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
Priority to 63/268,303, filed 2/2/1/2022 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) was submitted on 6/24/2024, before the mailing of a first office action. The submissions are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Status
Claims 1-12 are pending. Claims 1-12 are under examination.
Specification
The disclosure is objected to because of the following informalities: paragraph [70] of the specification indicates SEQ ID NO: 59 as having the sequence RGD. However, the sequence listing indicates that SEQ ID NO: 59 is a 224 amino acid polypeptide. Appropriate correction is required.
Appropriate correction is required.
Claim Interpretation
The term “growth factor binding motif” has been introduced in numerous places in the specification between the time of the filing of the provisional and the filing of the current application.
After analysis, this term is being used interchangeably and therefore no new matter is introduced.
The support for this is mostly clearly demonstrated by Martino et al. (Martino, et al. The FASEB Journal 24.12: 4711-4721 (2010)):
“Fibronectin (FN), a key adhesion protein found in the blood, in the interstitial ECM, and in the pericellular matrix, is known to possess specific interactions with a variety of GFs. For instance, TGF-β1, HGF, connective tissue growth factor (CTGF), and platelet-derived growth factor (PDGF)-A bind to immobilized FN (13, 15–18). Moreover, it has been demonstrated, in vivo, that VEGF-A165 is released from platelets in complex with FN (19), and the presence of IGF-I/IGF binding protein (IGFBP)-3/FN ternary complexes in human plasma has been detected by coimmunoprecipitation (20), while IGFBP-3 and FN colocalize in human articular cartilage (21). More precisely, FGF-2 and VEGF-A165 have been shown to bind with high affinity to a domain consisting of the 12th to 14th type III repeats of FN (FN III12–14), also known as the FN heparin-binding domain II (22, 23)” (Martino, et al., page 4711, col. 2, para. 2).
The specification alludes to this phenomenon in para. [20]:
“In an embodiment of the present invention, said growth factor binding motif can be
derived from fibronectin domain III, laminin globular domain, heparin binding domain of collagen, heparin binding domain of vitronectin, heparin binding domain of fibrinogen or heparin binding domain of bone sialoprotein.”
However, without the insights of Martino, it would not have been clear how a heparin binding motif is reasonably expected to bind a growth factor when heparin is not itself a growth factor. Therefore, the redefinition of the term “growth factor binding domain” to refer to a heparin-binding motif is the Applicant acting as their own lexicographer and this definition is against common interpretations.
Regarding the peptide sequences of claims 3 and 4, these have been interpreted to be open-ended sequences because the base claim 1 utilizes the transition phrase “comprising” and Figure 1 shows the microcarrier with more than one binding motif.
Claim Objections
Claims 1-12 are objected to because of the following informalities. Claims 1-12 lack status identifiers. See MPEP 714(II)(C) for more details. Appropriate correction is required.
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.
Claim 4 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 4 recites the limitation "heparin binding motif" in line 1. There is insufficient antecedent basis for this limitation in the claim. Neither claim 1 nor claim 2 recite “heparin binding motif”.
Claim 4 is rejected.
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 1-12 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.
Regarding claim 1, the breadth of claim 1 encompasses any possible growth factor and any possible binding motif for said growth factor. Claim 1 further establishes a structure-function relationship in that these binding motifs must be able to bind or sequester growth factors.
In this case, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), a "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures and phenotypes of the entire genus.
A large number of growth factors exist. For example, Ferrara et al. (Ferrara, et al. Nature medicine 9.6: 669-676. (2003)) discloses VEGF growth factors:
“Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.” (Ferrara et al., Abstract).
Nakamura et al. (Nakamura, Takahiro, et al. "Hepatocyte growth factor twenty years on: Much more than a growth factor." Journal of gastroenterology and hepatology 26: 188-202. (2011)) discloses hepatocyte growth factors:
“Liver regeneration depends on the proliferation of mature hepatocytes. In the 1980s, the method for the cultivation of mature hepatocytes provided an opportunity for the discovery of hepatocyte growth factor (HGF) as a protein that is structurally and functionally different from other growth factors. In 1991, the scatter factor, tumor cytotoxic factor, and 3-D epithelial morphogen were identified as HGF, and Met tyrosine kinase was identified as the receptor for HGF. Thus, the connection of apparently unrelated research projects rapidly enriched the research on HGF in different fields. The HGF-Met pathway plays important roles in the embryonic development of the liver and the placenta, in the migration of myogenic precursor cells, and in epithelial morphogenesis. The use of tissue-specific knockout mice demonstrated that in mature tissues the HGF-Met pathway plays a critical role in tissue protection and regeneration, and in providing less susceptibility to chronic inflammation and fibrosis. In various injury and disease models, HGF promotes cell survival, regeneration of tissues, and suppresses and improves chronic inflammation and fibrosis. Drug development using HGF has been challenging, but extensive preclinical studies to address its therapeutic effects have provided significant results sufficient for the development of HGF as a biological drug in the regeneration-based therapy of diseases. Clinical trials using recombinant human HGF protein, or HGF genes, are in progress for the treatment of diseases.” (Nakamura et al., Abstract).
Bafico et al. (Bafico et al. Holland-Frei cancer medicine 6. PMPH-USA, 2003.) further lists platelet, epidermal, fibroblast, insulin, neutrophin, ephrin, agrin, GDNF, angiopoietin, and further growth factors.
These growth factors are diverse in structure and function.
Applicant reduces SEQ ID NO: 20, SEQ ID NO: 59, and SEQ ID NO: 77 to practice. No binding data is provided. The binding motif peptides disclosed throughout the specification lack a common structural motif. Absent the conserved structure provided by the species reduced to practice, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally. In this case, the structure would need to be able to bind a growth factor.
Since only a limited number of species of peptides are taught within the claimed genus above, the instant claim above fails the written description requirement. Furthermore, it is not immediately clear to the skilled artisan which growth factors are being bound by the provided examples. A representative number of species has not been taught to describe these genera.
Regarding the peptides, a single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3).
Furthermore, many sequences allowed by the current scope of the claims, result in non-functional aggregates. Wang (Wang, et al. MAbs. Vol. 1. No. 3. Taylor & Francis, (2009)) discloses a variety of aggregation prone motifs that occur in commercial antibodies (Wang, page 262, Table 2). The scope of the claims currently may incorporate such motifs and result in non-functional aggregates.
Finally, Zhou et al. (Zhou, et al. Biochimica et Biophysica Acta (BBA)-Biomembranes 1858.8: 1914-1925 (2016)) discloses that peptides are also subject to significant activity changes from a single mutation: “In our study, we constructed two anticancer peptides with only one difference in residue, but they showed dissimilar modes of action. One could penetrate into cells, target on mitochondria, and induce cell apoptosis, while the other could cause cell membrane lysis. This finding provides us a good example to study the structure-function relationship of ACPs as important drugs.” (Zhou et al., Abstract).
Regarding the bound growth factors, it is not clear which of the possible above referenced growth factors are targeted by the provided examples. From examination of the prior art, each motif has limited binding capabilities. For example, Kim et al. (WO2021146455, published 7/22/2021) discloses that the sequence KYILRWRPKNS is capable of binding heparin:
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(Kim et al., page 96, Table II).
Lin et al. (Lin, et al. Journal of Investigative Dermatology 134.4:1119-1127 (2014) discloses that this motif also binds platelet growth factor:
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Figure 1. Peptide from first fibronectin type III repeat (FNIII1) binds platelet-derived growth factor-BB (PDGF-BB). (a) Schematic of human FN. FN type I repeats are shown as thin rectangles, FN type II repeats as ovals, and FN type III repeats as thick rectangles. PDGF-BB and cell-binding sites are indicated (arrows). (b) Sequence of FNIII1 (FN609-718). Sequences of P1 (FN634-658) and P2 (FN680-704) are underlined. (c) Equilibrium binding of PDGF-BB with anastellin (FN630-704). (d) Kinetic binding of PDGF-BB with FN630-704. Increasing concentrations (6.25–200 nM) of FN630-704 were injected across the biosensor chip coupled with PDGF-BB (first arrow), followed 120 seconds later by a continuing flow of buffer (second arrow). Chip without PDGF-BB was used as a reference. KD was calculated by averaging the koff divided by kon. Sensorgrams are representative of three different experiments. c.p.m., counts per minute; RU, relative units.
(Lin et al., page 1120, Fig. 1).
Given the limited scope of the provided examples and lack of binding data, the skilled artisan would not have been in possession of the breadth of growth factor binding motifs encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claim 1.
Consequently, claim 1 is rejected.
Regarding claim 2, claim 1 is rejected as described above. Claim limits the genus size to a Markush group of possibilities, but the target of the binding is still not clear. Furthermore, a huge amount of sequence space of peptides is contained within the recited Markush group. One of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claim 2.
Consequently, claim 2 is rejected.
Regarding claim 3, claim 2 is rejected as described above. Claim 3 limits the genus size to a Markush group of peptides. These peptides lack a common structural motif and also lack a common motif with the peptides reduced to practice. One of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claim 3.
Consequently, claim 3 is rejected.
Regarding claim 4, claim 2 is rejected as described above. Claim 4 limits the genus size to a Markush group of peptides. Two of the peptides from this Markush group were reduced to practice. However, the peptides of this Markush group lack a common structural motif. Furthermore, it is not explained which growth factor is bound by the example peptides. One of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claim 4.
Consequently, claim 4 is rejected.
Regarding claims 5-7, claim 2 is rejected as described above. These claims recite relatively small numbers of peptides. However, the examples provided above do not share a common structure motif and therefore are not representative examples of these genera. One of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claims 5-7.
Consequently, claims 5-7 are rejected.
Regarding claim 8, claim 1 is rejected as described above. Claim 8 reduces the size of the growth factor genus, but does not reduce the size of the binding motif genus. One of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claim 8.
Consequently, claim 8 is rejected.
Regarding claims 9-12, claim 1 is rejected as described above. These do not reduce the size of any relevant genera discussed above. One of skill in the art would conclude that applicant was not in possession of the structural and/or phenotypic attributes of a representative number of species possessed by the members of the genus of every growth factor binding motif recited by claims 9-12.
Consequently, claims 9-12 are rejected.
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.
Claims 1-3 and 8-11 are rejected under 35 U.S.C. 103 as being unpatentable over Cha et al. WO2008150101, published 1/29/2009 in view of Kupikowska-Stobba et al. (Kupikowska-Stobba, et al. Biomaterials science 8.6: 1536-1574 (2020), Kim et al. WO2021146455, published 7/22/2021, and Lin et al. (Lin, et al. Journal of Investigative Dermatology 134.4:1119-1127 (2014), as evidenced by Lu, et al. Journal of The Royal Society Interface 10.79: 20120759 (2013)).
Regarding claim 1, Cha discloses a mussel adhesive protein coupled to a biofunctional peptide:
“The present invention is related to a chimeric polypeptide comprising a mussel adhesive protein and a biofunctional peptide coupled thereto, a bioadhesive extracellular matrix comprising the chimeric polypeptide, and a method of controlling an adhesiveness of an extracellular matrix. The present invention also relates to compositions or bio-coating of said extracellular matrix mimic for life science and medical application with enhanced specific bioactivities and biocompatibility.” (Cha et al., page 1, line 11).
Cha also discloses that the biofunctional peptide may be derived from the heparin binding domain of fibronectin:
“The biofunctional peptide is derived from a cell binding domain or heparin binding domain of fibronectin. “ (Cha et al., page 10, line 15).
The mussel adhesive protein is positively charged as disclosed by Lu:
“Mfps from the Mytilus genus, comprising more than eight different proteins, are secreted from the mussel foot and responsible for adhesion and coating of the mussel byssus. All these proteins contain the post-translationally modified amino acid 3,4-dihydroxyphenyl-L-alanine (DOPA), derived from hydroxylation of tyrosine residue, and they are positively charged polyelectrolytes with high isoelectric points.” (Lu et al., page 1, para. 2).
Cha does not disclose a negatively charged component.
However, Kupikowska-Stobba discloses a microcarrier formed by electrostatic interactions:
“Polymer microcarriers are being extensively explored as cell delivery vehicles in cell-based therapies and hybrid tissue and organ engineering. Spherical microcarriers are of particular interest due to easy fabrication and injectability.” (Kupikowska-Stobba et al., Abstract).
“First semipermeable membranes were obtained from synthetic polycation poly-l-lysine (PLL) based on the ability of polyanionic alginate to form polyelectrolyte complexes with PLL.8 The alginate-poly-l-lysine (AP) membranes were formed by electrostatic interactions between anionic alginate chains and positively charged fragments of poly(amino acid) molecules.“ (Kupikowska-Stobba et al., page 1547, col. 2, para. 2).
Cha does not specifically disclose a growth factor binding domain motif which is capable of binding or sequestering growth factors.
However, Kim discloses that the sequence KYILRWRPKNS is capable of binding heparin:
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(Kim et al., page 96, Table II).
In turn, Lin discloses that this motif also binds platelet growth factor:
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Figure 1. Peptide from first fibronectin type III repeat (FNIII1) binds platelet-derived growth factor-BB (PDGF-BB). (a) Schematic of human FN. FN type I repeats are shown as thin rectangles, FN type II repeats as ovals, and FN type III repeats as thick rectangles. PDGF-BB and cell-binding sites are indicated (arrows). (b) Sequence of FNIII1 (FN609-718). Sequences of P1 (FN634-658) and P2 (FN680-704) are underlined. (c) Equilibrium binding of PDGF-BB with anastellin (FN630-704). (d) Kinetic binding of PDGF-BB with FN630-704. Increasing concentrations (6.25–200 nM) of FN630-704 were injected across the biosensor chip coupled with PDGF-BB (first arrow), followed 120 seconds later by a continuing flow of buffer (second arrow). Chip without PDGF-BB was used as a reference. KD was calculated by averaging the koff divided by kon. Sensorgrams are representative of three different experiments. c.p.m., counts per minute; RU, relative units.
(Lin et al., page 1120, Fig. 1).
Therefore, this peptide derived from fibronectin III is a growth factor binding domain motif (as defined by the specification) which is capable of binding or sequestering growth factors.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the polypeptide of Cha with the anionic alginate chain of Kupikowska-Stobba and furthermore substitute the fibronectin III peptide of Kim and Lin into the construct of Cha to arrive at the claimed invention because the mussel adhesive protein of Cha is positively charged as disclosed by Lu and therefore can replace the poly-lysine in the microcarrier of Kupikowska-Stobba to form a new microcarrier and because substituting one fibronectin III peptide .
A person of ordinary skill in the art would be motivated to make this combination to gain the heparin binding/growth factor binding capabilities or the adhesion capabilities of the polypeptide of Cha, Kim, and Lin in a microcarrier as disclosed by Kupikowska-Stobba.
A person of ordinary skill in the art would have a reasonable expectation of success on two fronts. First, the substitution of one fibronectin III derived peptide from Cha for a peptide of Kim and Lin can be reasonably expected to be successful because both are binding peptides derived from fibronectin III. Second, substitution of the positively charged mussel adhesion protein for the positively charged polylysine can be reasonably expected to also from electrostatic interactions and result in a microcarrier as disclosed by Kupikowska-Stobba.
Consequently, claim 1 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Regarding claim 2, claim 1 is obvious as described above. The growth factor of Cha, Kim, and Lin is a motif derived from fibronectin III.
Consequently, claim 2 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Regarding claim 3, claim 1 is obvious as described above. Kim and Lin disclose the sequence KYILRWRPKNS.
Consequently, claim 3 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Regarding claim 8, claim 1 is obvious as described above. Kim and Lin disclose the sequence KYILRWRPKNS. This peptide binds platelet growth factor as described above.
Consequently, claim 8 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Regarding claim 9, claim 1 is obvious as described above. Cha discloses a recombinant adhesive protein:
“The present invention is related to a chimeric polypeptide comprising a mussel adhesive protein and a biofunctional peptide coupled thereto, a bioadhesive extracellular matrix comprising the chimeric polypeptide, and a method of controlling an adhesiveness of an extracellular matrix. The present invention also relates to compositions or bio-coating of said extracellular matrix mimic for life science and medical application with enhanced specific bioactivities and biocompatibility.” (Cha et al., page 1, line 11).
Consequently, claim 9 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Regarding claim 10, claim 1 is obvious as described above. Cha discloses SEQ ID NO: 30 in claim 4, aligned against Applicant SEQ ID NO: 4 below:
%
Result Query Filing
No. Score Match Length ID Date Dups Description
-------------------------------------------------------------------------------------------------------------
1 444 100.0 76 ADQ78274 -- 168 Mgfp-5 amino acid sequence, seq id 4.
ALIGNMENT:
Query Match 100.0%; Score 444; Length 76;
Best Local Similarity 100.0%;
Matches 76; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 SSEEYKGGYYPGNTYHYHSGGSYHGSGYHGGYKGKYYGKAKKYYYKYKNSGKYKYLKKAR 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 SSEEYKGGYYPGNTYHYHSGGSYHGSGYHGGYKGKYYGKAKKYYYKYKNSGKYKYLKKAR 60
Qy 61 KYHRKGYKKYYGGGSS 76
||||||||||||||||
Db 61 KYHRKGYKKYYGGGSS 76
Consequently, claim 10 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Regarding claim 11, claim 1 is obvious as described above. Cha discloses the following linkage in claim 2:
“2 The chimeric polypeptide of claim 1, wherein the biofunctional peptide is linked to C-terminus, N-terminus or C- and N-terminus of the mussel adhesive protein.”
Consequently, claim 11 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. and rejected.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Cha et al. WO2008150101, published 1/29/2009 in view of Kupikowska-Stobba et al. (Kupikowska-Stobba, et al. Biomaterials science 8.6: 1536-1574 (2020), Kim et al. WO2021146455, published 7/22/2021, and Lin et al. (Lin, et al. Journal of Investigative Dermatology 134.4:1119-1127 (2014), as evidenced by Lu, et al. Journal of The Royal Society Interface 10.79: 20120759 (2013)) as applied to claim 2, further in view of Ishihara et al. (Ishihara, et al. Nature communications 9.1: 2163 (2018)) as evidenced by Uniprot (Q16787, accessed 9/18/2026, uploaded 11/1/1996).
Regarding claim 4, claim 2 is rejected as described above. Cha, Kupikowska-Stobba, Kim, Lin, and Lu contemplate the usage of laminin derived peptides:
“The biofunctional peptide is derived from laminin. The biofunctional peptide is selected from the group consisting of peptides comprising an amino acid sequence of SEQ ID NOs: 12 to 18. The biofunctional peptide is a peptide having an amino acid sequence of SEQ ID NO: 12 (Tyr He GIy Ser Arg) or a peptide having an amino acid sequence of SEQ ID NO: 17 (He Lys VaI Ala VaI).” (Cha et al., page 11, line 4).
Cha, Kupikowska-Stobba, Kim, Lin, and Lu do not specifically disclose the case wherein the growth factor binding motif is a heparin binding motif derived from laminin globular domain selected from the claimed peptides of claim 4.
However, Ishihara discloses a peptide derived from LAMA3 residues 3031-3043 (KNSFMALYLSKGR) that is specifically capable of binding heparin and growth factors:
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(Ishihara et al., page 6, Fig. 4).
“Laminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. Here, we show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin-binding domains (HBDs) located in the α chain laminin-type G (LG) domains. These domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We explore the application of these multifunctional laminin HBDs in wound healing in the type-2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrices improves retention of GFs and significantly enhances the efficacy of vascular endothelial cell growth factor (VEGF-A165) and platelet-derived growth factor (PDGF-BB) in promoting wound healing in vivo, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterial matrices as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration.” (Ishihara et al., Abstract).
KNSFMALYLSKGR reads on Applicant SEQ ID NO: 22.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide of Ishihara in the microcarrier of Cha, Kupikowska-Stobba, Kim, Lin, and Lu in place of the fibronectin-derived peptide to arrive at the claimed invention because Cha, Kupikowska-Stobba, Kim, Lin, and Lu contemplate the usage of laminin-derived peptides and Ishihara shows that the particular peptide in question is capable of binding heparin and growth factors.
A person of ordinary skill in the art would be motivated to make this substitution to change the activity of the microcarrier to bind a different set of growth factors and would have a reasonable expectation of success because Cha, Kupikowska-Stobba, Kim, Lin, and Lu contemplate the usage of laminin-derived peptides and Ishihara shows that the particular peptide in question is capable of binding heparin and growth factors.
Consequently, claim 4 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. as applied to claim 2 above, further in view of Ishihara et al. as evidenced by UniProt and rejected.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Cha et al. WO2008150101, published 1/29/2009 in view of Kupikowska-Stobba et al. (Kupikowska-Stobba, et al. Biomaterials science 8.6: 1536-1574 (2020), Kim et al. WO2021146455, published 7/22/2021, and Lin et al. (Lin, et al. Journal of Investigative Dermatology 134.4:1119-1127 (2014), as evidenced by Lu, et al. Journal of The Royal Society Interface 10.79: 20120759 (2013)) as applied to claim 2, further in view of Salber et al. (Salber, et al. Small 3.6: 1023-1031. (2007))
Regarding claim 5, claim 2 is obvious as described above. Cha, Kupikowska-Stobba, Kim, Lin, and Lu disclose the usage of the peptide GEFYFDLRLKGDK:
“In one embodiment of the invention, a method of preparing an ECM mimic is provided. The method comprises the steps of the construction of recombinant plasmid pFP151-ECM derived polypeptide or oligopeptide that can express fusion protein of hybrid fp-151 and a peptide derived from the peptide of which the amino acid sequence is selected from the group consisting of RGD-containing fragment such as GRGDSP (SEQ ID NO:2), can be constructed. Obviously ECM derived polypeptide or oligopeptide can be from any sources. Preferred fibronectin-, laminin-, collagen-, vitronectin-, heparin binding domain-derived peptide are GRGDSP(SEQ ID NO:2), YIGSR(SEQ ID NO:12) and/or IKAVA(SEQ ID NO: 17), GIy GIu Phe Tyr Phe Asp Leu Arg Leu Lys GIy Asp Lys (GEFYFDLRLKGDK)(SEQ ID NO: 21), and KNNQKSEP(SEQ ID NO: 7), respectively.” (Chu et al, page 16, line 3).
Furthermore, Salber discloses the role of GEFYFDLRKGDK in cell adhesion and self-assembly:
“Subsequently the substrates were biofunctionalized by covalently binding peptide sequences derived from fibronectin (GRGDS and the synergistic sequence PHSRN), laminin (YIGSR), and collagen IV (GEFYFDLRLKGDK), three major constituents of the ECM.32 These peptides are known to interact directly with connective tissue cells (e.g., fibroblasts) and epithelial cells (e.g., keratinocytes) and play a role in self-assembly of fibronectin fibrils, heparin, and cell-binding sites.” (Salber et al., page 1024, col. 2, para. 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide GEFYFDLRLKGDK as disclosed by Cha, Kupikowska-Stobba, Kim, Lin, and Lu in the microcarrier disclosed by Cha, Kupikowska-Stobba, Kim, Lin, and Lu to arrive at the claimed invention because Cha discloses this peptide as a preferred embodiment and Salber discloses its relationship with fibroblasts and self-assembly.
A person of ordinary skill in the art would make this combination to modify the activity of the microcarrier of Cha, Kupikowska-Stobba, Kim, Lin, and Lu to interact with the growth factors influenced by the peptide GEFYFDLRLKGDK.
A person of ordinary skill in the art would have a reasonable expectation of success because Cha discloses that GEFYFDLRLKGDK is a preferred embodiment and Salber discloses its relationship with fibroblasts and self-assembly.
Consequently, claim 5 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. as applied to claim 2 above, further in view of Salber et al. and rejected.
Claims 6 and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Cha et al. WO2008150101, published 1/29/2009 in view of Kupikowska-Stobba et al. (Kupikowska-Stobba, et al. Biomaterials science 8.6: 1536-1574 (2020), Kim et al. WO2021146455, published 7/22/2021, and Lin et al. (Lin, et al. Journal of Investigative Dermatology 134.4:1119-1127 (2014), as evidenced by Lu, et al. Journal of The Royal Society Interface 10.79: 20120759 (2013)) as applied to claim 2, further in view of Brizzi et al. (Brizzi, et al. Current opinion in cell biology 24.5: 645-651.) (2012)).
Regarding claim 6, claim 2 is obvious as described above. Kim discloses that the peptide KKQRFRHRNRKGYRSQ is an integrin binding motif:
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(Kim et al., page 85, Table 2).
Furthermore, Brizzi discloses that integrins associate with growth factors, despite not being growth factors in and of themselves:
“It is widely acknowledged that integrins, the major receptors for the extracellular matrix (ECM) proteins, exert an extensive crosstalk with many growth factor and cytokine receptors. Among them, growth factor receptors, such as the EGFR, MET, PDGFR and VEGFR, and the IL-3 receptor have been shown to be physically and functionally associated to integrins. The connection between integrins and other transmembrane receptors is bidirectional, integrins being essential for receptor signalling, and receptors being involved in regulation of integrin expression or activation. Moreover, there is accumulating evidence for direct binding of specific growth factors and morphogens to the ECM proteins, suggesting that ECM might spatially integrate different types of signals in a specific microenvironment, facilitating integrin/transmembrane receptors connection. These interactions are crucial in controlling a variety of cell behaviours including proliferation, survival and differentiation. The increasing interest for cell therapy in regenerative medicine has recently emphasized the role of cell-ECM adhesion as stem cell determinant. The relevance of ECM, integrins and growth factor receptor network in the establishment of stem cell niche, in maintenance of stem cells and in their differentiation will be analyzed in the present review.” (Brizzi et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide KKQRFRHRNRKGYRSQ as disclosed by Cha, Kupikowska-Stobba, Kim, Lin, and Lu in the microcarrier disclosed by Cha, Kupikowska-Stobba, Kim, Lin, and Lu to arrive at the claimed invention because Kim discloses this peptide as an integrin binder which in turn binds and associates with growth factors as disclosed by Brizzi.
A person of ordinary skill in the art would make this combination to modify the activity of the microcarrier of Cha, Kupikowska-Stobba, Kim, Lin, and Lu to interact with integrin by the peptide KKQRFRHRNRKGYRSQ.
A person of ordinary skill in the art would have a reasonable expectation of success because Kim discloses this peptide as an integrin binder which in turn binds and associates with growth factors as disclosed by Brizzi.
Consequently, claim 6 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. as applied to claim 2 above, further in view of Brizzi et al. and rejected.
Regarding claim 7, claim 2 is obvious as described above. Kim discloses that the peptide KRSR is an integrin binding motif:
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(Kim et al., page 85, Table 2).
Furthermore, Brizzi discloses that integrins associate with growth factors, despite not being growth factors in and of themselves:
“It is widely acknowledged that integrins, the major receptors for the extracellular matrix (ECM) proteins, exert an extensive crosstalk with many growth factor and cytokine receptors. Among them, growth factor receptors, such as the EGFR, MET, PDGFR and VEGFR, and the IL-3 receptor have been shown to be physically and functionally associated to integrins. The connection between integrins and other transmembrane receptors is bidirectional, integrins being essential for receptor signalling, and receptors being involved in regulation of integrin expression or activation. Moreover, there is accumulating evidence for direct binding of specific growth factors and morphogens to the ECM proteins, suggesting that ECM might spatially integrate different types of signals in a specific microenvironment, facilitating integrin/transmembrane receptors connection. These interactions are crucial in controlling a variety of cell behaviours including proliferation, survival and differentiation. The increasing interest for cell therapy in regenerative medicine has recently emphasized the role of cell-ECM adhesion as stem cell determinant. The relevance of ECM, integrins and growth factor receptor network in the establishment of stem cell niche, in maintenance of stem cells and in their differentiation will be analyzed in the present review.” (Brizzi et al., Abstract).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the peptide KRSR as disclosed by Cha, Kupikowska-Stobba, Kim, Lin, and Lu in the microcarrier disclosed by Cha, Kupikowska-Stobba, Kim, Lin, and Lu to arrive at the claimed invention because Kim discloses this peptide as an integrin binder which in turn binds and associates with growth factors as disclosed by Brizzi.
A person of ordinary skill in the art would make this combination to modify the activity of the microcarrier of Cha, Kupikowska-Stobba, Kim, Lin, and Lu to interact with integrin by the peptide KRSR.
A person of ordinary skill in the art would have a reasonable expectation of success because Kim discloses this peptide as an integrin binder which in turn binds and associates with growth factors as disclosed by Brizzi.
Consequently, claim 7 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. as applied to claim 2 above, further in view of Brizzi et al. and rejected.
Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over Cha et al. WO2008150101, published 1/29/2009 in view of Kupikowska-Stobba et al. (Kupikowska-Stobba, et al. Biomaterials science 8.6: 1536-1574 (2020), Kim et al. WO2021146455, published 7/22/2021, and Lin et al. (Lin, et al. Journal of Investigative Dermatology 134.4:1119-1127 (2014), as evidenced by Lu, et al. Journal of The Royal Society Interface 10.79: 20120759 (2013)) as applied to claim 2, further in view of Lee et al. KR101311325, published 9/30/2013.
Regarding claim 12, claim 1 is obvious as described above.
Kim discloses that the sequence KYILRWRPKNS is capable of binding heparin:
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(Kim et al., page 96, Table II).
Kim discloses that the peptide KKQRFRHRNRKGYRSQ is an integrin binding motif:
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(Kim et al., page 85, Table 2).
Cha, Kupikowska-Stobba, Kim, Lin, and Lu do not specifically disclose the usage of two or more peptide motifs even though such motifs are contemplated as described above.
However, Lee discloses such a construct:
“A three-dimensional microenvironmental structure comprising a biocompatible composition comprising a mussel adhesive protein and a cross-linking agent, wherein the mussel adhesive protein is one that regulates cellular behavior selected from the group consisting of cell adhesion, migration, growth and differentiation within its structure Wherein the extracellular matrix-derived peptide motif comprises a three-dimensional microenvironment selected from the group consisting of collagen, fibronectin, laminin, bitronectin, and cadherin; structure.” (Lee et al., claim 1)
“The method according to claim 1 or 2, wherein the extracellular matrix-derived peptide motif comprises a combination of activating two or more different cell surface receptors simultaneously selected from the group consisting of integrin, cindecane, cadherin or destroglycan Dimensional micro environmental structure.” (Lee et al., claim 3).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use a second peptide motif as disclosed by Lee with the microcarrier of Cha, Kupikowska-Stobba, Kim, Lin, and Lu because Lee is also adding functionality to a mussel adhesive scaffold.
A person of ordinary skill in the art would make this combination to introduce additional functionality to the microcarrier of Cha, Kupikowska-Stobba, Kim, Lin, and Lu, such as to have integrin and heparin binding.
A person of ordinary skill in the art would have a reasonable expectation of success because the peptide motifs of Kim are being substituted in the scheme of Lee which allows for more than one peptide motif. In this case, specifically one integrin binding domain and one heparin binding domain.
Consequently, claim 12 is obvious over Cha et al. in view of Kupikowska-Stobba et al., Kim et al., and Lin et al. as evidenced by Lu et al. as applied to claim 1 above, further in view of Lee et al. and rejected.
Conclusion
No claim is allowed.
Claims 1-12 are objected to.
Claims 1-12 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
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/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654
