release facilitated by high physiological ionic strength, generating release-mediated antimicrobial effects (page 3, paragraph 5 and page 9, paragraph 2).
Nyström does not explicitly teach microgel antimicrobial peptoids. However, it would have been prima facie obvious to one of ordinary skill in the art prior to the instant effective filing date to substitute the use of the antimicrobial peptides in the invention Nyström with the antimicrobial peptoids described by Molchanova to optimize the invention of Nyström, given that peptiods are designed to mimic the function of peptides but side chain attachment to the nitrogen atom rather than the alpha-carbon, as in peptides, to improve resistance to proteolytic degradation by protease enzymes, wherein peptoids can also improve cell permeability due to the lack of hydrogen bonding potential caused by the side chain shift and have reduced immunogenicity compared to peptides. In fact, the instant specification particularly makes reference to such (¶[0027]).
Nyström states “protecting incorporated peptides from enzymatic degradation” is advantageous (page 2, right column, paragraph 1). Thus, one would have a reasonable expectation of enhanced success by optimization of the Nyström invention with the substitution of the antimicrobial peptoids of Molchanova for the antimicrobial peptides in the invention of Nyström, while using the more specific biomedical devices described by Kirshenbaum as suitable for cyclic or linear peptoid incorporation being made of the specific biomedical alloys taught by Jablokov.
In summary, Molchanova directly teaches the antimicrobial use of the peptoid species/genera and sequences. Kirshenbaum teaches peptoid coatings for biomedical devices and Jablokov specifically teaches the claimed alloys as biomedical materials for biomedical devices. Nyström teaches antimicrobial peptide incorporated polyanionic microgels and their loading behavior. As such, loading known antimicrobial peptoids into known polyanionic microgels used for antimicrobial peptides and depositing the microgel on implants is rendered obvious.
Claim Rejections – Nonstatutory 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).
Claims 1-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 5, 6, 8-20, 34-36, and 38-50 of the co-pending Application No. 18/255,468 (hereinafter referred to as the “reference application”). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference application discloses a similar biomedical device surfaces and the instant application claims would be obvious in view of the reference application. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The instant application discloses biomedical devices such as implants, prostheses, and heart valves with surfaces including metals, ceramics, glass and polymers coated with a microgel to obtain a 3D cross-linked colloidal structure loaded with a peptoid by complexation between the peptoid and microgel (¶[0010]).
Metals can contain metal oxide functional groups, sulfhydryl sulfur-containing functional groups, and carboxyl surface bio-functionalization groups. Ceramics can contain oxygen-based functional groups, hydroxyl and carboxyl, phosphate functional groups (e.g., CaP), metal/metal oxide functional groups (e.g., alumina aluminum oxide). Glass can contain hydroxyl functional groups (e.g., silica-based glass), amine functional groups (e.g., silanized), thiol functional groups (e.g., organosilane) and borono functional groups (e.g., borosilicate glass). Polymers can contain linking group segments derived from ethylene glycol and diethylene glycol and oxygen-containing functional groups including hydroxyl (e.g., polyethylene glycol and polyvinyl alcohol), carboxyl (e.g., polylactic-co-glycolic acid and acrylic acid copolymers), esters (e.g., polylactide and polycaprolactone), and carbonyl, aldehyde, epoxy, and methoxy functional groups can be found in a range of polymers. Polymers can also contain nitrogen-containing functional groups such as amines (e.g., polyethyleneimine), carboxyamides (e.g., polyamides), azides (e.g., "click chemistry" grafted molecules onto the polymer surface) and sulfur-containing groups such as thiols for tethering molecules and creating disulfide bonds or sulfonates present in sulfonated polymers.
The reference specification along with claims 1-3, 5, 6, 8-20, 34-36, and 38-50 disclose the same general genus of devices in the specification and surfaces in claims. Using the specific polymeric materials or metal alloys of the instant claims would have been an obvious selection from the known biomedical device surface materials.
The polyanionic microgel of the instant application is a cross-linked colloidal structure species of the broader grafting hydrogel/polymer composite coating genus disclosed in the reference application specification (¶[0026]).
The peptoid disposed in the polyanionic microgel in the instant application (e.g., H-(NLys-Nspe-Nspe)4-NH2) is a known class of antimicrobial peptidomimetics with bacterial inhibitory activity against Staphylococcus aureus and is a species of the reference application claimed peptoids. Using the specific peptoids (linear or cyclic) disclosed in the instant application is an obvious alternative to other known antimicrobial peptoids for preventing infection on implantable devices (see reference application specification background section).
To overcome this rejection, the Applicant may demonstrate that the claimed invention is patentably distinct from the reference (e.g., by showing that the specific combination of a polyanionic microgel with a peptoid yields unexpected or superior results not achieved by the broader disclosures of the prior art), amend the claims to include limitations that are not disclosed or suggested in the reference to make them patentably distinct, or file a terminal disclaimer to statutorily disclaim any patent term extending beyond the term of the reference patent.
New Rejections
The following new rejections are made from the previous Office Correspondence dated 29 October 2025, as the Applicant's amendment necessitated the new grounds of rejection presented below based on the amended/newly cited limitations.
Claim Rejections - 35 USC § 112(b)
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 Applicant regards as his invention.
Claim 15 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, regards as the invention.
Amended claim 15 recites, recites, “The biomedical device of claim 11, wherein the polyanionic microgel releases the peptoid in the presence of a pathogen…”. The phrase “releases the peptoid in the presence of a pathogen” is ambiguous because it lacks a temporal or quantitative threshold. The claim does not specify the extent of release required (e.g., 1%, 50%, 100%, etc. of the loaded peptoid), the timeframe over which release occurs (e.g., seconds, minutes, hours, etc.), nor and the environmental conditions (e.g., temperature, pH, ionic strength, presence of serum proteins, flow conditions). One of ordinary skill in the art would not know with reasonable certainty whether a device that releases, for example, 0.1% of the peptoid over 72 hours in the presence of a pathogen, falls within the scope of the claim.
In addition, the claims a baseline or control. The claim does not specify release relative to what condition (i.e., what in the presence of a pathogen is compared to- the absence of the pathogen, the presence of a non-pathogenic bacterium, or the presence of sterile buffer, etc.). The claim provides no baseline and without a defined baseline, it is not possible to determine whether the claimed device meets the limitation. These ambiguities render the claim indefinite (see Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 901 (2014).
Further, the claim recites release in the presence of a pathogen, without reciting any structural features or mechanisms that achieve that result. The claim must provide sufficient structural definition to inform a person of ordinary skill in the art of the scope. Here, the claim depends from claim 11, which recites specific peptoid sequences, but claim 11 does not include any limitation regarding pathogen-triggered release. Thus, a device having any of the claim 11 peptoids in any polyanionic microgel on any surface would ostensibly meet claim 15 if it happens to release the peptoid in the presence of a pathogen, even if the release is accidental, non-specific, or occurs only under extreme conditions. Thus, the claim recites a result without reciting a clear means of achieving that result, rendering the claim indefinite (see In re Swinehart, 439 F.2d 210, 213 (CCPA 1971).
To overcome this rejection, the applicant may amend claim 15 to provide objective structural or operational limitations defining the release condition, such as specifying a minimum percentage of release, a timeframe, or a comparative baseline.
Response to Arguments
Applicant Arguments/Remarks of the reply, filed 04 March 2026, have been fully considered. The applicant argues that Nyström does not teach peptoids or pathogen-triggered release, Molchanova does not teach microgel incorporation, the combination lacks motivation and reasonable expectation of success, and the claimed system exhibits unexpected pathogen-triggered release and stable sequestration. These arguments are not persuasive.
The applicant argues that Molchanova contains no disclosure, teaching, or suggestion at least of a polyanionic microgel disposed on said surface; and a peptoid disposed in said polyanionic microgel. This argument is not persuasive. The rejection is a combination rejection. No single reference is required to disclose every element. The rejection explicitly relies on Nyström for the polyanionic microgel disposed on a surface and loaded with an antimicrobial agent, and on Molchanova for the specific class of antimicrobial peptoids. Kirshenbaum and Jablokov provide the motivation to apply such coatings to specific biomedical device surfaces and alloys. The fact that Molchanova alone does not disclose a microgel is irrelevant.
The applicant argues that Nyström teaches protease-sensitive peptides, not peptoids and that there is no motivation to substitute. This argument ignores the express rationale in the original Office Correspondence and the state of the art. As of the effective filing date, peptoids were a well-known class of peptidomimetics designed specifically to overcome the limitations of peptides, including proteolytic degradation (see, e.g., Molchanova, Background and ¶[0027]). A person of ordinary skill in the art would have recognized known interchangeability and that substituting a peptoid for a peptide in a microgel coating is a routine optimization, not an unpredictable leap. The substitution of peptoids (Molchanova) for peptides (Nyström) remains prima facie obvious because both are functionally analogous antimicrobial agents, the art explicitly recognizes peptoids as peptide mimetics with improved stability.
The motivation to combine is that Nyström expressly identifies protection from enzymatic degradation as a design goal. Molchanova provides peptoids with enhanced proteolytic stability, thus, the substitution is a predictable optimization. There is a reasonable expectation of success in making the substitution as Nyström teaches that the mechanism of release is driven by ionic strength, wherein the cationic peptide is electrostatically bound to the polyanionic microgel and is released when salt concentration increases. The peptoids of Molchanova are also cationic (e.g., H-(NLys-Nspe-Nspe)4-NH2 contains multiple lysine-like NLys residues bearing positive charges at physiological pH). A person of ordinary skill in the art would have reasonably expected that a cationic peptoid would likewise bind electrostatically to a polyanionic microgel and be released under similar ionic strength conditions. No unpredictable change in binding behavior would be expected.
The applicant’s argument that peptoids lack backbone amide hydrogens and have altered conformation is not a teaching away. These differences are precisely why one would choose a peptoid to improve stability. The mere existence of structural differences does not render a substitution nonobvious when the functional purpose is the same (see, e.g., In re Gal, 980 F.2d 717, 719 (Fed. Cir. 1992), wherein obviousness does not require absolute predictability of success; all that is required is a reasonable expectation of success).
The applicant has amended claim 15 to depend from claim 11 and to recite release in the presence of a pathogen selected from Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella, Proteus, Enterobacter, Clostridium difficile, Salmonela, and Streptococci. Claim 15, even as amended, broadly recites release “in the presence of a pathogen” without structural limitations. Even with this amendment, the obviousness rejection is maintained for the following reasons.
Nyström teaches ionic-strength-mediated release (e.g., ~0.35 M Na⁺), wherein the presence of bacteria locally increases ionic strength due to metabolic byproducts, secreted molecules, and the charged nature of the bacterial surface itself. Nyström’s ionic-strength trigger is the same mechanism as the applicant’s “pathogen presence” trigger. The applicant’s specification itself teaches that release occurs when the polyanionic microgel encounters a “high local anionic hydrophobic concentration” (¶[0046]). Bacterial surfaces including S. aureus, E. coli, and others are anionic and hydrophobic. Therefore, the alleged “pathogen-triggered” mechanism is not clearly distinguished from environmental ionic effects already taught in Nyström. A person of ordinary skill in the art would recognize that the Nyström system, loaded with a cationic peptoid, would likewise release the peptoid upon contact with bacterial surfaces.
The applicant’s specification does not disclose a pathogen-specific sensor or configuration that distinguishes pathogens from non-pathogenic anionic hydrophobic surfaces. As noted in the prior Office Correspondence, the specification teaches that a sodium ion threshold of about 0.35 M at pH 7.4 enables release. This is not pathogen-specific, rather it is a general physicochemical trigger. There is no requirement in the amended claim 15 wherein release does not occur in the presence of non-pathogenic anionic surfaces or high salt conditions. The claim is therefore not directed to a pathogen-specific mechanism, and the cited art’s ionic-strength trigger remains applicable.
The applicant points to data in the specification (Figs. 2B, 8, 4, 9) as showing stable sequestration in complex biofluids and zero colonization on Ti implants. These arguments are not persuasive. The applicant does not provide any comparative data showing that the claimed combination yield results superior to Nyström’s peptide-loaded microgel, or Molchanova’s free peptoid, or a peptoid-loaded non-polyanionic gel. Unexpected results must be unexpected in view of the closest prior art (see In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984)). Without such a comparison, the alleged unexpected results are unsubstantiated.
In addition, the data are limited to a limited subset of peptoids (TM1/H-(NLys-Nspe-Nspe)4-NH2), a single microgel (poly(acrylic acid)), and two bacterial strains. The claims encompass numerous peptoids (including all those listed in claim 11, the generic formula in claim 12, and cyclic peptoids in claim 13), multiple device surfaces (i.e., metals, ceramics, polymers, multiple specific alloys), and multiple pathoges. Accordingly, the alleged unexpected results are insufficient to overcome the prima facie case (see MPEP § 716.02(d) and In re Vaeck, 947 F.2d 488, 493 (Fed. Cir. 1991), wherein a single working example does not render the full scope nonobvious).
The applicant has not shown that the alleged unexpected properties are attributable to the combination of a polyanionic microgel and a peptoid, as opposed to the peptoid alone or the microgel alone. The presence of data showing that the invention works is not objective indicia of nonobviousness, it is simply evidence of utility.
The applicant further argues that Kirshenbaum and Jablokov are silent on microgels or peptoids. Kirshenbaum teaches peptoid-coated medical devices (claims 22-23) and explicitly lists suitable substrate materials including metals, ceramics, polymers, and alloys (column 34, lines 12-17). Jablokov teaches the specific titanium alloys (e.g., Ti-12Mo-6Zr-2Fe) claimed in dependent claims 5 and 8. A person of ordinary skill in the art would have been motivated to apply Nyström’s microgel coating technology to the specific biomedical device surfaces taught by Kirshenbaum and Jablokov because such surfaces are standard in the art. No inventive step is required to select a known surface material from a finite list of known options. Obviousness here is consistent with the principles taught by KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 421 (2007), wherein when there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp.
In summary, Nyström teaches microgel-based antimicrobial coatings with controlled release. Molchanova teaches peptoids as superior antimicrobial agents. It would have been obvious to incorporate any known antimicrobial agent, including peptoids, into Nyström’s microgel system and perform routine optimization of release kinetics depending on environmental conditions. The specific device materials (claims 2-9) are taught or suggested by Kirshenbaum and Jablokov and represent well-known biomedical substrates. Accordingly, the rejection of claims 1-13 and 15 under 35 U.S.C. § 103 over Molchanova, Kirshenbaum, Jablokov, and Nyström is maintained.
Regarding the 35 U.S.C. § 112(a) rejection, the applicant has amended claim 15 to depend from claim 11 (which lists many specific peptoid sequences) and to recite release “in the presence of a pathogen selected from the group consisting of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Klebsiella, Proteus, Enterobacter, Clostridium difficile, Salmonella, and Streptococci.” The applicant contends that amendment of claim 15 to depend from claim 11 and recite bacteria possessing anionic hydrophobic surface properties resolves the previous enablement rejection issue. This argument is not persuasive.
While claim 15 has been narrowed to depend from claim 11 and recite specific pathogens, the specification continues to disclose a single microgel composition (poly(acrylic acid); ¶[0029]), One peptoid (H-(NLys-Nspe-Nspe)4-NH2 (TM1); ¶[0028], Examples), and activity demonstrated only two bacterial strains (Staphylococcus aureus (MSSA) and Staphylococcus epidermidis; ¶[0035], Figs. 4, 9-10; notably, S. epidermidis is not even listed in claim 15), whereas the claim still encompasses over 30 distinct peptoid sequences, any polyanionic microgel, and a range of distinct bacterial species.
Claim 11 recites three separate Markush groups containing over 30 distinct peptoid sequences, including sequences with para-bromophenylalanine analogs (Nspe(p-Br)), sequences with Nssb, and sequences with Npm. The specification provides no working examples for the vast majority of these sequences. The only peptoid actually synthesized and tested is H-(NLys-Nspe-Nspe)4-NH2 (TM1) (¶[0028], Examples). There is no data showing that any of the other claimed peptoids (e.g., H-(NLys-Nspe(p-Br)-Nspe(p-Br))2-NH2, H-(NLys-Nssb-Nssb)4-NH2, or any of the >20 sequences in the third Markush group of claim 11 will release in the presence of any pathogen, let alone the specific pathogens listed in claim 15. A person of ordinary skill in the art would not know, without undue experimentation, whether substituting a bromine atom on the Nspe ring, replacing Nspe with Npm, or changing the length of the peptoid oligomer would preserve the electrostatic binding and pathogen-triggered release properties. The specification provides no structure-activity relationship data or guidance on which structural features are critical.
The specification provides no working examples or guidance for the listed pathogens in claim 15, other than Staphylococcus aureus (gram-positive coccus bacterium), including Pseudomonas aeruginosa (gram-negative, different outer membrane composition), Escherichia coli (gram-negative, variable surface charge/hydrophobicity), Klebsiella (gram-negative, capsule-forming), Proteus (gram-negative, swarming motility), Enterobacter (gram-negative), Clostridium difficile (gram-positive, spore-forming, variable surface properties), Salmonella (gram-negative), and Streptococci (gram-positive, multiple species with varying surface properties). As previously indicated, surface properties (e.g., charge, hydrophobicity) vary significantly across these pathogens and even within species depending on environmental conditions, growth phase, and strain.
The specification’s hypothesized mechanism of electrostatic competition between the polyanionic microgel and anionic hydrophobic bacterial surfaces may not operate uniformly across this diverse list. For example, Clostridium difficile spores have different surface properties than vegetative cells, Pseudomonas aeruginosa produces alginate (anionic) but also forms biofilms that may alter accessibility, and Klebsiella capsules may shield the bacterial surface from interacting with the microgel. A person of ordinary skill in the art would be required to engage in undue experimentation to determine which of the claimed peptoids (from the dozens listed in claim 11) and which of the claimed microgel compositions (polyanionic, but not limited to poly(acrylic acid)) will release in the presence of each of these pathogens.
There remains no representative number of species or structural guidance correlating peptoid structure, microgel interaction, and pathogen-triggered release. The functional limitation of “the polyanionic microgel releases the peptoid in the presence of a pathogen…” is still not tied to defined structural parameters, relies on a mechanism (i.e., electrostatic competition) that is only hypothesized, and is not demonstrated across the full scope of claimed pathogens. Even as amended, the claim still requires predictable release behavior across multiple bacterial genera, which differ significantly in surface charge density, hydrophobicity, and biofilm formation characteristics. The prior Wands (858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988) analysis remains applicable and weigh heavily against enablement.
In particular, the quantity of experimentation is still undue and would require screening dozens of peptoids (including brominated variants, Nssb-containing sequences, Npm-containing sequences, and sequences with decyl or tridecyl terminal alkylations) against multiple pathogens and microgel combinations under various conditions, requiring hundreds of experiments. The amount of guidance and working examples are still minimal (only one peptoid, one microgel, two bacterial strains- one of which is not even claimed), which is insufficient to extrapolate beyond disclosed embodiments. The nature of the invention remains unpredictable, wherein peptoid-pathogen-microgel interactions are not routine and surface interactions vary with peptoid sequence, microgel composition, pathogen surface properties.
The state of the prior art provides no predictive tools or routine methods for predicting pathogen-triggered release across diverse pathogens and microgel interactions, wherein even given the high level of skill in the art, extensive screening would still be required. The unpredictability remains high, wherein small changes in peptoid sequence or bacterial strain can alter binding and release and while narrowed, the breadth of claims is still excessive relative to disclosure, claiming nine pathogen types, over 30 distinct peptoid sequences, and numerous microgel compositions.
Because the specification provides only a single species of microgel, a single peptoid, and two bacterial strains (only one of which is claimed), the disclosure is not commensurate in scope with claim 15. Practice of the claimed invention across its full scope would require undue experimentation and, accordingly, claim 15 is not enabled under 35 U.S.C. § 112(a) and remains rejected. In addition, the amend claim 15 is further rejected as indefinite under 35 U.S.C. § 112(b) as set forth above.
The applicant may consider narrowing claims to a specific microgel composition (i.e, poly(acrylic acid)), a specific peptoid structure (i.e., (H-(NLys-Nspe-Nspe)4-NH2 (TM1)), and specific pathogens (i.e., Staphylococcus aureus (MSSA) and/or Staphylococcus epidermidis); clearly defining release mechanisms and providing objective structural or operational limitations (e.g., relative temporal and baseline metrics) defining releases; providing evidence demonstrating that the specification enables the full scope of claim 15 and that the claim is definite or comparative data demonstrating unexpected results across the full claimed scope (e.g., declaration under 37 CFR 1.132), or cancel claim 15.
The provisional nonstatutory double patenting rejection is maintained, as it is not the sole remaining rejection (see MPEP § 804(I)). The applicant may remedy this rejection by filing a terminal disclaimer.
Conclusion
No claims are allowed.
The 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 (87 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.
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/RL Scotland/
Examiner, Art Unit 1615
/Robert A Wax/Supervisory Patent Examiner, Art Unit 1615
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