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 .
Response to Amendment
The Amendment filed 07/28/2025 has been entered. Applicant’s amendments are in response to in the Non-Final Office Action mailed 05/05/2025. Applicant’s claims have been amended in the following manner: independent claim 9 (directed to a hydrogel composition) has been modified to incorporate several method limitations from previously dependent claims to draw a modified rejection that maintains the thrust of the original rejection. The rejection is further clarified in response to the arguments by pointing to different sections of the previously used references.
The Examiner further acknowledges the following:
Claims 1-10 are pending.
Claims 1-8 and 10 are withdrawn from consideration as directed to non-elected inventions.
Claim 9 are presented for examination and rejected as set forth below.
Modified/Maintained Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Cheng (ACS Appl. Mater. Interfaces, 2018), and in further view of Zhang (Langmuir, 2011) and Gkioni (Tissue Engineering, 2010).
Applicant’s claim is directed to a biomimetic mineralized hydrogel (a hydrogel is a gel where water is the primary constituent) prepared by the method of claim 9. It must be remembered: "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). Thus, the examiner interprets the mineralized hydrogel composition of instant claim 9 to be comprised of ingredients and amounts mentioned by the method. The active method steps do not provide patentable weight to the mineralized hydrogel that is claimed in instant claim 9, unless Applicant demonstrate evidence that causes unexpected benefits that are not suggested by the art.
Cheng teaches a method that involves cooperative assembly of a peptide gelator and silk fibroin to afford an injectable hydrogel for tissue engineering (title, abstract) such as bone repair (reference 10 – “Silk based biomaterials to heal critical sized femur defects”)
Regarding claim 9: Cheng teaches the gelation of a silk fibroin (SF) solution by adding a self-assembling polypeptide 2-naphthalene acetic acid-phenylalanine-phenylalanine (NapFF) (abstract). The formation of the resultant hydrogel is described as cooperative assembly (title) or supramolecular self-assembly (abstract). Cheng uses 0.1-0.4 wt% of the polypeptide and 0.1-2.0 wt% of the silk fibroin to form gels (Table 1), which is consistent with amounts used in the instant method of claim 9.
In summary, Cheng teaches a method that involves cooperative assembly of a peptide gelator (NapFF) and silk fibroin in specified amounts to afford an injectable hydrogel for tissue engineering. However, Cheng does not teach the alkaline phosphatase (instant claim 9).
Zhang teaches a method that uses small modified polypeptides such as NapFF (note this is the same compound used by Cheng above), NapFF-tyrosine phosphate and NapFF-tyrosine (pg 530, Scheme 1) as molecular hydrogelators that self-assemble in water to result in nanofibers. These types of nanofibers can be used for drug delivery or wound healing (tissue engineering is accomplished by these kinds of hydrogels by healing a wound that prevents scarring in a mouse model) (abstract, pg 537, paragraph 3). With respect to instant claim, Zhang teaches that NapFF-tyrosine phosphate (reads on 2-naphthalene acetic acid-phenylalanine-phenylalanine-phosphotyrosine) can be converted into NapFF-tyrosine through the action of alkaline phosphatase, which undergoes self-assembly to form a hydrogel (pg 532, paragraph 5, also directly discusses Figures 5A and 5C). Zhang notes that this approach allows for formation of supramolecular hydrogels in vivo (Figure 8E), and is a demonstration of an enzyme-switch regulation for drug delivery that depends from enzymatic expression of phosphatase in tissues, organs, or diseases (pg 533, paragraph 3; pg 534, paragraph 1).
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine Zhang’s alkaline phosphatase dephosphorylation of small molecule peptides to form self-assembled hydrogels with Cheng’s teachings of combining a peptide gelator and silk fibroin to form a hydrogel because Zhang teaches that the enzymatic approach allows for enzyme-switch-regulated hydrogelation in vivo for drug delivery, and Cheng discusses the use of silk fibroin hydrogels for use in drug delivery and tissue engineering (introduction) such that the NapFF found in Cheng is simply substituted by the NapFF-tyrosine phosphate/alkaline phosphatase system in terms of a peptide gelator to cooperatively assemble with silk fibrin. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Thus, the use of Zhang’s teachings provided an enzyme-switch-regulated hydrogelator modification toward the silk fibroin hydrogel compositions of Cheng.
To summarize, Zhang and Cheng then teach a silk fibroin hydrogel material formed by dephosphorylation of a precursor polypeptide phosphate to afford a self-assembling polypeptide that co-assembles with silk fibroin. However, they do not teach the mineralization of the resulting hydrogel, including ingredients and relative amounts used in the process (instant claim 9).
Gkioni teaches that hydrogels are commonly mineralized to render these hydrogels suitable for bone regeneration (abstract) and drug delivery (pg 581, ‘indirect mineralization’). Gkioni teaches CaCl2 (pg 580, paragraph 2; pg 581, paragraph 6) and beta-glycerophosphate (pg 580, paragraph 8; pg 581, paragraph 3 and 9) as common ingredients in mineralization techniques of hydrogels. Gkioni teaches using different CaCl2 concentrations (i.e., the amount of mineralizing ion) to treat hydrogels for mineralization (pg 581, paragraph 6), such that it would be routine to optimize the concentration of the mineralizing solution for optimal mineralization of the hydrogel. See In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (indicating that where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation). Thus, the art teaches mineralized hydrogel compositions that are consistent with the method limitations described in claim 9.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine a mineralization technique using different concentrations of minerals with the silk fibroin hydrogel material taught by Zhang and Cheng to afford a mineralized hydrogel because Gkioni teaches hydrogels are commonly mineralized using different mineralizing solution concentrations to render these hydrogels suitable for bone regeneration (abstract), including CaCl2 and beta-glycerophosphate. Furthermore, Cheng references tissue engineering application (pg 12474, ‘introduction’) with application to bone repair (reference 10 – “Silk based biomaterials to heal critical sized femur defects”).
Response to Arguments
Applicants arguments, see pg 4-6, filed 07/28/2025, with respect to the 103 rejection of claim 9 under rejection are not persuasive. The 103 rejection has been modified with respect to amendments made to the claim set and with further clarifying language.
On page 4-5, Applicant argues that limitations of the product as defined by the process (i.e., product-by-process) should be considered in evaluation per the claim 9 directed to a hydrogel composition. Note that for a product-by-process claim, the composition determines patentability. It must be remembered: "[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985). In view of claim 9, the claim is read as a composition comprising the ingredients and relative amounts that are disclosed in the process, and properly combined art has been provided to read on the composition of claim 9 (see 103 above).
Furthermore, Applicant points to a use of the hydrogel where it can be used as a biomimetic scaffold for application of rat bone marrow mesenchymal stem cells to heal femoral defects. A recitation of an intended use will not limit the scope of the claim because it merely defines a context in which the invention may operate. Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp., 320 F.3d 1339, 1345 (Fed. Cir. 2003). However, if Applicant claims that the intended use as a “biomimetic mineralized hydrogel” is an unexpected result, the results do not constitute unexpected results because Gkioni teaches mineralized hydrogels (where Cheng and Zhang teach hydrogels based on silk fibroin, and reference 10 of Cheng is directed to silk-based biomaterials to heal critical sized femur defects) for the same purpose of scaffolding cells and bone healing defects (abstract, pg 581, paragraph 7 and ‘indirect mineralization’ section). Note that any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Consequently, we must determine whether the results obtained in the closest prior art and those set forth by Applicants are sufficiently different in kind, and not merely in degree, so as to be unexpected by a person of ordinary skill in the art at the time of invention. See Iron Grip Barbell Co. v. USA Sports, Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (Unexpected results that are probative of nonobviousness are those that are "different in kind and not merely in degree from the results of the prior art") (citation omitted). In this case, the application of a silk-based mineralized hydrogels toward bone defect repair appears reasonably suggested by the art. To further make this point, see also Melke (Acta, Biomaterialia 2016) for silk fibroin biomaterials such as hydrogels and in combination with inorganic components to repair bone defects with stem cells (abstract, section “4.1 gels” and “4.5 silk fibroin composite scaffolds”).
On page 5, Applicant argues that Cheng does not tech the specified self-assembling micromolecular polypeptide, as required by claim 9. In this argument, references are treated piecewise, which is per se unpersuasive. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually. Zhang provides the teaching of NapFF-tyrosine phosphate (pg 530, Scheme 1), reading on 2-naphthalene acetic acid-phenylalanine-phenylalanine-phosphotyrosine, that proper rational is discussed in the 103 rejection to combine Cheng with Zhang.
On page 5, Applicant argues Cheng’s use of RGD[Arg-Gly-Asp]. The Examiner does not rely on this specific embodiment of the rejection (see 103 rejection). Art is art for all that it teaches, not just specific or preferred embodiments. Portions of the references are argued against when the Examiner does not rely on the portions of the reference. The test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). The obviousness rejection is based on the combined elements of Cheng using NapFF, and Zhang using NapFF and NapFF-tyrosine phosphate and demonstrating the relationship between the two molecules in their purpose for formation of hydrogels, as explained in the 103 rejection above. The selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). Furthermore, Zhang presents scenarios where it is advantageous to use alkaline phosphatase to promote gelation from a phosphate-type precursor of a peptide molecular hydrogelator.
On page 5, Applicant argues a subtle difference between Cheng’s cooperative assembly and Zhang’s self-assembly. Applicant is reminded that the scope of analogous art is to be considered broadly. Wyers v. Master Lock Co., No. 2009-1412, 2010 WL 2901839 (Fed. Cir. July 22, 2010). Art is analogous if it is (1) from the same field of endeavor, regardless of the problem addressed, or (2) reasonably pertinent to the particular problem with which the inventor is involved. In re Clay, 966 F.2d 656, 658–59 (Fed. Cir. 1992). No matter the difference in nuance of description both references are analogous to the claimed instant invention. Additionally, appropriate rationale is provided in the 103 rejection to combine the references.
On page 6, Applicant argues that Gkioni does not suggest all elements of the hydrogel of claim 9. All elements of each prior art reference need not read on the claimed invention, rather, the proper test for obviousness is what the combined teachings would have suggested to a person of ordinary skill in the art. In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). In this case, Gkioni teaches mineralization of hydrogels with different ingredients and in various amounts, and the benefits of a mineralized hydrogel for bone regeneration (abstract).
Correspondence
Applicant's amendment necessitated the new ground 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 extension fee 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 date of this final action.
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/R.P./Examiner, Art Unit 1614 8/21/2025
/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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