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 .
Priority
The instant application, filed 05/05/2023, claims domestic benefit to US provision application 63/341,174, filed 05/12/2022.
Claim Status
The Amendment, filed on 02/06/2026, is acknowledged in which:
Claims 7, 11, and 17 are currently amended.
Claims 1-6, 8-10, 12-16, and 18-20 are original.
Claims 1-20 are pending in the instant application and are examined on the merits herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/10/2023 has been considered by the examiner.
The listing of references in the specification (pg 34-35) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because of the following informalities: “Fc-Noggin” also appears as lowercase “Fc-noggin” (pg 6, line 15; pg 9, line 10; pg 15, line 11; pg 17, lines 4, 7, and 10). If these refer to the same fusion protein, examiner recommends that a consistent naming convention (i.e. capitalized or lowercase) is maintained throughout the application. Otherwise, the alternative species should be explicitly defined.
Appropriate correction is required.
The use of the terms: Octet (pg 16, line 18; pg 25, line 21), Tween (pg 16, line 20; pg 23, line 5), SuperBlock (pg 16, line 22), GraphPad [Prism] (pg 24, line 15), which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 2, 3, 10, and 13 are objected to because of the following informalities:
Claims 2, 3, and 13 have improperly formatted superscripts in reference to dissociation constant values.
Claim 10, line 6: “mixing aqueous solution” should read “mixing an aqueous solution”
Appropriate correction is required.
Claim Interpretation
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Regarding the term “peptidic ligand” as recited in instant claims 1-2, 6, 9-10, 13, 16, and 18-20, examiner has interpreted this to mean a short peptide chain of amino acids 2-50 residues in length as would be understood by a person of ordinary skill in the art as evidenced by UniProt (Published 2026. Accessed May 8, 2026. https://www.uniprot.org/help/peptide).
Regarding the term “greater” as recited in instant claims 2 and 13, examiner has interpreted this to mean an overall larger value (i.e. dissociation constant > 10-10 M) as implied by the specification (pg 4, lines 13-17), rather than stronger binding affinity which would result in a lower integer value (i.e. < 10-10 M).
Claim Rejections - Improper Markush
Claims 7 and 17 rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of peptidic ligands is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: Based on prior art Choe (Materials (Basel). 2016;9(12):994), SEQ ID NO: 9 (FYTHCAKE) does not have Fc/immunoglobin binding affinity, and the peptide is instead referenced as a negative control for binding (pg 9, ¶ 3).
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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 the applicant regards as his invention.
Claim 17 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 17 recites the limitation "the amino acid sequence" in line 1-2. There is insufficient antecedent basis for this limitation in the claim and there is further ambiguity as there are multiple potential amino acid containing elements of the base claim.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 7 and 17 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Base claims 1 and 10, respectively, recite peptidic ligands that have binding affinity to an Fc region. Dependent claims 7 and 17, respectively, recite SEQ ID NO: 9 which comprises a sequence used as a negative control for immunoglobin binding (i.e. does not have binding affinity and therefore improperly dependent) as evidenced by Choe (Materials (Basel). 2016;9(12):994) (pg 9, ¶ 3).
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
Claims 1-6, 8-16, and 18-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claim 1 is drawn to a protein-release system comprising (a) a hydrogel, (b) proteins comprising an Fc region, (c) and peptidic ligands with affinity to said Fc domain covalently bound to hydrogel polymeric network.
Independent claim 10 is drawn to a method of producing a protein-release system of proteins having an Fc region comprising (a) selecting a peptidic ligand having affinity to the Fc region, (b) covalently linking the ligand to polymeric network precursors, (c) mixing an aqueous solution of the ligand conjugated polymeric network precursors with the Fc-proteins, and (d) forming a hydrogel loaded with the Fc-proteins for sustained release.
The respective claims contain functional language by claiming a genus of peptide ligands by their function rather than providing a specific structure. MPEP 2173.05(g) teaches that "Unlimited functional claim limitations that extend to all means or methods of resolving a problem may not be adequately supported by the written description or may not be commensurate in scope with the enabling disclosure, both of which are required by 35 U.S.C. 112(a) and pre-AIA 35 U.S.C. 112, first paragraph. In re Hyatt, 708 F.2d 712, 714, 218 USPQ 195, 197 (Fed. Cir. 1983); Ariad, 598 F.3d at 1340, 94 USPQ2d at 1167. For instance, a single means claim covering every conceivable means for achieving the stated result was held to be invalid under 35 U.S.C.112, first paragraph because the court recognized that the specification, which disclosed only those means known to the inventor, was not commensurate in scope with the claim. Hyatt, 708 F.2d at 714-715, 218 USPQ at 197."
While subsequent dependent claims (7 and 17, respectively) recite several species claimed within this genus, the instant disclosure does not adequately describe a common structure sufficient to achieve the claimed function in such a way as to demonstrate to a skilled artisan that applicant was in possession of the genus as claimed at the time of filing.
The state of the art at the time of filing, demonstrates the variability in Fc-binding peptide structure. Choe (Materials (Basel). 2016;9(12):994) teaches a vast number of short cyclic peptides have been reported to bind to immunoglobin derived Fc domains (Table 2; Figure 2), however additional non-cyclic conformations unrelated to these motifs have also been identified (e.g. branched Fc-III (pg 6, ¶ 3) and linear peptides (pg 8, ¶ 2)).
Overall, it is not evident by the disclosure, or the prior art, that applicant was in possession of an adequate number of species of peptidic ligands with Fc domain affinity as recited in the instant claims. Furthermore, as discussed above, there is no disclosed or art recognized correlation between structure and function which would allow for the predictable generation of peptides with Fc-domain affinity. Therefore, instant claims 1 and 10, as currently written, and subsequent dependent claims 2-6, 8-9, 11-16, and 18-20 that do not rectify this issue, were determined not to meet the written description requirement of 35 USC 112(a).
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.
Claims 1-6 and 10-16 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pham (Biomater Sci. 2019;7(3):760-772) as evidenced by Zhang (Proc Natl Acad Sci USA. 1993;90(8):3334-3338).
Pham teaches a synthetic peptide derived from SpA (selected based on known affinity of parental peptide for IgG at approximately 20 nM) fused with self-assembling peptide (SAP) EAK with a GGGGS spacer (i.e. non-binding amino acid sequence within scope of a chain extender as defined in the instant specification; pg 6, lines 16-20), resulting peptide named Z15_EAK (Abstract; pg 761-762 spanning ¶; Figure 1). EAK peptides undergo sol-gel phase transition in the presence of salt, forming β fibril matrix (i.e. hydrogel; pg 760, Introduction, ¶ 1), each filament measuring 10-20 nm in diameter (i.e. nanoparticle) as evidenced by Zhang (Abstract). The one-site binding affinity (Kd or dissociation constant) of the gel-like coacervate generated by admixing Z15_EAK with EAK for IgG was determined to be 1.27 ± 0.14 μM (or 1.27 x 10-6 M) (Abstract). Flank and footpad injections (i.e. in situ hydrogel formation) of IgG800 admixed with Z15_EAK had greater retention of antibody in comparison with IgG800 delivered in EAK alone (Figures 5 and 6). Pham demonstrates that rather than trapping IgG through entanglements with polymer fibers, Z15_EAK facilitates an affinity mechanism by which the release kinetics of Fc-based biotherapeutics can be spatiotemporally controlled (Abstract; Figure 6; Discussion, ¶ 1).
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.
Claims 7, 9, 17, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Pham as applied to claims 1 and 10 above, and further in view of Choe (Materials (Basel). 2016;9(12):994).
Regarding claims 7 and 17, Pham teaches claims 1 and 10 as discussed above.
Pham does not teach a peptidic ligand with identity to recited functional species.
Choe references studies that teach a variety of SpA mimic peptides and alternative peptides with IgG binding affinity with identity to the recited instant sequences (instant SEQ ID NOs: 1-4, 8, 10, and 12-13) (Table 2; Figure 2). Choe further teaches several of these Ab affinity ligands have been successfully immobilized on various solid supports for Ab binding (pg 8-10; Figure 5A).
It would be generally understood by a skilled artisan that these Fc-binding peptides as referenced by Choe would reasonably function the similarly in binding immunoglobins (i.e. art recognized suitability for an intended purpose) (See MPEP 2144.07). Therefore, it would be obvious to one of ordinary skill in the art that peptides with identity to those within scope of the instant claim as taught by Choe could be substituted for the SpA peptide as taught by Pham with a reasonable expectation of generating a protein-release system as instantly claimed (See MPEP 2143(I)(B)).
Regarding claims 9 and 20, Pham teaches claims 1 and 10 as discussed above.
Pham does not teach the use of two or more peptidic ligands.
Choe teaches that an antibody affinity column comprising FYWHCLDE and FYCHTIDE (instant SEQ ID NOs: 8 and 10, respectively) at a molar ratio of 2:1 showed synergistically enhanced binding affinity toward IgG (Kd = 0.7 μM) (pg 9, ¶ 3).
Therefore it would be obvious to one of ordinary skill in the art that the Fc-affinity gel as taught by Pham can be modified to included two or more peptidic ligands and a skilled artisan would be motivated to do so because Choe teaches this can lead to synergistic improvements to Fc binding affinity and therefore a means to further fine tune the spatiotemporal release of Fc-based proteins.
Claims 8 and 18-19 are rejected under 35 U.S.C. 103 as being unpatentable over Pham as applied to claims 1 and 10 above, and further in view of Kim (Nanomaterials (Basel). 2021;11(2):471) and Abune (Trends Pharmacol Sci. 2021;42(4):300-312).
Pham teaches claims 1 and 10 as discussed above.
Pham does not teach the use of two or more different Fc-proteins for their protein release system.
Kim teaches sustained release of combination immunotherapy (antibodies blocking CTLA-4 and PD-1 signaling) from in situ crosslinked hydrogels injected ipsilateral to tumor tissue (Abstract; Scheme 1). Kim further teaches this formulation results in efficient and durable anticancer effects with reduced systemic toxicity compared to bolus delivery of free antibodies (Abstract; Figures 2 and 3).
Abune teaches several challenges associated with traditional hydrogels designed without molecular recognition including diffusion-controlled protein release kinetics largely dependent on the degree of hydrogel swelling and can lead to rapid diffusion or degradation-controlled release dependent on the degradation of hydrogel chains (pg 301, ¶ 3; Table 1). Protein release from affinity based hydrogels can be slowed in comparison with traditional hydrogels (Figure 1). Abune teaches protein release kinetics of peptide-based affinity hydrogels can also be tuned by using peptides with different affinities (i.e. multiple ligands) (pg 305, ¶ 2). Abune further teaches that mounting evidence points to the need for more that one drug for the treatment of human diseases (e.g. cancer), and thus hydrogel based therapeutics should be designed to control the release of multiple proteins (pg 307, ¶ 4).
Therefore, it would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention that an affinity based hydrogel as taught by Pham could be modified for dual immunotherapy treatment as taught by Kim (i.e. delivery of two or more Fc based therapeutics) and a skilled artisan would be motivated to do so because Kim teaches hydrogel based delivery improved antitumor effects of dual therapies while reducing off-target toxicity and Abune teaches affinity based hydrogels offer superior control in comparison to traditional hydrogels and diseases frequently need multiple proteins (i.e. different antibodies) for effective treatment. Furthermore, it would be It would have been obvious to one of ordinary skill to combine a multitherapeutic approach as taught by the combined teachings of Pham and Kim with multiple peptidic ligands because Abune teaches using peptides with different affinities can be used to finetune temporal release for a longer therapeutic window (i.e. increasing overall time range of protein release by combining Fc ligands with weaker and stronger interactions).
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.
US 9,498,539 B2
Claims 1-4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 9 of U.S. Patent No. 9,498,539 (herein US539). Although the claims at issue are not identical, they are not patentably distinct from each other.
Claim 1 of US539 claims an extended release composition comprising (a) a chimeric molecule comprising a biologically active molecule, and a first binding moiety covalently linked thereto; and (b) a polymer comprising a polymeric matrix having a second binding moiety, which specifically binds to the first moiety, covalently linked to the matrix, wherein the first and second binding moieties are reversibly bound to each other in a complex having a dissociation constant (Kd) of between 10-3 and 10-9 M (i.e. moieties selected to give a preselected Kd and overlapping in scope of the instantly claimed Kd values). Subsequent dependent claim 9 of US539, dependent on claim 1, claims the polymer matrix as a hydrogel.
The instant specification defines proteins to include fusion proteins comprising a portion of an Fc region (instant specification, pg 6, lines 13-15). Therefore, by broadest reasonable interpretation of the instant claims this is within scope of a chimeric molecule comprising a covalently linked first binding moiety, which would necessarily mean that a specific second binding moiety would have affinity to said Fc domain. Moreover, US539 does not provide a strict definition of the genus “moiety” and instead teaches species to include short peptides with affinities to SH3 covalently attached to the matrix of a hydrogel (column 6, ¶ 3). Therefore, it would also be obvious to one of ordinary skill that the second moiety as recited in US539 claim 1 would by broadest reasonable interpretation include peptidic ligands.
Conclusion
No claims are currently allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to HANNAH SUNSHINE whose telephone number is (571)270-7417. The examiner can normally be reached M-Th & Second Friday 8:30am-5pm EST.
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/HANNAH SUNSHINE/Examiner, Art Unit 1647 /JOANNE HAMA/Supervisory Patent Examiner, Art Unit 1647
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