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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on March 17, 2026, has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I (Claims 1, 7-9, and 12-17; drawn to a hydrogel composition) in the reply filed on April 18, 2025, is acknowledged.
Claims 28-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (Group II), there being no allowable generic or linking claim.
Applicant further elected the following species:
a. methacrylate as the species of polymerizable or assemblable moiety
In light of the Applicant’s elected species, claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
DETAILED ACTION
The amended claims filed on March 17, 2026, have been acknowledged. Claims 2-6, 10-11, 18-27, and 34 were cancelled. Claim 1 was amended. In light of the Applicant’s elected invention and species, claims 9 and 28-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 1, 7-8, and 12-17 are pending and examined on the merits.
Applicant’s response has been considered. Rejections and/or objections not reiterated from the previous office action mailed November 17, 2025, are hereby withdrawn. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The applicant claims foreign priority from PT115689 filed on July 31, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55, received January 28, 2022. Claims 1, 7-8, and 12-17 find support in foreign application PT115689 filed on July 31, 2019.
Declaration under 37 CFR 1.132
The declaration under 37 CFR 1.132 filed by Dr. Catarina Custodio on March 17, 2026, has been considered but is insufficient to overcome the rejections of instant claims based upon 35 U.S.C 103 as set forth in the current Office action for the following reasons:
First, the Custodio declaration argues that claim 1 requires a protein extract to polymerizable moiety ratio from 10:1x10 to 10:1x10 (v/v). This represents a "trace-level" functionalization strategy. In contrast, Brew operates in a polymer-dominant, heavily methacrylated regime (approx. 1g protein to -6g methacrylic anhydride). Brew explicitly teaches that increasing functionalization is necessary to achieve gelation and stability, thereby teaching away from our discovery that a stable, protein-dominated architecture can be achieved with minimal chemical modification.
Second, the Custodio declaration argues that while Murphy mentions solubilized amniotic membrane (SAM), the SAM in Murphy functions solely as a bioactive additive within an external polymer matrix (e.g., hyaluronic acid or PEG). In our invention, the placental protein extract itself is the primary structural, network-forming component (page 2, paragraphs 3-4).
The Custodio arguments have been fully considered but are considered unpersuasive.
As an initial matter, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Brew teaches they generated a hydrogel by decellularizing human placental chorionic villi tissue, solubilizing it, functionalizing the solubilized decellularized chorionic villi tissue with a methacrylate and methacrylamide group, and using a photoinitiator (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) to crosslink the hydrogel (page 10, paragraph 2-page 33, paragraph 1 and Figures 5 and 14-15). As can be seen in Figure 14, the methacrylate and methacrylamide are bound to the decellularized placental tissue following functionalization. As can be seen in Figure 15, a hydrogel is formed after photoinitiation occurs.
Therefore, Brew provides the scientific concept for functionalizing placental extracts with methacrylate to form a hydrogel.
Murphy teaches a hydrogel composition comprising a solubilized amniotic membrane (SAM) collected from a human that is decellularized. SAM is a cell-free solution, containing cytokines, extracellular matrix (ECM) ECM-associated proteins and other factors that are known to promote wound healing and modulate inflammatory responses. The hydrogel further comprises a biopolymer and synthetic polymer wherein the biopolymer can be hyaluronic acid and the synthetic biopolymer can be methacrylate. The hydrogel can comprise a UV sensitive photoinitiator, such as 1-hydroxycyclohexylphenyl ketone. Murphy teaches that components of amniotic membrane may be interspersed within the hydrogel. As part of this, the SAM may be added to the hydrogel prior to polymerization of the gel. Murphy teaches that the SAM may be crosslinked to the hydrogel to form a SAM hydrogel and that this can be done by photocrosslinking (paragraphs 0011-0016, 0075-0076, 0099-0111, 0155-0156, and 0178).
Although Applicant argues that Murphy does not disclose chemical functionalization of the amniotic or placental proteins, Murphy specifically identifies that the method of the invention is used to crosslink SAM together with a hyaluronic acid (HA)-based hydrogel, thereby forming a SAM hydrogel (paragraph 0155).
Therefore, Murphy does teach functionalizing their SAM placental extract.
Furthermore, Murphy successfully reduces to practice that solubilized decellularized amniotic membrane tissue (similar to the solubilized decellularized chorionic villi tissue of Brew) can be incorporated into a hydrogel with a photoinitiator and functionalized methacrylate groups. Murphy teaches that their hydrogels typically are composed of 10% polymer and that the SAM to hydrogel ratio is 10:1 (paragraphs 0099-0111). This equates to a SAM protein extract:polymerizable moiety ratio of 100:1 (a ratio that falls within what is claimed).
Somuncu teaches a superior decellularization method that maintains biological orientation of ECM proteins because maintenance of the ECM organization contributes to the production of useful tissue engineered structures and development of the hydrogel.
Therefore, it would have been obvious to combine the teachings of Brew, Murphy, and Somuncu.
Regarding Applicant’s argument that Brew explicitly teaches increasing functionalization is necessary to achieve gelation and stability, thereby teaching away from the presently claimed invention,as an initial matter, it is unclear where Brew explicitly teaches increasing the degree of functionalization to tune mechanical properties and achieve hydrogel stability. Brew does teach that the degree of functionalisation can be adjusted by changing the ratio of proteins to MAAh, an increased concentration of MAAh, results in an increased DOF which corresponds to stiffer gels and could certainly be researched in future, and chemical functionalisation not only provides increased stability and mechanical strength, but as shown in this project, and in previous literature, it facilitates the tuning and tailoring of the mechanical properties (page 46, paragraph 2-page 47, paragraph 2). However, none of these statements suggest increasing the degree of functionalization is the ultimate goal of Brew. Instead, Brew seems to suggest that the functionalization can be adjusted (either more functionalization or less) depending on the needs of the experimental setup. Therefore, Brew is not considered to teach away from reducing the amount of functionalization, as argued by the Applicant.
Third, the Custodio declaration cites to experimental data showing that amniotic membrane and placental tissue have different proteomics. These differences in matrisome composition (collagens and glycoproteins) directly impact functionalization efficiency and reaction conditions. This difference will necessarily result in a different number of amine and hydroxyl groups that are available to react with the methacylic anhydride, affecting the reaction conditions and time (page 2, paragraph 5).
The Custodio arguments have been fully considered but are considered unpersuasive.
As stated in the rejection below, although Brew does not teach that they used placental membrane tissue, Brew teaches that the amnion (also known as the amniotic membrane) and placental membranes have a well established history as a biotissue for wound healing and ocular repair. Brew also specifically identifies that the success of amnion as a biotissue gave them confidence that the substantially similar region of the placenta comprising the chorionic villi could also be utilized as a biomaterial (page 6, paragraph 2-page 10, paragraph 1).
Murphy teaches a hydrogel composition comprising a solubilized amniotic membrane (SAM) collected from a human that is decellularized. SAM is a cell-free solution, containing cytokines, extracellular matrix (ECM) ECM-associated proteins and other factors that are known to promote wound healing and modulate inflammatory responses. The hydrogel further comprises a biopolymer and synthetic polymer wherein the biopolymer can be hyaluronic acid and the synthetic biopolymer can be methacrylate. The hydrogel can comprise a UV sensitive photoinitiator, such as 1-hydroxycyclohexylphenyl ketone. Murphy teaches that components of amniotic membrane may be interspersed within the hydrogel. As part of this, the SAM may be added to the hydrogel prior to polymerization of the gel. Murphy teaches that the SAM may be crosslinked to the hydrogel to form a SAM hydrogel and that this can be done by photocrosslinking (paragraphs 0011-0016, 0075-0076, 0099-0111, 0155-0156, and 0178).
Therefore, it would have been obvious to one of ordinary skill in the art to have substituted the chorionic villi tissue of Brew with the amniotic membrane tissue of Murphy because Brew identifies that amniotic membrane tissue have previously been used as a biotissue and that its prior success gave them confidence that chorionic villi tissue could also work. Furthermore, Murphy successfully reduces to practice that solubilized decellularized amniotic membrane tissue (similar to the solubilized decellularized chorionic villi tissue of Brew) can be incorporated into a hydrogel with a photoinitiator and functionalized methacrylate groups. Therefore, it would have been obvious that amniotic membranes would have also been a viable option for the solubilized decellularized tissue in the hydrogel composition of Brew.
Regarding the specific proteomic results identified by the Custodio declaration, one of ordinary skill in the art would understand that different placental tissues (such as amniotic membrane and chorionic villi) would have different proteomic profiles. However, Brew and Murphy clearly identify the amniotic membrane as a known option for generating a hydrogel through crosslinking of the amniotic membrane tissue with methacrylate.
Fourth, the Custodio declaration argues that claimed trace-level functionalization preserves native bioactivity in a way not possible in the heavily modified systems of the prior art. Evidence shows that while Brew failed to obtain stretched cells even after 28 days of culture, the claimed approach achieves cell stretching as early as 24 hours after encapsulation (page 3, paragraph 1).
The Custodio arguments have been fully considered but are considered unpersuasive.
It appears that the Custodio declaration is trying to argue that their results lead to unexpected results related to achieving stretched cells after encapsulation in the hydrogel. The Custodio declaration cites to a Figure 4 (which appears to correspond to Figure 6 of the instant application) to show that cell stretching occurs at 24 hours. Figure 6 is specific to top seeding experiments (Spec paragraph 0069) while Figure 7 involves encapsulation (Spec paragraph 0070) which does not show a stretched morphology at 24 hours. Additionally, the stretching morphology appears to be specific to the adipose derived stem cells and not to the HUVECs which do not show stretching at any time point. Furthermore, the claims do not require any cells to be part of the hydrogel. As such the declaration does not show that the objective evidence of nonobviousness is commensurate in scope with the claims. See MPEP § 716.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
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, 7-8, 12-14, and 16-17 are rejected under 35 U.S.C. 103 as being unpatentable over Brew (Development of a crosslinkable hydrogel derived from placental tissue. Master of Philosophy thesis, Queensland University of Technology. 2019; Published April 2019), United States Patent Application No. 2014/0342015 (Murphy), and Somuncu et al. (Journal of Clinical Neuroscience 59: 291–297. 2019. Published October 2018), as evidenced by Hopkinson et al. (Journal of Proteome Research 5: 2226-2235. 2006). This is a new rejection made in response to Applicant’s amendments to the claims that is substantially similar to a previous rejection of record. Any aspect of Applicant’s traversal relevant to the new rejection of record and not already addressed in the response to the Custodio declaration above is addressed below.
Regarding claim 1, Brew teaches they generated a hydrogel by decellularizing human placental chorionic villi tissue, solubilizing it, functionalizing the solubilized decellularized chorionic villi tissue with a methacrylate and methacrylamide group, and using a photoinitiator (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) to crosslink the hydrogel (page 10, paragraph 2-page 33, paragraph 1 and Figures 5 and 14-15). As can be seen in Figure 14, the methacrylate and methacrylamide are bound to the decellularized placental tissue following functionalization. As can be seen in Figure 15, a hydrogel is formed after photoinitiation occurs. Brew teaches that they used 2.5 or 5% w/v lyophilized Plac MA to form hydrogels (page 18, paragraph 2). Although Brew does not identify that they bioprinted their hydrogel, they do specifically identify that bioprinting techniques could be used to create hollow-fibers of placMA in user-defined architectures for vascular engineering. The combination of bioprinting with a cell-instructive, cytokine and growth factor rich biomaterial such as placMA would be revolutionary. However, this is certainly possible in the future as more material will be made and specifically applied to bioprinting (page 43, paragraph 2). Therefore, Brew clearly identifies that their placental hydrogel can be 3D bioprinted.
Brew does not teach that they used placental membrane tissue.
However, Brew teaches that the amnion (also known as the amniotic membrane) and placental membranes have a well established history as a biotissue for wound healing and ocular repair. Brew also specifically identifies that the success of amnion as a biotissue gave them confidence that the substantially similar region of the placenta comprising the chorionic villi could also be utilized as a biomaterial (page 6, paragraph 2-page 10, paragraph 1).
Murphy teaches a hydrogel composition comprising a solubilized amniotic membrane (SAM) collected from a human that is decellularized. SAM is a cell-free solution, containing cytokines, extracellular matrix (ECM) ECM-associated proteins and other factors that are known to promote wound healing and modulate inflammatory responses. The hydrogel further comprises a biopolymer and synthetic polymer wherein the biopolymer can be hyaluronic acid and the synthetic biopolymer can be methacrylate. The hydrogel can comprise a UV sensitive photoinitiator, such as 1-hydroxycyclohexylphenyl ketone. Murphy teaches that components of amniotic membrane may be interspersed within the hydrogel. As part of this, the SAM may be added to the hydrogel prior to polymerization of the gel. Murphy teaches that the SAM may be crosslinked to the hydrogel to form a SAM hydrogel and that this can be done by photocrosslinking (paragraphs 0011-0016, 0075-0076, 0099-0111, 0155-0156, and 0178).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the chorionic villi tissue of Brew with the amniotic membrane tissue of Murphy to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because Brew identifies that amniotic membrane tissue have previously been used as a biotissue and that its prior success gave them confidence that chorionic villi tissue could also work. Furthermore, Murphy successfully reduces to practice that solubilized decellularized amniotic membrane tissue (similar to the solubilized decellularized chorionic villi tissue of Brew) can be incorporated into a hydrogel with a photoinitiator and functionalized methacrylate groups. Therefore, it would have been obvious that amniotic membranes would have also been a viable option for the solubilized decellularized tissue in the hydrogel composition of Brew. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
As can be seen in Figure 5, Brew used a ratio of 1 gram protein extract: .6 grams methacrylic anhydride but does not identify the ratio of protein extract: methacrylate in the functionalized product. Furthermore, Brew teaches that the degree of functionalisation can be adjusted by changing the ratio of proteins to MAAh (page 46, paragraph 2).
Brew does not teach wherein the ratio of protein extract: polymerizable moiety is from 10:1x10-5 to 10:1x10-1.
However, Murphy teaches that their hydrogels typically are composed of 10% polymer and that the SAM to hydrogel ratio is 10:1 (paragraphs 0099-0111). This equates to a SAM protein extract:polymerizable moiety ratio of 100:1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the ratio of the protein extract: polymerizable moiety to be within 10:1x10-5 to 10:1x10-1 to arrive at the instantly claimed invention. One of ordinary skill in the art would have been motivated to make the modification with a reasonable expectation of success because although Brew teaches a specific ratio of the starting materials, Brew is silent as to the resulting ratio of the protein extract: polymerizable moiety, Brew teaches that the degree of functionalisation can be adjusted by changing the ratio of proteins to MAAh. Furthermore, Murphy teaches that their hydrogels typically are composed of 10% polymer and that the SAM to hydrogel ratio is 10:1. This equates to a SAM protein extract:polymerizable moiety ratio of 100:1. Therefore, it would have been obvious that the ratio used by Murphy would also be a viable option. Furthermore, as taught by MPEP 2144.05 (II)(A), generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art."). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Murphy teaches that the process of decellularization removes the specialized tissue, leaving behind the complex three-dimensional network of connective tissue. The connective tissue infra-structure is primarily composed of collagen (paragraph 0044). Hopkinson evidences that amniotic membrane tissue expresses collagen type VI (Table 2). Murphy teaches that their hydrogel scaffold can be used to treat skin wounds (paragraph 0160). Brew identifies that placental tissue have been used for wound healing previously and specifically identifies the potential for their PlacMA hydrogel to be useful for recreating vascular tissue (page 48, paragraph 1). Furthermore, Brew identified that their hydrogel was useful for maintaining MSCs (page 22, paragraph 3-page 24 and page 37, paragraph 5-page 38, paragraph 3 and Figures 18-20). Murphy teaches that the amniotic membrane is decellularized using any method of decellularization known in the art (paragraph 0075). Brew teaches that the successful decellularization method using ammonium hydroxide, which has been previously demonstrated to remove cellular components without disrupting the ECM, removed almost three-quarters of double-stranded DNA from human tissues while retaining over half of the sulphated sGAGs and maintaining ECM microstructure was identified as an important aspect for developing the hydrogel (page 43, paragraph 2-page 45, paragraph 1).
The combined teachings of Brew and Murphy do not teach wherein the placental membrane protein extract comprises collagen and keratin.
However, Somuncu teaches a method of decellularizing placental tissues for skin transplantation that generates acellular scaffold with well-kept ECM, three dimensional design wherein key components of the ECM proteins kept their biological organization after decellularization as noted by immunohistochemistry. Somuncu teaches that maintenance of the ECM organization contributes to the production of useful tissue engineered structures. Somuncu teaches that their method preserved a normal skin 3D construction and vasculature along with significant ECM arrangements. The well-kept placental ECM scaffold were supportive of mesenchymal cell types (page 296, column 1, paragraph 2-column 2, paragraph 3 and abstract). As part of their method, they identified that their decellularized placental tissue maintained expression of keratin (Figure 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have used the decellularization method of Somuncu for decellularizing the amniotic membrane tissue of the combined teachings of Brew and Murphy to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to use the decellularization method of Somuncu with a reasonable expectation of success because Brew teaches that maintaining ECM microstructure was identified as an important aspect for developing the hydrogel and Somuncu teaches a method of decellularizing placental tissues for skin transplantation that generates acellular scaffold with well-kept ECM, three dimensional design wherein key components of the ECM proteins kept their biological organization after decellularization. As this method maintains biological orientation of ECM proteins, it would have been obvious to use the method of decellularizing of Somuncu because maintenance of the ECM organization contributes to the production of useful tissue engineered structures and development of the hydrogel. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
The decellularization method of Somuncu does not use collagenase (page 292, column 1, paragraph 6 and Figure 1). Therefore, the decellularization method of Somuncu would maintain expression of collagen and keratin in the decellularized protein extract.
Regarding claims 7-8, Brew, as stated supra, teaches that the polymerizable moiety is methacrylate (Figure 14).
Regarding claim 10, Murphy, as stated supra, teaches that the human placental tissue is amnion membrane tissue (SAM) (paragraphs 0011-0016 and 0099-0111).
Regarding claim 12, Brew teaches that they performed chemical functionalization of the placental tissue to generate polymerizable methacrylate and methacrylamide side chains and performed crosslinking using the photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate. Lithium phenyl-2,4,6-trimethylbenzoylphosphinate is a chemical compound that causes covalent crosslinking. As such, the photoinitiator lithium phenyl-2,4,6-trimethylbenzoylphosphinate is considered to cause chemical coupling upon exposure to light and would fall within the limitations of chemical crosslinking.
Regarding claim 13, Brew does not teach using one of the photoinitiators of claim 13.
However, Murphy, as stated supra, teaches that the hydrogel can comprise a UV sensitive photoinitiator, such as 1-hydroxycyclohexylphenyl ketone (paragraph 0107).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the photoinitiator of Brew (Lithium phenyl-2,4,6-trimethylbenzoylphosphinate) with the photoinitiator of Murphy (1-hydroxycyclohexylphenyl ketone) to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to substitute with a reasonable expectation of success because a multitude of different photoinitiator could be used for crosslinking and Murphy identifies a compound similar to the one used by Brew (Ethyl (2,4,6-trimethylbenzoyl) phenylphosphinate), as well as one used in claim 13 (1-hydroxycyclohexylphenyl ketone). Therefore, 1-hydroxycyclohexylphenyl ketone would be a reasonable substitute for the photoinitiator used by Brew and there would be a reasonable expectation that 1-hydroxycyclohexylphenyl ketone would work as a photoinitiator in the hydrogel of the combined teachings of Brew, Murphy, and Somuncu.
Furthermore, the simple substitution of one known element for another would have yielded predictable results to one of ordinary skill in the art at the time of the invention. M.P.E.P. §2144.07 states "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).” “Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).” When substituting equivalents known in the prior art for the same purpose, an express suggestion to substitute one equivalent component or process for another is not necessary to render such substitution obvious. In re Fout, 675 F.2d 297, 213 USPQ 532 (CCPA 1982). M.P.E.P. §2144.06. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 14, Murphy teaches that the hydrogel, which includes the SAM hydrogel with crosslinked SAM protein extract, can be modified to form linkages to a therapeutic agents via a protease sensitive linker or other biodegradable linkage (paragraph 0104). It would have been obvious to include biodegradable linkers to attach therapeutic agents to the protein extract as Brew, Murphy, and Somuncu, as stated supra, teach the potential for using placental membrane hydrogels and placental membranes for wound healing and the linking of therapeutic agents to the placental membrane protein extract would improve the wound healing effect of the hydrogel. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 16, Murphy teaches that the hydrogel can comprise a biopolymer and synthetic polymer wherein the biopolymer can be hyaluronic acid and the synthetic polymer can be methacrylate (paragraphs 0099-0111). Murphy teaches that they performed in vivo studies wherein SAM is incorporated into a bioprintable, UV crosslinked hydrogel. Specifically, SAM was implemented together with a hyaluronic acid (HA)-based hydrogel that may be bioprinted over wounds and photocrosslinked in place nearly instantaneously. The results presented herein demonstrate the effectiveness of using HA-SAM to treat wounds in a murine wound healing model (paragraph 0179). It would have been obvious to include hyaluronic acid as part of the hydrogel as Brew, Murphy, and Somuncu, as stated supra, teach the potential for using placental membrane hydrogels and placental membranes for wound healing and Murphy teaches that HA-SAM was effective at treating wounds in a murine wound healing model. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Regarding claim 17, in regard to the protein extract being autologous, it must be noted that this limitation is directed to the intended use of the hydrogel and does not necessarily change the structure of the protein extract themself. Nevertheless, Brew and Murphy teaches the decellularized human amnion membrane were derived from human donors, and thus could have been used in an autologous transplant (page 12, paragraph 3 of Brew and paragraphs 0011-0016 of Murphy).
Response to Arguments
Applicant's arguments filed March 17, 2026, are acknowledged.
Applicant argues that Brew discloses hydrogels derived from decellularized placental tissue that are chemically functionalized using methacrylic anhydride under conditions that employ high concentrations of protein extract and large excesses of methacrylic anhydride. Brew describes protein concentrations in the range of approximately 2.5-5% (w/v) and reaction conditions involving substantial functionalization to achieve hydrogel stability. Such conditions correspond to a polymer-dominant regime in which a high degree of methacrylation is required to produce gelation and mechanical integrity. In contrast, the claimed 3D printable hydrogel composition operates within a different functionalization regime in which the ratio of protein extract to polymerizable moiety is tightly controlled within the range of 10:1x10-5 to 10:1x10-' (v/v). This represents a trace-level functionalization regime that is several orders of magnitude lower than the modification conditions disclosed in Brew. Brew therefore neither teaches nor suggests the claimed approach, which relies on minimal chemical modification while preserving the biological functionality of placental proteins. To the contrary, Brew teaches that increased functionalization is required to achieve hydrogel stability, thereby teaching away from the presently claimed architecture.
Likewise, Murphy fails to disclose or suggest the presently claimed 3D printable hydrogel composition. Specifically, Murphy describes hydrogel compositions in which solubilized amniotic membrane material is incorporated into hydrogels formed from external polymer backbones such as hyaluronic acid. In Murphy, the amniotic membrane material functions only as a bioactive additive within a polymer-dominated hydrogel matrix. Murphy does not disclose chemical modification of the amniotic or placental proteins themselves with polymerizable or assemblable moieties, does not disclose covalent attachment of such moieties to the protein extract, and does not disclose that the placental proteins themselves form the crosslinkable structural network of the hydrogel. Instead, polymerization occurs through the external polymer backbone, and the placental material remains a dispersed biological additive. In contrast, the present claims require that the polymerizable or assemblable moiety be bound directly to the protein extract derived from the decellularized placental membrane so that the protein extract itself becomes an active, crosslinkable hydrogel precursor. Murphy therefore fails to disclose or suggest the central inventive concept.
Somuncu also fails to remedy the deficiencies of Brew and Murphy. Somuncu describes methods for decellularizing placental tissues for use as extracellular matrix scaffolds in tissue engineering. These scaffolds maintain the native ECM structure and are not solubilized or chemically modified to form hydrogel precursors. Somuncu does not teach solubilization of placental membranes to produce a protein extract suitable for chemical functionalization, does not disclose attachment of polymerizable moieties to such proteins, and does not describe hydrogel formation through covalent crosslinking of modified placental proteins. Rather, Somuncu preserves intact ECM scaffolds for structural implantation. Therefore, Somuncu does not suggest transforming placental proteins into chemically functionalized hydrogel precursors as required by the present claims (page 7, paragraph 2-page 9, paragraph 3).
Applicant's arguments have been fully considered but are considered unpersuasive.
As an initial matter, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Brew teaches they generated a hydrogel by decellularizing human placental chorionic villi tissue, solubilizing it, functionalizing the solubilized decellularized chorionic villi tissue with a methacrylate and methacrylamide group, and using a photoinitiator (lithium phenyl-2,4,6-trimethylbenzoylphosphinate) to crosslink the hydrogel (page 10, paragraph 2-page 33, paragraph 1 and Figures 5 and 14-15). As can be seen in Figure 14, the methacrylate and methacrylamide are bound to the decellularized placental tissue following functionalization. As can be seen in Figure 15, a hydrogel is formed after photoinitiation occurs.
Therefore, Brew provides the scientific concept for functionalizing placental extracts with methacrylate to form a hydrogel.
Murphy teaches a hydrogel composition comprising a solubilized amniotic membrane (SAM) collected from a human that is decellularized. SAM is a cell-free solution, containing cytokines, extracellular matrix (ECM) ECM-associated proteins and other factors that are known to promote wound healing and modulate inflammatory responses. The hydrogel further comprises a biopolymer and synthetic polymer wherein the biopolymer can be hyaluronic acid and the synthetic biopolymer can be methacrylate. The hydrogel can comprise a UV sensitive photoinitiator, such as 1-hydroxycyclohexylphenyl ketone. Murphy teaches that components of amniotic membrane may be interspersed within the hydrogel. As part of this, the SAM may be added to the hydrogel prior to polymerization of the gel. Murphy teaches that the SAM may be crosslinked to the hydrogel to form a SAM hydrogel and that this can be done by photocrosslinking (paragraphs 0011-0016, 0075-0076, 0099-0111, 0155-0156, and 0178).
Although Applicant argues that Murphy does not disclose chemical functionalization of the amniotic or placental proteins, Murphy specifically identifies that the method of the invention is used to crosslink SAM together with a hyaluronic acid (HA)-based hydrogel, thereby forming a SAM hydrogel (paragraph 0155).
Therefore, Murphy does teach functionalizing their SAM placental extract.
Furthermore, Murphy successfully reduces to practice that solubilized decellularized amniotic membrane tissue (similar to the solubilized decellularized chorionic villi tissue of Brew) can be incorporated into a hydrogel with a photoinitiator and functionalized methacrylate groups. Murphy teaches that their hydrogels typically are composed of 10% polymer and that the SAM to hydrogel ratio is 10:1 (paragraphs 0099-0111). This equates to a SAM protein extract:polymerizable moiety ratio of 100:1 (a ratio that falls within what is claimed).
Somuncu teaches a superior decellularization method that maintains biological orientation of ECM proteins because maintenance of the ECM organization contributes to the production of useful tissue engineered structures and development of the hydrogel.
Therefore, it would have been obvious to combine the teachings of Brew, Murphy, and Somuncu.
Regarding Applicant’s argument that Brew explicitly teaches increasing functionalization is necessary to achieve gelation and stability, thereby teaching away from the presently claimed invention, as an initial matter, it is unclear where Brew explicitly teaches increasing the degree of functionalization to tune mechanical properties and achieve hydrogel stability. Brew does teach that the degree of functionalisation can be adjusted by changing the ratio of proteins to MAAh, an increased concentration of MAAh, results in an increased DOF which corresponds to stiffer gels and could certainly be researched in future, and chemical functionalisation not only provides increased stability and mechanical strength, but as shown in this project, and in previous literature, it facilitates the tuning and tailoring of the mechanical properties (page 46, paragraph 2-page 47, paragraph 2). However, none of these statements suggest increasing the degree of functionalization is the ultimate goal of Brew. Instead, Brew seems to suggest that the functionalization can be adjusted (either more functionalization or less) depending on the needs of the experimental setup. Therefore, Brew is not considered to teach away from reducing the amount of functionalization, as argued by the Applicant.
Claims 1 and 15 are rejected under 35 U.S.C. 103 as being unpatentable over Brew (Development of a crosslinkable hydrogel derived from placental tissue. Master of Philosophy thesis, Queensland University of Technology. 2019; Published April 2019), United States Patent Application No. 2014/0342015 (Murphy), and Somuncu et al. (Journal of Clinical Neuroscience 59: 291–297. 2019. Published October 2018) as applied to claim 1 above, and further in view of United States Patent Application No. 2019/0015553 (Lee, Published January 2019) and Zhang et al. (RSC Adv. 9: 18344-18352. 2019. Published June 2019). This rejection is repeated with regards to the previous rejection of record from the Final Office action mailed on November 11, 2025. Applicant’s traversal has been addressed above.
The teachings of Brew, Murphy, and Somuncu are as discussed above. Brew, Murphy, and Somuncu, as stated supra, teach the potential for using placental membrane hydrogels and placental membranes for wound healing. Murphy teaches that the composition of the invention may be administered to an individual in need thereof through intravenous, intravascular, intramuscular, subcutaneous, intracerebral, intraperitoneal, and soft tissue injection (paragraph 0173).
The combined teachings of Brew, Murphy, and Somuncu do not teach wherein the hydrogel comprises calcium phosphate.
However, Lee teaches an injectable extracellular matrix based hydrogel using decellularized tissue and calcium phosphate. Lee teaches that injection-type tissue engineering has attracted much attention since it can minimize the risk of infection and scarring and reduce costs, and is used to fill irregularly sized defects (paragraphs 0006-0007). Furthermore, Lee teaches that the biphasic calcium phosphate powder increases the rate of gelation of the injectable extracellular matrix-based hydrogel (paragraph 0030).
Zhang teaches that although ultraviolet light has been extensively used in the optical cross-linking of different biopolymers, it has been reported to be associated with DNA and tissue damage. In addition, the duration of ultraviolet irradiation had a great influence on the biological stability and matrix permeability of photo-cross-linked AM [amnion membrane] materials (page 18345, column 1, paragraph 4).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have combined the hydrogel composition of the combined teachings of Brew, Murphy, and Somuncu with calcium phosphate to make an injectable hydrogel formulation to arrive at the instantly claimed invention. One of ordinary skill in the art would have a reason to combine with a reasonable expectation of success because Murphy teaches that their hydrogel could be delivered by multiple injection routes (e.g. intravascular) and Lee teaches that they used calcium phosphate powder with their hydrogel to generate an injectable hydrogel composition. Furthermore, Lee teaches that the biphasic calcium phosphate powder increases the rate of gelation of the injectable extracellular matrix-based hydrogel. Additionally, Zhang teaches that although ultraviolet light has been extensively used in the optical cross-linking of different biopolymers, it has been reported to be associated with DNA and tissue damage. In addition, the duration of ultraviolet irradiation had a great influence on the biological stability and matrix permeability of photo-cross-linked AM [amnion membrane] materials
As such, it would have been obvious to combine them into a single injectable composition to improve the rate of gelation and limit the amount of UV radiation required for polymerization, limiting the potential negative impacts of using UV radiation for crosslinking. Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success. Furthermore MPEP 2144.06 states "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted). Because the prior art teaches all of the elements of the claimed invention, there is a reasonable expectation of success.
Conclusion
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/KEENAN A BATES/Examiner, Art Unit 1631
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