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 .
Status of Claims
Receipt of Arguments/Remarks filed on 12/4/2025 is acknowledged. Claim 1 was amended. Claim 11 was canceled. Claims 1 and 12-20 are pending. Claims 14-20 are withdrawn from consideration.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 12/24/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Withdrawn Rejections
The objections to the drawings are withdrawn.
The rejection of claim 11 under 35 U.S.C. § 112(b) is withdrawn, as this claim is now canceled.
New and modified rejections necessitated by amendment
Claim Rejections - 35 USC § 112
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 1 and 12-13 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.
Claim 1 recites the limitation "the two chimeric proteins". There is insufficient antecedent basis for this limitation in the claim. Claim 1, line 1, recites “a chimeric protein”. Thus, it is unclear what the limitation directed to two chimeric proteins refers to.
In the remarks filed 12/4/2025, applicant states:
In claim 1, the phrase "wherein two molecules of the chimeric protein associate with each other through their N-terminal regions to form a hexamer" is being added.
However, the limitation in amended claim 1 instead recites “wherein the two chimeric proteins associate with each other through their N-terminal regions to form a hexamer”. Further, based on applicant remarks, it appears this amendment is made to incorporate the limitation of claim 11, which is now canceled, into claim 1. The previous claim 11 was directed to a heterotrimer formed by the two fibrinogen fragments associated with each other through their N-terminal regions to form a hexamer. If this is the limitation that applicant is incorporating into claim 1, claim 1 should be amended to clarify that it is the fibrinogen fragments associating through their N-terminal regions to form a hexamer. For the purposes of examination, it is considered that this limitation is referring to fibrinogen fragments associating through their N-terminal regions, as previously recited cancelled claim 11.
Claims 12-13 are included in this rejection because they depend on a rejected claim and do not clarify the issue.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1 and 12-13 are rejected under 35 U.S.C. 103 as being unpatentable over Baker et al., US 2019/0192739 A1 in view of Sekiguchi et al., US 9,758,765 B2; and Hubbell et al., US 2010/0009409 A1.
Regarding claim 1, Baker teaches a laminin peptide conjugated to fibrinogen (Baker pg. 8 para. 67-70; pg. 9 Table 2). Baker teaches that fibrinogen is cleaved by thrombin to form a fibrin hydrogel (Baker pg. 5 para. 50). Baker teaches that any suitable laminin peptide can be conjugated to fibrinogen to form the fibrin hydrogel, including AG73 (Baker pg. 6 para. 55).
Baker does not teach a heterotrimeric laminin fragment and a heterotrimeric fibrinogen fragment wherein the chains are fused and the fibrinogen fragments associate through their N-terminal regions to form a hexamer as set forth in claim 1, or a protein having growth factor binding activity as set forth in claims 12 and 13.
Regarding claim 1, Sekiguchi teaches a chimeric laminin fragment, wherein laminin is fused to a cell-growth regulatory protein (Sekiguchi col. 1 “Technical Field”; col. 22 lines 50-67). Sekiguchi teaches that the laminin fragment is in the form of a heterotrimer comprising C-terminal regions of laminin α, β, and γ chains (Sekiguchi col. 5 lines 9-22, lines 49-67). The C-terminal laminin fragment in the heterotrimeric form, or laminin E8, is necessary for integrin binding activity (Sekiguchi col. 5 lines 55-58; col. 7 lines 26-46).
Regarding claims 12 and 13, Sekiguchi teaches a chimeric laminin protein wherein laminin is fused to a protein having growth factor-binding activity (Sekiguchi col. 7 lines 50-67; col. 10 lines 1-19). Sekiguchi teaches that an example of such a protein includes heparan sulfate proteoglycans (Sekiguchi col. 10 lines 1-5). Sekiguchi teaches that the growth factor binding molecule functions to capture growth factors and allow growth factors to more efficiently act on cells and stimulate cell growth, proliferation, and differentiation (Sekiguchi col. 7 lines 53-65; col. 9 lines 56-67).
Regarding claim 1, Hubbell teaches a fibrinogen fusion protein (or chimeric protein), wherein a non-fibrinogen protein or peptide is attached to the fibrinogen α chain (Hubbell “Abstract”). Hubbell teaches that fibrinogen has a complex oligomeric structure comprised of three chains, Aα, Bβ, and γ, which form a heterotrimeric structure (Hubbell pg. 1 para. 3; pg. 2 para. 18). Hubbell teaches that fibrinogen is cleaved by thrombin to create fibrin hydrogel (Hubbell pg. 1 para. 5) and that the amino-terminus, or N-terminus, of fibrinogen is critical for thrombin cleavage (Hubbell pg. 2 para. 18).
Hubbell teaches that the structure of fibrinogen is a complex oligomeric structure comprising three pairs of polypeptide chains, Aα2, Bβ2, and γ2, and that two Aα, Bβ, and γ subunits are oriented in an anti-parallel configuration (Hubbell pg. 1 para. 3). Hubbell teaches that the amino terminal, or N-terminal, portions of the six chains bundle together to create the fibrinogen oligomer, or hexamer (Hubbell pg. 1 para. 3). Hubbell teaches that the fibrinogen of the invention is a homodimer of the heterotrimer (Hubbell pg. 1 para. 19), indicating that the chimeric fibrinogen protein includes two fibrinogen heterotrimers that associate with each other to form the homodimer, or hexamer of six chains.
It would have been obvious to a skilled artisan, before the effective filing date, to modify the laminin-fibrinogen protein of Baker to construct a chimeric protein with a laminin heterotrimer as taught by Sekiguchi and a fibrinogen heterotrimer as taught by Hubbell. While Baker teaches a laminin peptide attached to fibrinogen, the laminin peptides taught by Baker are fragments of single laminin chains, and therefore not a trimeric structure comprising fragments from the α, β, and γ chains fused to fibrinogen as claimed. However, chimeric laminin proteins comprising a heterotrimer of C-terminal laminin fragments are known in the art, as taught by Sekiguchi. Similarly, Hubbell teaches chimeric fibrinogen proteins that are heterotrimers. Therefore, it would have been obvious to a skilled artisan that fibrinogen and laminin could be fused as a chimeric protein in a heterotrimer, rather than the monomeric conjugation taught by Baker.
Regarding the limitation “wherein each of the Aα , Bβ , and γ chains of the fibrinogen fragment is fused to any one of the α, β, and γ chains of the laminin fragment in any one of the following combinations (1) to (3)”, it would have been obvious to a person having ordinary skill in the art that, when creating a recombinant fusion protein of laminin and fibrinogen, that each fibrinogen chain could be fused to any of the laminin chains, resulting in a protein having the combinations of 1-3.
As Sekiguchi teaches that laminin is fused to a growth factor-binding molecule, it would have been obvious to a skilled artisan that a laminin-fibrinogen chimeric protein could similarly be fused to a growth factor-binding protein such as a heparan sulfate proteoglycan.
It would additionally have been obvious, given the teachings of Hubbell that fibrinogen forms a hexameric structure comprised of two heterotrimers, to create a chimeric protein wherein there are two fibrinogen fragments that interact to form a hexamer.
A person of ordinary skill in the art would have been motivated to modify the teachings of Baker and create a chimeric fibrinogen and laminin protein with a heterotrimer from the C-terminal regions of laminin chains and the N-terminal regions of fibrinogen chains, because Sekiguchi teaches that a heterotrimeric C-terminal fragment is crucial for integrin binding activity of laminin (Sekiguchi col. 7 lines 26-46) and Hubbell teaches that the fibrinogen structure of two heterotrimeric polypeptide chains which form a hexamer, particularly the N-terminal region of the Aα and Bβ chains, is crucial for thrombin activation of fibrinogen (Hubbell pg. 2 para. 18). It would therefore be considered advantageous, for the purpose of creating a laminin-fibrinogen protein that can be activated by thrombin and bind to integrins, to create a chimeric protein wherein each chain of fibrinogen is fused to a chain of laminin, utilizing C-terminal regions of laminin and N-terminal regions of fibrinogen. Both Sekiguchi and Hubbell teach the importance of the heterotrimeric structure of these proteins, providing motivation to modify the teachings of Baker and create a heterotrimeric protein comprising laminin and fibrinogen.
Additionally, a skilled artisan would have been motivated to incorporate a growth factor-binding protein such as a heparan sulfate proteoglycan, because these proteins when fused to laminin promote cell growth and differentiation, which would be an advantageous function for use of the chimeric protein in cell culture (Sekiguchi col. 7 lines 53-65).
A skilled artisan would have a reasonable expectation of success in combining these teachings to achieve a chimeric protein having the structure as instantly claimed, as chimeric proteins of both laminin and fibrinogen heterotrimers are known in the art, enabling a skilled artisan to create a chimeric protein comprised of laminin fused to fibrinogen using known and established techniques. As Baker teaches fibrinogen connected to laminin, a skilled artisan could reasonably expect success in creating a heterotrimeric chimera of these two proteins.
Response to Arguments
Applicant's arguments filed 12/4/2025 have been fully considered but they are not persuasive.
Applicant argues that a skilled artisan would not have been motivated to replace the laminin peptide of Baker with a laminin fragment that has integrin binding activity and forms a heterotrimer, because the laminin peptides of Baker do not participate in integrin binding.
In response to this argument, it is acknowledged by the examiner that the laminin peptides taught by Baker do not participate in integrin binding. However, it is known in the art that C-terminal laminin fragment in the heterotrimeric form, or laminin E8, is necessary for integrin binding activity, as discussed in the above rejection (Sekiguchi col. 5 lines 55-58; col. 7 lines 26-46). Chimeric proteins comprising laminin heterotrimers, as well as chimeric proteins comprising fibrinogen heterotrimers, are known in the art. Therefore, a skilled artisan interested in creating a chimeric laminin protein with integrin binding activity would have found it obvious to utilize a heterotrimeric laminin for this purpose, and thus would have been motivated to modify the teachings of Baker and create a fusion protein with laminin and fibrinogen heterotrimers, rather than monomers, as it is known that the heterotrimeric form is required for integrin binding. Thus, it is the position of the examiner that a skilled artisan would have been motivated, with a reasonable expectation of success, to modify the teachings of Baker based on the teachings of Sekiguchi and Hubbell and create a chimeric protein comprising fibrinogen and laminin heterotrimers as instantly claimed.
Conclusion
Claims 1 and 12-13 are rejected. No claims are allowed.
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 (37 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY F EIX whose telephone number is (571)270-0808. The examiner can normally be reached M-F 8am-5pm ET.
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/EMILY F EIX/Examiner, Art Unit 1653
/JENNIFER M.H. TICHY/Primary Examiner, Art Unit 1653