DETAILED ACTION
Claims 1-15 are currently pending.
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 .
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-8, in the reply filed on 2/5/2026 is acknowledged.
Claims 9-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 2/5/2026.
Priority
Acknowledgement is made of the instant application being a national stage entry under 35 USC 371 of international application PCT/EP2020/073586, filed August 24, 2020. Acknowledgment is further made of applicants' claim for foreign priority to EP application 19195855.2, filed 9/6/2019. A certified copy of the foreign priority document is present in the application file.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 4/25/2022 and 3/14/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: claim 1 recites the term “prefera-bly”. The term should be spelled “preferably”. 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.
Claims 1-8 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.
The term “insensitive” in claim 6 is a relative term which renders the claim indefinite. The term “insensitive” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The limitation directed to enzymatic degradation is rendered indefinite by the use of the term “insensitive”. The only disclosure of “insensitive” in applicant’s specification is at page 25 and recites:
“Therefore, the hydrogels of the present invention preferably are insensitive to enzymatic degradation that requires specific enzymatically cleavable pep- tide sequences, such as MMP or cathepsin degradation, i.e. they do not contain any moiety that is susceptible to enzymatic cleavage by cell-secreted proteases.”
Given the ambiguity of ‘preferably’ and ‘such as’, the specification does not specifically define what is meant by “insensitive”, one of ordinary skill in the art would not understand the metes and bounds of the term.
It is noted the dictionary definition of “insensitive” encompasses “not responsive or susceptible” or “not physically or chemically sensitive” (see Merriam Webster: Insensitive; PTO-892). Thus, in the interest of compact prosecution, the phrase “insensitive to enzymatic degradation” is considered to encompass hydrogels that are not susceptible or response to degradation by cell-secreted proteases.
Regarding claim 1 and the limitation “for example laminin-111”, it is noted the phrase "for example" renders the claim indefinite because it is unclear whether the limitation(s) following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 1 and the limitations “prefera-bly two nucleophilic groups” and “preferably laminin-511”, the phrase “preferably” is synonymous with "such as" and therefore renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Since each of claims 2-8 depend directly or indirectly from claim 1 they each inherit the deficiency thereof, and thus are rejected on the same basis.
Appropriate correction is required.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-2 and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2011/131642 (previously cited) (“WO ‘642”).
WO ‘642 is directed to a hydrogel precursor formulation, its process of production as well as a kit comprising said formulation and a method of production of a hydrogel using said formulation (Abstract).
Regarding claims 1 and 2, WO ‘642 teaches of preparing a biofunctional hydrogel wherein a solution comprising 7.5% w/v of a branched PEG with 4 arms (claim 2) functionalized with vinyl sulfone (i.e., multi-arm PEG containing ethylenically unsaturated groups selected from the group consisting of vinlysulfone and acrylate moieties) is mixed with 2% w/v of a peptide comprising an RGD sequence (bioactive compound), and this solution is then subsequently mixed with solution B comprising 1% w/v of a peptide linker (i.e., crosslinker molecule) comprising two cysteines, one near the C- and the other near the N-terminus, in mixing step 1 (Abstract; pages 10 and 15-16).
WO ’642 teaches the linker comprises at least two nucleophilic groups, preferably thiol groups. Thiols are strong nucleophiles readily undergoing Michael-Type addition reactions with unsaturated bonds or groups at physiological pH (page 6).
The linker peptide has a length of 16 amino acids wherein, the cysteines are located at the N- and C- terminus of the peptide, resulting in peptides with the structure ¾N-CXXXXXXXXC-COOH (SEQ ID NO: 1), more specifically the sequence of the linker compound is N¾-GCRE-GPQGIWGQERCG-COOH [SEQ ID NO: 4] or NH2-GCREGDQGIAGFERCG-COOH [SEQ ID NO: 5] (pages 6-7).
Although WO ‘642 does not further teach the linker comprises at least one RGD motif, it is noted WO ‘642 acknowledges the bioactive compound (i.e., bioactive compound comprising RGD) comprises at least one nucleophilic group, e.g., a thiol group, and is conjugable (crosslinking) through a self-selective reaction (Michael-type addition) that is the same reaction as the self-selective reaction between the structural compound (multi-arm PEG) and the linker compound (peptide crosslinker), especially between the same type of nucleophile and conjugated unsaturated bond or group (page 5). Thus, one would be motivated to modify the crosslinker molecule to comprise at least on RGD motif as WO 642 teaches this motif can be crosslinked with the multi-arm PEG structural compound via the same crosslinking reaction and RGD further promotes cell adhesion.
As to the limitation of a biofunctional ligand, WO ‘642 teaches the bioactive compound of the hydrogel may comprise the YISG peptide sequence from laminin, useful for cell adhesion (page 5, second paragraph), thus meeting the limitation of claim 1.
Regarding claim 6 and the limitation “wherein said hydrogel is insensitive to enzymatic degradation”, it is noted that WO ‘642 does not further comment on enzymatic degradation of the hydrogel. However, although WO ‘642 does not state the hydrogel is insensitive to enzymatic degradation (i.e., susceptible to degradation by cell-secreted proteases), the fact that WO ‘642 employs the same multi-arm PEG-VS as the instant application (page 13) means that any and all results of the method of WO ‘642, whether recognized at the time of publication or not, were inherently achieved by the reference method.
It is further noted that the crosslinker peptide disclosed by WO ‘642 does not comprise the protease degradable peptide sequence GPQ-W (see specification at page 5).
Regarding claim 7, it is noted as set forth above WO ‘642 teaches solution B comprising 1% w/v of a peptide linker (i.e., crosslinker molecule) comprising two cysteines, thus meeting the limitation of claim 7.
Further regarding claim 7 and the limitation the crosslinker peptide comprises at least two RGD motifs, it is noted, as set forth above at the rejection of claim 1, one would be motivated to modify the crosslinker molecule to comprise at least one RGD motif since WO ‘642 (page 10) teaches this RGD motif can be crosslinked with the multi-arm PEG structural compound via the same crosslinking reaction, and RGD further promotes cell adhesion. Given the intention of WO ‘642 is employing the hydrogel as a three-dimensional cell culture scaffold, and WO ‘642 acknowledges the RGD motifs promote cell adhesion, one would be motivated to modify the crosslinker molecule to comprise additional RGD motifs, i.e., at least two. Duplication of parts has no patentable significance unless a new and unexpected result is produced. See MPEP 2144.04 (VI)(B).
Claim(s) 3-5 are rejected under 35 U.S.C. 103 as being unpatentable over WO ‘642, as applied to claims 1-2 and 6-7 above, and further in view of Lutolf et al., (US 2018/0258403; IDS 3/14/2023) (“Lutolf”).
The teaching of WO ‘642 is set forth above.
Regarding claims 3 and 5 and the limitations directed to shear modulus, it is noted that although WO ‘642 teaches variation of concentrations of compounds in each of solutions A and B in order to provide optimal physiochemical properties (page 11), WO ‘642 does not further comment on the shear modulus property of the disclosed hydrogel comprising a shear modulus in the range of 50 to 1000 Pa (claim 3), or wherein the shear modulus degrades over time (claim 5).
However, Lutolf is also directed to employing hydrogels for three-dimensional cell culture (Abstract), wherein the hydrogels comprise multi-arm PEG vinylsulfone (formed by thiol Michael-type addition reactions) and RGD peptides ([0021]). Lutolf teaches the hydrogels are optimized for the formation of organoids wherein decreased stiffness is achieved by optimizing the specific ratios of PEG-VS and PEG-Acr ([0092]) and the hydrogels have an initial shear modulus ranging from 0.5 to 2.5 kPa (correlates to 500 to 2500 Pa) and have a final shear modulus of 80-150 Pa after 4 days of cell culture ([0094]), i.e., the claimed ranges overlap or lie inside ranges disclosed by the prior art. Lutolf teaches a hydrogel stiffness ranging from 50-200 Pa, and specifically below 200 Pa, is crucial for successful initiation of organoid (three-dimensional) formation ([0086]).
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the ratio (concentration) of the hydrogel components, e.g., PEG-VS, to achieve a shear modulus that is optimized for three-dimensional cell culture.
The person of ordinary skill in the art would have been motivated to modify the hydrogel shear modulus of WO ‘642 to achieve a shear modulus ranging from 50-200 Pa, as taught by Lutolf, for the predictable result of successfully permitting successful initiation of organoid (three-dimensional) formation, thus meeting the limitation of claims 3 and 5.
The skilled artisan would have had a reasonable expectation of success in combining the teachings of WO ‘642 and Lutolf because each of these teachings are directed at methods of employing hydrogels for three-dimensional cell culture.
Regarding claim 4, it is noted as set forth above at the rejection of claim 7, the teaching of WO ‘642 renders obvious the hydrogel product is a 4-arm PEG vinylsulfone cross-linked with a peptide comprising at least two thiol groups (two cysteines), and at least two RGD motifs. WO ‘642 differs in that WO ‘642 does not further teach an 8-arm PEG vinylsulfone. However, Lutolf further teaches preparing the hydrogels for three-dimensional cell culture comprising 8-arm PEG molecules ([0071]).
Therefore, it would have been prima facie obvious to one having ordinary skill in the art at the time of filing the invention to substitute an 8-arm PEG for the 4-arm PEG, as taught by WO ‘642, since both multi-arm PEG molecules are known for preparing hydrogels for three-dimensional cell culture. Therefore, one of ordinary skill in the art would recognize this as simply substituting one type of multi-arm PEG molecule for another useful for the same purpose ((KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398 (2007) pg 14 and 12).
The skilled artisan would have had a reasonable expectation of success in combining the teachings of WO ‘642 and Lutolf because each of these teachings are directed at methods of employing hydrogels for three-dimensional cell culture.
Claim(s) 8 is rejected under 35 U.S.C. 103 as being unpatentable over WO ‘642, as applied to claims 1-2 and 6-7 above, and further in view of Griffin et al., (US 2016/0279283; see PTO-892) (“Griffin”) and Babcock et al., (US 2014/0193474; see PTO-892).
The teaching of WO ‘642 is set forth above and renders obvious instant claim 7.
Regarding claim 8, which depends from claim 7, and the limitation specifying the crosslinker peptide comprising the RGD motifs is GCREGRGDSPGGRGDSPGERCG, it is noted that WO ‘642 teaches the crosslinker comprising the RGD motifs comprises SEQ IDs NO. 4 or 5:
SEQ ID NO: 4 is GCREGPQGIWGQERCG;
SEQ ID NO: 5 is GCREGDQGIAGFERCG (pages 6-7).
Although instant claim 8 shares the identical N-terminal and C-terminal sequences of GCREG (residues 1-5) and ERCG (residues 19-22), respectively, it is noted that the core sequence of claim 8, i.e., …RGDSPGGRGDSPG… (residues 6-18), differs from WO ‘642.
Griffin is also directed to hydrogel scaffolds for biomedical applications, e.g., cell culture, wherein the hydrogels comprise multi-arm PEG-VS (e.g., 4-arm) that have been functionalized for cell adhesive properties to include cell adhesive peptides comprising RGD motifs (Abstract; [0008]-[0009], [0013], [0021] and [0101]). Griffin teaches the cell adhesive peptide of SEQ ID NO:13 having the sequence:
Ac-RGDSPGERCG-NH2, which is identical to residues 13-22 of instant claim 8.
Babcock further teaches using ECM cell adhesive peptides since it is known in the art that ECM proteins, e.g., fibronectin, provide cell attachment support to cells and such peptides comprise core peptide sequences and further having one or more additional number of amino acids that flank the core sequence, including wild type or variant amino acid residues in order to optimize/enhance properties of the peptide such as enhanced ligand interaction. Babcock further teaches that active portions (cell adhesive portions) of ECM proteins are known and can be determined by routine experimentation thus determining the activity of the peptide sequence for promoting cell attachment ([0140]-[0142]). Babcock teaches preferred peptides comprising RGD motifs from fibronectin include the peptide sequence GRGDSP (SEQ ID NO:13) ([0155]), which are identical to instant claim 8 residues 5-10 and 12-17.
Thus, taking in hand the teachings of Griffin and Babcock, the claimed peptide sequence comprises a range of core sequence that is an obvious variation achieved by routine experimentation.
It would have been obvious to one having ordinary skill in the art at the time the invention was made to optimize the cell adhesive peptide sequence of the crosslinker since the prior art teaches that cell adhesive portions of ECM proteins are known and can be determined by routine experimentation thus determining the activity of the peptide sequence for promoting cell attachment, and it has been held to be within the general skill of a worker in the art to select a known material on the basis of its suitability for the intended use as a matter of obvious design choice. In re Leshin, 125 USPQ 416. “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id., 82 USPQ2d at 1396 (see MPEP § 2141.03).
One of ordinary skill in the art would have been motivated to optimize the crosslinker cell adhesive peptide since the prior art recognizes that variation and optimization of cell adhesive amino acid residues results in optimizing/enhancing properties of the peptide such as enhanced ligand interaction. The ordinary artisan would have had a reasonable expectation of success since WO ‘642, Griffin and Babcock are directed to biofunctional materials comprising cel adhesive peptides.
Conclusion
No claim is allowed. No claim is free of the prior art.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to E. YVONNE PYLA whose telephone number is (571)270-7366. The examiner can normally be reached M-F 9am - 6pm.
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E. YVONNE PYLA
Primary Examiner
Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633