DETAILED CORRESPONDENCE
Status of the Application
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 August 11, 2026 has been entered.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s amendment to the claims, filed August 11, 2026, is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Claims 1, 4, 7-20, and 26-29 are pending in the application.
Applicant’s remarks filed August 11, 2026 in response to the final rejection filed May 13, 2026 have been fully considered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Restriction/Election
In response to a requirement for restriction/election mailed August 9, 2022, applicant elected without traverse the invention of Group I, pending claims 1, 3, 4, 7, 11-13, 19, 20, and 26-28, drawn to the technical feature of a synthetic compound, a pharmaceutical or diagnostic composition or formulation, and a device; Species A), a therapeutic agent including a growth factor, a therapeutically active polypeptide, an antibody, a polymer, a small molecule, or a combination thereof; and Species AA), FXIII.
Claims 8-10 and 14-18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim.
Claim 4 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 7, 11-13, 19, 20, and 26-29 are being examined on the merits to the extent the claims read on the elected subject matter.
Claim Rejections - 35 USC § 103
The rejection of claims 1, 7, 11-13, 19, and 20 under 35 U.S.C. 103 as being unpatentable over Mûller-Maissen et al. (US 2013/0183279 A1; cited on Form PTO-892 filed October 25, 2022; hereafter “Mûller-Maissen”) in view of Sivaramakrishnan et al. (Biochim. Biophys. Acta 1833:3176-3185, 2013; cited on the IDS filed June 5, 2020; hereafter “Sivaramakrishnan”) and as evidenced by Qian et al. (J. Immunol. 181:660-668, 2008; cited on Form PTO-892 filed May 13, 2026; hereafter “Qian”), and
the rejection of claims 26-28 under 35 U.S.C. 103 as being unpatentable over Mûller-Maissen in view of Sivaramakrishnan and as evidenced by Qian as applied to claims 1, 7, 11-13, 19, and 20 above, and further in view of Traoré et al. (J. Agric. Food Chem. 39:1892-1896, 1991; cited on Form PTO-892 filed January 16, 2024; hereafter “Traoré”)
are withdrawn in view of applicant’s amendment to claim 1 to delete the alternative of “an anti-inflammatory molecule.”
Claims 1, 7, 11-13, 19, and 20 are newly rejected under 35 U.S.C. 103 as being unpatentable over Mûller-Maissen in view of Sivaramakrishnan and as evidenced by Saile et al. (Hepatology 30:196-202, 1999; cited on the attached Form PTO-892; hereafter “Saile”).
This rejection is necessitated by applicant’s amendment to claim 1 to delete the alternative of “an anti-inflammatory molecule.”
Regarding the instant claim 1 limitation “A pharmaceutical or diagnostic composition,” Mûller-Maissen teaches a fibrin formulation comprising fibrinogen, thrombin, and an added bioactive factor (claim 1 of Mûller-Maissen).
Regarding the “synthetic compound” of instant claim 1, part 1), Mûller-Maissen teaches the added bioactive factor includes peptides, proteins, and polysaccharides (paragraphs [0093] and [0136]), and are preferably a growth factor or hormone (paragraph [0093]).
Mûller-Maissen teaches the added bioactive factor of the fibrin formulation is a fusion protein comprising at least two domains wherein the first domain comprises a growth factor and the second domain comprises a transglutaminase substrate domain (claim 10 of Mûller-Maissen). Mûller-Maissen teaches various growth factors including transforming growth factor β (TGFβ) (e.g., paragraph [0155]).
Mûller-Maissen does not explicitly teach TGFβ is an anti-apoptotic molecule. However, evidentiary reference Saile is cited to show that TGFβ inhibits apoptosis in activated rat hepatic stellate cells (title and abstract). In view of evidentiary reference Saile, TGFβ of the fibrin formulation of Mûller-Maissen is considered to be a therapeutically active anti-apoptotic molecule. As such, the fusion protein of Mûller-Maissen comprises at least one anchor domain (i.e., the transglutaminase substrate domain of the fusion protein of Mûller-Maissen) and comprises at least one therapeutically active anti-apoptotic molecule (i.e., TGFβ).
Mûller-Maissen teaches the transglutaminase substrate domain is a Factor XIIIa substrate domain (claim 11 of Mûller-Maissen).
Regarding the instant claim 1 limitations “(c) a heterologous cleavable linker peptide between the at least one anchor domain and the at least one therapeutically or diagnostically active molecule, wherein the cleavable linker peptide is cleaved to release the therapeutically or diagnostically active molecule” and “the heterologous cleavable linker peptide between the at least one anchor domain and the at least one therapeutically or diagnostically active molecule, wherein the cleavable linker peptide is cleaved in a desired environment of use or administration of the pharmaceutical or diagnostic composition,” Mûller-Maissen teaches the fusion protein comprises an enzyme degradation site between the first and second domains, e.g., an enzymatic degradation site that is cleaved by an enzyme selected from plasmin and matrix metalloprotease (paragraphs [0039] and [0126]), exemplified by a 21 amino acid “TG-hook” comprising a plasmin degradation site (paragraph [0166]).
Given a broadest reasonable interpretation, the TG hook between the transglutaminase substrate domain and TGFβ or hormone of the fusion protein of Mûller-Maissen is considered to be “a heterologous cleavable linker peptide” in instant claim 1 because it is “heterologous” to the transglutaminase substrate domain and TGFβ or hormone, directly links the transglutaminase substrate domain and TGFβ or hormone, and has an enzyme degradation site that is enzymatically cleaved to release the TGFβ or hormone from the transglutaminase substrate domain.
Regarding the “enzyme having transglutaminase activity” of instant claim 1, part 2), Mûller-Maissen teaches the fibrinogen of the fibrin formulation is in a fibrinogen precursor solution (paragraph [0097]). Mûller-Maissen teaches that preferably, factor XIII is present in the fibrinogen precursor solution (paragraph [0120]), which is activated to Factor XIIIa by mixing with thrombin (paragraphs [105] and [0108]).
The difference between Mûller-Maissen and claim 1 is that Mûller-Maissen does not teach the transglutaminase substrate domain of the fusion protein (i.e., the “anchor domain” of claim 1) comprises the sequence of instant SEQ ID NO: 1 or a derivative thereof as recited in parts i), ii), and iii) of instant claim 1.
Sivaramakrishnan teaches the amino acid sequence surrounding K68 (PAK68SA) of IGF-I is in broad agreement with the consensus (P/L)-(S/L/A/R)-K-(OH/L/G/V) substrate motif for transglutaminases (p. 3183, column 1, middle). Sivaramakrishnan teaches that the D domain sequence CAPLKPAKSA of IGF-I is cross-linked by FXIIIa (p. 3176, Abstract; p. 3179, column 2; p. 3180, Figure 4). According to Sivaramakrishnan, the data indisputably demonstrates that IGF-I is a lysine donor substrate to FXIIIa and that K68 is the key lysine donor site in IGF-I to FXIIIa (p. 3183, column 1, middle).
In view of the combined teachings of Mûller-Maissen and Sivaramakrishnan, it would have been obvious to one of ordinary skill in the art before the effective filing date to modify Mûller-Maissen to use the sequence surrounding K68 of IGF-I, e.g., PAKSA or CAPLKPAKSA, as the Factor XIIIa substrate domain of the fusion protein. One would have been motivated and would have expected success to do this because Mûller-Maissen discloses the fusion protein of the fibrin formulation comprises a transglutaminase substrate domain, particularly a Factor XIIIa substrate domain, and Sivaramakrishnan teaches that K68 of IGF-I is within a consensus substrate motif for transglutaminases and is a lysine donor for Factor XIIIa cross-linking.
Regarding instant claim 7, given that claim 7 does not define to what the composition is being locally administered, the modified fibrin formulation of combined Mûller-Maissen and Sivaramakrishnan is considered to be encompassed by claim 7.
Regarding instant claim 11, Mûller-Maissen discloses various “devices” comprising the fibrin formulation, including a fibrin foam (paragraph [0135]) and a fibrin matrix (paragraph [0135]).
Regarding instant claim 12, Mûller-Maissen discloses fibrin matrices have been used as drug delivery devices (paragraph [0107]).
Regarding instant claim 13, Mûller-Maissen discloses fibrin matrices have been used as a material for cell in-growth matrices (paragraph [0107]) and discloses adding cells to the matrix prior to implantation (paragraph [0162]).
Regarding instant claims 19 and 20, Mûller-Maissen discloses fibrin is polymerized fibrinogen (paragraph [0108]) and thus, the fibrin matrices used as a material for cell in-growth as noted above for claim 13 are polymer networks.
Therefore, the invention of claims 1, 7, 11-13, 19, and 20 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 26-28 are rejected under 35 U.S.C. 103 as being unpatentable over Mûller-Maissen in view of Sivaramakrishnan and as evidenced by Saile as applied to claims 1, 7, 11-13, 19, and 20 above, and further in view of Traoré.
This rejection is necessitated by applicant’s amendment to claim 1 to delete the alternative of “an anti-inflammatory molecule.”
The relevant teachings of Mûller-Maissen and Sivaramakrishnan and evidentiary reference Saile as applied to claims 1, 7, 11-13, 19, and 20 are set forth above.
Regarding instant claims 26-28, as noted above for instant claim 1, Mûller-Maissen teaches that preferably, factor XIII is present in the fibrinogen precursor solution (paragraph [0120]), which is activated to Factor XIIIa by mixing with thrombin (paragraphs [105] and [0108]).
The combination of Mûller-Maissen and Sivaramakrishnan does not teach or suggest the Factor XIII is mammalian or human Factor XIII.
Traoré teaches thrombin activation of human Factor XIII (p. 1892, column 1, bottom) and cross-linking of caseins by thrombin-activated human Factor XIIIa (p. 1894, Table II).
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Mûller-Maissen, Sivaramakrishnan, and Traoré to use human Factor XIII of Traoré in the fibrin formulation of Mûller-Maissen. One would have been motivated to and would have had a reasonable expectation of success to do this because Mûller-Maissen teaches thrombin-activated Factor XIII in the fibrin formulation as a cross-linking agent and Traoré teaches human Factor XIII is activated by thrombin and teaches thrombin-activated human Factor XIII as a cross-linking agent.
Therefore, the invention of claims 26-28 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Mûller-Maissen in view of Sivaramakrishnan and as evidenced by Saile as applied to claims 1, 7, 11-13, 19, and 20 above, and further in view of Turner et al. (Wound Practice & Research: Journal of the Australian Wound Management Association 23:16–24, 2015; cited on the attached Form PTO-892; hereafter “Turner”) and Birch et al. (Advanced Drug Delivery Reviews 58:671-685, 2006; cited on the attached Form PTO-892; hereafter “Birch”).
This rejection is necessitated by applicant’s amendment to add new claim 29.
The relevant teachings of Mûller-Maissen and Sivaramakrishnan and evidentiary reference Saile as applied to claims 1, 7, 11-13, 19, and 20 are set forth above.
Regarding instant claim 29, Mûller-Maissen teaches the added bioactive factor of the fibrin formulation includes peptides, proteins, and polysaccharides (paragraphs [0093] and [0136]) and the fibrin formulation is for wound healing (title, abstract).
The combination of Mûller-Maissen and Sivaramakrishnan does not teach or suggest the bioactive factor is an antibody, polyethylene glycol, or a small molecule.
Turner teaches that currently, the treatment of acute and chronic wounds is an area of unmet clinical need and therapeutic monoclonal antibodies (mAbs) may provide a valuable new tool for wound treatment (p. 16, Abstract). Turner teaches that a key factor for consideration when developing mAb therapies includes optimal delivery route, noting that recent research into the development of delivery systems has focused on using nanotechnological approaches to control release rates (p. 17, column 1, first full paragraph).
Birch teaches methods for recombinant mAb production (see entire document).
It would have been obvious to one of ordinary skill in the art before the effective filing date to combine Mûller-Maissen, Sivaramakrishnan, Turner, and Birch to use a mAb with wound healing activity as the bioactive factor in the fibrin formulation of Mûller-Maissen. One would have been motivated to do so because Mûller-Maissen teaches the added bioactive factor of the fibrin formulation includes proteins and the fibrin formulation is for wound healing and Turner teaches therapeutic mAbs, which are proteins, for wound healing. One would have expected success because Mûller-Maissen taught the fusion protein of the fibrin formulation is produced by recombinant expression (e.g., paragraph [0127]) and Birch teaches methods for recombinant expression and production of mAbs.
Therefore, the invention of claim 29 would have been obvious to one of ordinary skill in the art before the effective filing date.
RESPONSE TO REMARKS: Applicant argues the combination of cited prior art fails to teach or suggest all limitations of the claims because the TGFβ component of the fusion protein of Mûller-Maissen is not an antibody, polyethylene glycol, a small molecule, an anti-apoptotic molecule, an antibiotic, a hormone, or a combination thereof.
Applicant’s arguments are not found persuasive. Given a broadest reasonable interpretation and in view of the evidentiary reference of Saile, the TGFβ of the fusion protein of Mûller-Maissen is considered to be a therapeutically active anti-apoptotic molecule in claim 1.
For these reasons, it is the examiner’s position that the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the claims:
Claims 1, 4, 7-20, and 26-29 are pending in the application.
Claims 4, 8-10, and 14-18 are withdrawn from consideration.
Claims 1, 7, 11-13, 19, 20, and 26-29 are rejected.
No claim is in condition for allowance.
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/David Steadman/Primary Examiner, Art Unit 1656
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