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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 11/07/2025 has been entered.
Status of Claims
Receipt of Remarks/Amendments filed on 11/07/2025 is acknowledged. Claims 12-14 and 22 are cancelled and claim 26 is new. Claims 1-11, 15-21, and 23-26 are currently pending and are examined on the merits herein.
Declaration
Applicants’ submission of a declaration under Rule 132, dated 12/05/2025, is acknowledged.
Priority
The instant application filed 12/17/2021, is a 371 filing of PCT/EP2020/067187, filed 06/19/2020, which claims benefit to EP19181458.1, filed 06/20/2019.
Withdrawn Objections/Rejections
In the office action of 05/07/2025:
Claims 1-11, 14-19, 21, 23, and 24 were rejected under 35 U.S.C. 103 as being unpatentable over Appel in view of Alsberg. In view of Applicant’s remarks and upon further consideration the rejection is overcome and is withdrawn.
Claims 20 and 25 were rejected under 35 U.S.C. 103 as being unpatentable over Appel, Alsberg, and Cattolico. In view of Applicant’s remarks and upon further consideration the rejection is overcome and is withdrawn.
Claims 1-11, 14-21, and 23-25 were rejected on the ground of nonstatutory double patenting as being unpatentable U.S. Patent No. 11,045,429 B2 in view of Alsberg. In view of Applicant’s remarks and upon further consideration the rejection is overcome and is withdrawn.
Claim Interpretation
Claim 15 recites the term “green body”. While the specification does not explicitly define the term “green body”, it refers to a “green state” which is afforded by extrusion of the cross-linkable hydrogel composition through a nozzle of a direct ink writing apparatus (p. 9). Similarly, a “green object” may be obtained in general by subjecting the cross-linkable hydrogel composition to shear such as to fluidize it and depositing the fluidized cross-linkable hydrogel composition, for example by direct ink writing the cross-linkable hydrogel composition or by injecting the cross-linkable hydrogel composition, prior to cross-linking the cross-linkable hydrogel composition (p. 9-10). As such, the Examiner has interpreted the limitation of “obtaining a green body” in claim 15 to be any injection or fluidization method of the hydrogel composition.
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.
1. Claims 1-10, 15-19, 21, 23-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Appel, E., et al. (US 2017/0319506 A1, 09 NOV 2017, IDS dated 12/17/2021), hereinafter Appel, in view of Detamore, M., et al. (US 2016/0038643 A1, 11 FEB 2016, PTO-892), hereinafter Detamore, and Foster AA, et al. (2017), The Diverse Roles of Hydrogel Mechanics in Injectable Stem Cell Transplantation. Curr Opin Chem Eng. 15:15-23 (PTO-892), hereinafter Foster.
Appel discloses network materials which exhibit both shear thinning and self-healing properties containing particles and gel-forming compounds. The networks are useful for a variety of biomedical uses, including drug delivery (abstract), cell carriers for tissue engineering, and bone fillers ([0106]). Appel discloses shear-thinning injectable hydrogels utilizing non-covalent interactions between core-shell nanoparticles (NPs) and hydrophobically-modified hydroxypropylmethylcellulose (HPMC-x) ([0016]; Fig. 1).
Regarding claim 1: Appel discloses shear-thinning, self-healing networks formed from appropriately paired nanoparticles and polymers. The polymers selectively adsorb to the nanoparticles. The polymers and nanoparticles of the PNP gels are used at a concentration where the polymer alone or nanoparticle alone do not form a gel, and that only when the nanoparticle and polymer are combined does gel formation occur ([0012]). Such a network reads on the aqueous base carrier.
Regarding claim 2: PNP gel networks were formed from an aqueous solution comprising 10 wt% of carboxy-functionalized polystyrene NPs (PSNPs) with a Dx or Dh of about 50 nm ([0071]; [0074]; [0138]).
Regarding claim 3: PNP gel networks were formed from an aqueous solution comprising a cellulose based polymer, such as HPMC ([0071]). The gel forming polymer may be modified to give HPMC-x, wherein x refers to hexyl, adamantyl or dodecyl functionality ([0074]; [0138]), which reads on a semisynthetic polysaccharide.
Regarding claim 4: The HPMC above has a molecular weight (Mn) of 700 KDa ([0071]; [0138]).
Regarding claims 5 and 6: Multiple therapeutic agents can be encapsulated into the PNP gel network for a range of biomedical applications, including injectable drug delivery systems, cell carriers for tissue engineering, and bone fillers ([0106]). Such agents included pharmaceutically active agents ([0113]) and natural killer cells and helper T-cells ([0108]).
Regarding claim 15: Appel teaches PNP in vivo release studies. In the studies PNP gels where prepared, which reads on step a, and injected subcutaneously into mice, which reads on step b, wherein a green body is necessarily formed by the injection of the shear-thinning composition.
Regarding claim 16: PNP gel networks were formed from an aqueous solution comprising 10 wt% of carboxy-functionalized polystyrene NPs (PSNPs) with a Dx or Dh of about 50 nm ([0071]; [0074]; [0138]).
Regarding claims 17-19: PNP gel networks were formed from an aqueous solution comprising a cellulose based polymer, such as HPMC (i.e., hydroxypropylmethyl cellulose) ([0071]). The gel forming polymer may be modified to give HPMC-x, wherein x refers to hexyl, adamantyl or dodecyl functionality ([0074]; [0138]), which reads on a semisynthetic cellulose ether.
Regarding claim 21: When the particle contains an agent (such as a bioactive agent or other excipient or additive), the agent is heterogeneously distributed in the particle and is typically centrally located within the membrane or coating ([0058]).
Appel further teaches that the continuous phase of the PNP gel networks may further include polysaccharides, proteins, naturally occurring polymers, synthetic polymers and combinations thereof ([0091]). Exemplary proteins include collagen and exemplary polysaccharides include alginate and hyaluronic acid ([0092]-[0093]).
The teachings of Appel differ from that of the instantly claimed invention in that Appel does not teach the hydrogel composition to further comprise a cross-linkable hydrogel precursor as defined in claims 1 and 7, specifically a heteropolysaccharide or protein as defined in claims 9-10, 23-24, and 26, nor a photoinitiator as defined in claim 8. Appel also fails to teach the entire manufacturing method of claim 15.
Detamore teaches an implantable hydrogel precursor composition that includes: a cross-linkable polymer matrix that is biocompatible; and a plurality of polymer particles in the cross-linkable polymer matrix. The composition can further include live cells or a biologically active agent and is useful for tissue engineering applications and delivery of bioactive agents (abstract; [0025]-[0026]; [0034]). The hydrogel precursor has shear-thinning and self-healing behavior ([0026]).
The cross-linkable polymer of Detamore reads on the cross-linkable hydrogel precursor of claim 1.
The cross-linkable polymer matrix comprises methacrylate hyaluronic acid polymer (abstract; Examples; claim 3). Furthermore, the cross-linkable polymer can include collagen, alginate, and other natural polymers. These cross-linkable polymers can be used in place of or in addition to the hyaluronic acid polymer ([0061]). The cross-linkable polymer is present from about 2% to about 10% ([0004]; claim 8). Methacrylate hyaluronic acid (MeHA) and alginate read on the plant or animal heteropolysaccharide of claim 9, specifically those of claim 23. Collagen reads on the protein of claim 10, specifically the collagen of claim 24 and the natural protein of claim 26.
A photoinitiator, Irgacure (I-2959), is used in a MeHA hydrogel precursor composition to crosslink the MeHA when exposed to UV ([0070];[0076]), thereby reading on the photoinitiator of claim 8. The MeHA, which is cross-linked by UV radiation therefore reads on claim 7. Alginate is cross-linked via an ionic crosslinking agent and collagen is crosslinked via a change in pH, as evidenced by Applicant’s own specification, thereby reading on claim 7 as well.
Detamore further teaches a method of forming an implant which includes providing an implantable hydrogel precursor composition, which reads on step a of claim 15; and crosslinking the cross-linkable polymer matrix to form a hydrogel, which reads on step c of claim 15 ([0006]). In one embodiment, the hydrogel precursor and hydrogel can be used for nerve regeneration, where the injectable paste-like hydrogel precursor can be implanted and then crosslinked into a hydrogel in order to deliver cells and/or materials and/or bioactive signals to the spinal cord ([0034]). In the case where the hydrogel precursor is implanted via injection, as reasonably suggested by Detamore, the injection/implantation step reads on step b of claim 15.
Foster teaches that one approach to modify biomaterial properties over time is the use of dual-stage or multi-stage crosslinking strategies. For example, several shear-thinning and self-healing hydrogels have been designed to undergo a second stage of crosslinking, and hence mechanical stiffening, in response to various stimuli. Temperature is a common stimulus to induce secondary crosslinking in situ, since many self-assembling hydrogels can be modified to include a thermoresponsive element. In this approach, cell viability is improved during the injection stage due to the shear thinning mechanical properties, acute cell retention is improved during the acute post-injection stage due to the rapid self-healing kinetics, and the temperature-triggered secondary crosslinking increases long-term cell survival due to the decreased degradation rate. Alternatively, covalent crosslinking can be used as a secondary crosslinking mechanism to reinforce and strengthen injectable hydrogels. For example, HA can be modified to undergo a first-stage of guest-host self-assembly followed by a second-stage of covalent crosslinking to prolong material retention and to improve integration with host tissue (p. 7-8, bridge paragraph).
It would have been prima facie obvious to one of ordinary skill in the art to add the cross-linkable polymer of Detamore into the PNP hydrogel of Appel in order to provide secondary crosslinks which decrease the hydrogel’s degradation rate, prolong material retention, and improve integration in the host tissue as reasonably suggested by Foster. Additionally, the cross-linkable polymer of Detamore is known and routine for manufacturing hydrogel-nanoparticle composites for tissue engineering and drug delivery similar to those of Appel. “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). The incorporation of the cross-linkable polymer of Detamore given the motivation of Foster therefore yields the cross-linkable hydrogel precursor of claim 1 obvious.
Regarding the amount of the cross-linkable polymer to include in the combined composition, Detamore teaches an amount of 2% to about 10%. While the instant claims do not specify how much of the cross-linkable precursor to include, claims 1 and 26, recite wherein it is comprised at a concentration at which the cross-linkable hydrogel precursor, taken alone, does not form a hydrogel. It is well within the abilities of an ordinary artisan to optimize the amount of cross-linkable polymer in the composition depending on the desired properties and applications of the cross-linkable solution. As such, one of ordinary skill in the art would have arrived at the instantly claimed concentration through no more than routine experimentation. 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).
It would have been further obvious to use any one of methacrylate hyaluronic acid, collagen or alginate as the cross-linkable polymer above (i.e., as the cross-linkable precursor of the instant invention), since these polymers are known and routine polymers suitable for use in hydrogels of the instant art. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. Additionally, one of ordinary skill in the art could have substituted any one of these cross-linkable polymers for another to achieve the predictable result of generating the desired hydrogel. See MPEP 2143. The selection of MeHA or alginate yields claims 7, 9, and 23 obvious, while the selection of collagen yields claims 7, 10, 24, and 26 obvious.
It would have been further obvious to incorporate the photoinitiator of Detamore in the combined hydrogel composition above, specifically in the case of MeHa, since a photoinitiator enables the formation of MeHA crosslinks when exposed to UV radiation. The formation of secondary crosslinks is desirable as reasonably suggested by Foster above. As such, claim 8 would have been obvious.
Regarding claim 15: It would have been obvious to use the combined composition of Appel, Detamore, and Foster in a method of a) providing the combined composition; b) injecting said composition to obtain a green body; and c) cross-linking the green body to form an object. Such a method would have been obvious given the methods taught by Appel and Detamore which teach providing a precursor solution (Appel and Detamore), injecting/implanting said solution (Appel and Detamore), and cross-linking said solution (Detamore), since this is a known and routine technique for using injectable hydrogel compositions to generate implantable hydrogels that deliver cells and bioactive agents to the body. Since the combined composition is an injectable shear-thinning and self-healing composition, a green body would have necessarily been formed during the injection step. The combination of such prior art elements would have yielded the predictable result of forming a cross-linked hydrogel (i.e., object) at the injection site.
One of ordinary skill in the art would have had a reasonable expectation of success and predictability in performing the above modifications since Detamore teaches cross-linkable polymers which are compatible in hydrogel precursor compositions comprising nanoparticles and Appel welcomes the addition of polymers like collagen, alginate, and hyaluronic acid.
Regarding properties of the cross-linkable hydrogel precursor as defined in claims 1 and 26: Since the composition made obvious by the prior art is identical to the composition claimed, the composition must necessarily have the characteristics claimed as an inherent property, specifically regarding the fact that the cross-linkable hydrogel precursor of Detamore will not selectively adsorb or form a shear-thinning/self-healing hydrogel with the nanoparticles of Appel. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.
2. Claims 1-10, 15-21, 23-24, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Appel, Detamore, and Foster as applied to claims 1-10, 15-19, 21, 23-24, and 26 above, and further in view of US 2017/0327813 A1 (Cattolico, R. A., et al) 16 NOV 2017 (PTO-892 dated 02/10/2025).
The combined teachings of Appel, Detamore, and Foster are discussed above.
The combined teachings of Appel, Detamore, and Foster differ from that of the instantly claimed invention in that neither Appel, Detamore, or Foster teach wherein the cross-linkable hydrogel comprises one or more microorganism cells as recited in claim 20.
Cattolico teaches hydrogel compositions that are responsive to temperature, applied pressure (shear thinning) and chemical crosslinking ([0006]). Because of these properties, the hydrogel compositions can be uniformly embedded with a loading agent, extrusion (“3D”) printed, and crosslinked ([0006]). The loading agent can be any material, soluble or insoluble that can be mixed with the hydrogel composition prior to extrusion printing ([0088]). For example, the loading agent can be a pharmaceutical drug, a hydrophobic additive, an organic or inorganic chemical substance, a catalyst, nanomaterials such as nanoparticles, nanotubes, and graphene, a polymer, a biopolymer, or a living cell ([0088]). When the loading agent is a living cell, it may be a plant or animal cell, protist, fungal, or bacterial cells (i.e., a microorganism cell) ([0089]). The cell may be a freshwater or marine organism, an algal cell, a yeast cell, and/or a modified or transformed cell ([0089]).
Thus, it would have been prima facie obvious to one of ordinary skill in the art to modify the combined composition of Appel, Detamore, and Foster before the effective filing date of the claimed invention by replacing the cells taught by the combined composition with the microorganism cells of Cattolico since microorganism cells are known and routine loading agents for injectable/extrudable hydrogel compositions. One of ordinary skill in the art would have been able to perform the simple substitution of one known loading agent for another (i.e., a microorganism cell) to predictably form a hydrogel loaded with a microorganism as instantly claimed.
One of ordinary skill in the art would have had a reasonable expectation of success in making the above modification since Appel, Detamore, and Foster teach hydrogel compositions for injecting and encapsulating various bioactive agents, which include cells.
3. Claims 1-8, 11, 15-19, 21, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Appel, E., et al. (US 2017/0319506 A1, 09 NOV 2017, IDS dated 12/17/2021), hereinafter Appel, in view of Frank, C., et al. (US 2011/0256183 A1, 20 OCT 2011, PTO-892), hereinafter Frank, and Foster AA, et al. (2017), The Diverse Roles of Hydrogel Mechanics in Injectable Stem Cell Transplantation. Curr Opin Chem Eng. 15:15-23 (PTO-892), hereinafter Foster.
Appel discloses network materials which exhibit both shear thinning and self-healing properties containing particles and gel-forming compounds. The networks are useful for a variety of biomedical uses, including drug delivery (abstract), cell carriers for tissue engineering, and bone fillers ([0106]). Appel discloses shear-thinning injectable hydrogels utilizing non-covalent interactions between core-shell nanoparticles (NPs) and hydrophobically-modified hydroxypropylmethylcellulose (HPMC-x) ([0016]; Fig. 1).
Regarding claim 1: Appel discloses shear-thinning, self-healing networks formed from appropriately paired nanoparticles and polymers. The polymers selectively adsorb to the nanoparticles. The polymers and nanoparticles of the PNP gels are used at a concentration where the polymer alone or nanoparticle alone do not form a gel, and that only when the nanoparticle and polymer are combined does gel formation occur ([0012]).
Regarding claim 2: PNP gel networks were formed from an aqueous solution comprising 10 wt% of carboxy-functionalized polystyrene NPs (PSNPs) with a Dx or Dh of about 50 nm ([0071]; [0074]; [0138]).
Regarding claim 3: PNP gel networks were formed from an aqueous solution comprising a cellulose based polymer, such as HPMC ([0071]). The gel forming polymer may be modified to give HPMC-x, wherein x refers to hexyl, adamantyl or dodecyl functionality ([0074]; [0138]), which reads on a semisynthetic polysaccharide.
Regarding claim 4: The HPMC above has a molecular weight (Mn) of 700 KDa ([0071]; [0138]).
Regarding claims 5 and 6: Multiple therapeutic agents can be encapsulated into the PNP gel network for a range of biomedical applications, including injectable drug delivery systems, cell carriers for tissue engineering, and bone fillers ([0106]). Such agents included pharmaceutically active agents ([0113]) and natural killer cells and helper T-cells ([0108]).
Regarding claim 15: Appel teaches PNP in vivo release studies. In the studies PNP gels where prepared, which reads on step a, and injected subcutaneously into mice, which reads on step b, wherein a green body is necessarily formed by the injection of the shear-thinning composition.
Regarding claim 16: PNP gel networks were formed from an aqueous solution comprising 10 wt% of carboxy-functionalized polystyrene NPs (PSNPs) with a Dx or Dh of about 50 nm ([0071]; [0074]; [0138]).
Regarding claims 17-19: PNP gel networks were formed from an aqueous solution comprising a cellulose based polymer, such as HPMC (i.e., hydroxypropylmethyl cellulose) ([0071]). The gel forming polymer may be modified to give HPMC-x, wherein x refers to hexyl, adamantyl or dodecyl functionality ([0074]; [0138]), which reads on a semisynthetic cellulose ether.
Regarding claim 21: When the particle contains an agent (such as a bioactive agent or other excipient or additive), the agent is heterogeneously distributed in the particle and is typically centrally located within the membrane or coating ([0058]).
Appel further teaches that the continuous phase of the PNP gel networks may further include polysaccharides, proteins, naturally occurring polymers, synthetic polymers and combinations thereof ([0091]). Exemplary synthetic polymers include polyethylene glycol (PEG) ([0094]).
The teachings of Appel differ from that of the instantly claimed invention in that Appel does not teach the hydrogel composition to further comprise a cross-linkable hydrogel precursor as defined in claims 1 and 7, specifically a synthetic polymer as defined in claims 11 and 25, nor a photoinitiator as defined in claim 8. Appel also fails to teach the full manufacturing method of claim 15.
Frank discloses the encapsulation of cells within a hydrogel matrix by combining hydrophilic nanoparticles and a prepolymer to form a precursor solution. A cell suspension is mixed with the precursor solution and crosslinked to form the hydrogel ([0020]). The hydrogel of Frank provides appropriate mechanical strength for long term structural stability, and the viscosity of the fluid prepolymer is low enough for the prepolymer to flow into microscale structures ([0010]). The cell containing hydrogels of Frank are used for tissue-engineering applications [0055] and the nanoparticles may further comprise biologically active agents ([0009]). The percent of polymer in the precursor solution ranges between about 1% w/w and about 40% w/w ([0019]-[0020]).
The prepolymer of Frank reads on the cross-linkable hydrogel precursor of the instant invention.
In a specific example, Frank discloses cell encapsulation in PEG matrices. Polyethylene glycol diacrylate (i.e., PEG-DA) was dissolved in PBS with a photoinitiator. For hydrophilic particles, polystyrene beads surface-modified with carboxyl groups were used. The final prepolymer solution was cured with UV light ([0096]), which reads on a polymer cross-linkable by radiation as recited in instant claim 7. The photoinitiator above reads on the photoinitiator of claim 8. The PEG-DA reads on the synthetic polymer of claim 11, specially, the polyethylene glycol diacrylate of claim 25.
Foster teaches that one approach to modify biomaterial properties over time is the use of dual-stage or multi-stage crosslinking strategies. For example, several shear-thinning and self-healing hydrogels have been designed to undergo a second stage of crosslinking, and hence mechanical stiffening, in response to various stimuli. Temperature is a common stimulus to induce secondary crosslinking in situ, since many self-assembling hydrogels can be modified to include a thermoresponsive element. In this approach, cell viability is improved during the injection stage due to the shear thinning mechanical properties, acute cell retention is improved during the acute post-injection stage due to the rapid self-healing kinetics, and the temperature-triggered secondary crosslinking increases long-term cell survival due to the decreased degradation rate. Alternatively, covalent crosslinking can be used as a secondary crosslinking mechanism to reinforce and strengthen injectable hydrogels. For example, HA can be modified to undergo a first-stage of guest-host self-assembly followed by a second-stage of covalent crosslinking to prolong material retention and to improve integration with host tissue (p. 7-8, bridge paragraph).
It would have been prima facie obvious to one of ordinary skill in the art to add the prepolymer of Frank, specifically PEG-DA, into the PNP hydrogel of Appel in order to provide secondary crosslinks which decrease the hydrogel’s degradation rate, prolong material retention, and improve integration in the host tissue as reasonably suggested by Foster. Additionally, the PEG-DA of Frank is known and routine for manufacturing hydrogel-nanoparticle composites for tissue engineering and drug delivery similar to those of Appel. “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). The incorporation of the PEG-DA of Frank given the motivation of Foster therefore yields the cross-linkable hydrogel precursor of claim 1 obvious, as well as the limitations of claims 7, 11, and 25.
Regarding the amount of the prepolymer/PEG-DA to include in the combined composition, Frank teaches an amount of about 1% w/w and about 40% w/w. While the instant claims do not specify how much of the cross-linkable precursor to include, claim 1 recites wherein it is comprised at a concentration at which the cross-linkable hydrogel precursor, taken alone, does not form a hydrogel. It is well within the abilities of an ordinary artisan to optimize the amount of cross-linkable polymer in the composition depending on the desired properties and applications of the cross-linkable solution. As such, one of ordinary skill in the art would have arrived at the instantly claimed concentration through no more than routine experimentation. 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).
It would have been further obvious to incorporate the photoinitiator of Frank in the combined hydrogel composition above, since a photoinitiator enables the formation of PEG-DA crosslinks when exposed to UV radiation. The formation of secondary crosslinks is desirable as reasonably suggested by Foster above. As such, claim 8 would have been obvious.
Regarding claim 15: It would have been obvious to use the combined composition of Appel, Frank, and Foster in a method of a) providing the combined composition; b) injecting said composition to obtain a green body; and c) cross-linking the green body to form an object. Such a method would have been obvious given the methods taught by Appel and Frank which teach providing a precursor solution (Appel and Frank), injecting said solution (Appel), and cross-linking said solution (Frank), since this is a known and routine technique for using hydrogel precursor compositions to generate hydrogels that deliver cells and bioactive agents to the body. A green body would have necessarily been formed during the injection step. The combination of such prior art elements would have yielded the predictable result of forming a cross-linked hydrogel (i.e., object) at the injection site.
One of ordinary skill in the art would have had a reasonable expectation of success and predictability in performing the above modifications since Frank teaches successful hydrogel formation when PEG-DA and a photoinitiator are combined with carboxyl modified polystyrene particles, which are also utilized in the PNP gels of Appel. Furthermore, Appel welcomes the addition of polymers such as PEG.
4. Claims 1-8, 11, 15-21, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Appel, Frank, and Foster as applied to claims 1-8, 11, 15-19, 21, and 25 above, and further in view of US 2017/0327813 A1 (Cattolico, R. A., et al) 16 NOV 2017 (PTO-892 dated 02/10/2025).
The combined teachings of Appel, Frank, and Foster are discussed above.
The combined teachings of Appel, Frank, and Foster differ from that of the instantly claimed invention in that neither Appel, Frank, or Foster teach wherein the cross-linkable hydrogel comprises one or more microorganism cells as recited in claim 20.
Cattolico teaches hydrogel compositions that are responsive to temperature, applied pressure (shear thinning) and chemical crosslinking ([0006]). Because of these properties, the hydrogel compositions can be uniformly embedded with a loading agent, extrusion (“3D”) printed, and crosslinked ([0006]). The loading agent can be any material, soluble or insoluble that can be mixed with the hydrogel composition prior to extrusion printing ([0088]). For example, the loading agent can be a pharmaceutical drug, a hydrophobic additive, an organic or inorganic chemical substance, a catalyst, nanomaterials such as nanoparticles, nanotubes, and graphene, a polymer, a biopolymer, or a living cell ([0088]). When the loading agent is a living cell, it may be a plant or animal cell, protist, fungal, or bacterial cells (i.e., a microorganism cell) ([0089]). The cell may be a freshwater or marine organism, an algal cell, a yeast cell, and/or a modified or transformed cell ([0089]).
Thus, it would have been prima facie obvious to one of ordinary skill in the art to modify the combined composition of Appel, Frank, and Foster before the effective filing date of the claimed invention by replacing the cells taught by the combined composition with the microorganism cells of Cattolico since microorganism cells are known and routine loading agents for injectable/extrudable hydrogel compositions. One of ordinary skill in the art would have been able to perform the simple substitution of one known loading agent for another (i.e., a microorganism cell) to predictably form a hydrogel loaded with a microorganism as instantly claimed.
One of ordinary skill in the art would have had a reasonable expectation of success in making the above modification since Appel, Frank, and Foster teach hydrogel compositions for injecting and encapsulating various bioactive agents, which include cells.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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1. Claims 1-11, 15-21, and 23-26 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1, 7-19, 26-31 of U.S. Patent No. 11,045,429 B2 (PTO-892 dated 02/10/2025) in view of Detamore and Foster. The Obviousness Double Patenting rejection is appropriate because while the conflicting claims are not identical, the examined claims are not patentably distinct from the reference claims and would have been obvious over the reference claims in view of Detamore and Foster.
US’429 claims a shear-thinning injectable hydrogel (i.e., aqueous) comprising: one or more biocompatible gel-forming polymers selected from the group consisting of polysaccharides and proteins, optionally modified with one or more ester, carbonate, amide, carbamate, urea, ether or amine-linked capping groups, and nanoparticles having a diameter between 10 nm and 1000 nm, wherein the nanoparticles are non-covalently bound to multiple biocompatible gel-forming polymers to form the shear-thinning injectable hydrogel comprising between about 1 and 15 wt % nanoparticles in the shear-thinning injectable hydrogel, the hydrogel optionally comprising one or more therapeutic, prophylactic or diagnostic agents encapsulated within the nanoparticles, associated with the surface of the particles and/or dispersed through the hydrogel (US’429 claim 1). The one or more biocompatible gel-forming polymers comprise hydrophobic capping groups selected from the group consisting of hexyl, dodecyl, and adamantyl (US’429 claim 26). Thus, the claims of US’429 define an aqueous base carrier composition comprising one or more polymers and nanoparticles that, together, form a shear-thinning hydrogel (instant claim 1).
The claims of US’429 differ from the instantly claimed invention in that the claims of US’429 do not recite wherein the composition comprises a cross-linkable hydrogel precursor, such as a natural protein, nor does US’429 teach a method according to claim 15.
Detamore teaches an implantable hydrogel precursor composition that includes: a cross-linkable polymer matrix that is biocompatible; and a plurality of polymer particles in the cross-linkable polymer matrix. The composition can further include live cells or a biologically active agent and is useful for tissue engineering applications and delivery of bioactive agents (abstract; [0025]-[0026]; [0034]). The hydrogel precursor has shear-thinning and self-healing behavior ([0026]). The cross-linkable polymer of Detamore reads on the cross-linkable hydrogel precursor of claim 1. The cross-linkable polymer matrix comprises methacrylate hyaluronic acid polymer (abstract; Examples; claim 3). Furthermore, the cross-linkable polymer can include collagen, alginate, and other natural polymers. These cross-linkable polymers can be used in place of or in addition to the hyaluronic acid polymer ([0061]). The cross-linkable polymer is present from about 2% to about 10% ([0004]; claim 8). Collagen reads on the natural protein of claim 26.
Detamore further teaches a method of forming an implant which includes providing an implantable hydrogel precursor composition, which reads on step a of claim 15; and crosslinking the cross-linkable polymer matrix to form a hydrogel, which reads on step c of claim 15 ([0006]). In one embodiment, the hydrogel precursor and hydrogel can be used for nerve regeneration, where the injectable paste-like hydrogel precursor can be implanted and then crosslinked into a hydrogel in order to deliver cells and/or materials and/or bioactive signals to the spinal cord ([0034]). In the case where the hydrogel precursor is implanted via injection, as reasonably suggested by Detamore, the injection/implantation step reads on step b of claim 15.
Foster teaches that one approach to modify biomaterial properties over time is the use of dual-stage or multi-stage crosslinking strategies. For example, several shear-thinning and self-healing hydrogels have been designed to undergo a second stage of crosslinking, and hence mechanical stiffening, in response to various stimuli. Temperature is a common stimulus to induce secondary crosslinking in situ, since many self-assembling hydrogels can be modified to include a thermoresponsive element. In this approach, cell viability is improved during the injection stage due to the shear thinning mechanical properties, acute cell retention is improved during the acute post-injection stage due to the rapid self-healing kinetics, and the temperature-triggered secondary crosslinking increases long-term cell survival due to the decreased degradation rate. Alternatively, covalent crosslinking can be used as a secondary crosslinking mechanism to reinforce and strengthen injectable hydrogels. For example, HA can be modified to undergo a first-stage of guest-host self-assembly followed by a second-stage of covalent crosslinking to prolong material retention and to improve integration with host tissue (p. 7-8, bridge paragraph).
It would have been prima facie obvious to one of ordinary skill in the art to add the cross-linkable polymer of Detamore into the hydrogel of US’429 in order to provide secondary crosslinks which decrease the hydrogel’s degradation rate, prolong material retention, and improve integration in the host tissue as reasonably suggested by Foster. The incorporation of the cross-linkable polymer of Detamore given the motivation of Foster therefore yields the cross-linkable hydrogel precursor of claim 1 obvious.
It would have been further obvious to use any one of methacrylate hyaluronic acid, collagen or alginate as the cross-linkable polymer above (i.e., as the cross-linkable precursor of the instant invention), since these polymers are known and routine polymers suitable for use in hydrogels of the instant art. Generally, it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See MPEP 2144.07. Additionally, one of ordinary skill in the art could have substituted any one of these cross-linkable polymers for another to achieve the predictable result of generating the desired hydrogel. See MPEP 2143. The selection of collagen yields claim 26 obvious.
Regarding claim 15: It would have been obvious to use the combined composition of US’429, Detamore, and Foster in a method of a) providing the combined composition; b) injecting said composition to obtain a green body; and c) cross-linking the green body to form an object. Such a method would have been obvious given the method taught by Detamore which teach providing a precursor solution, injecting/implanting said solution, and cross-linking said solution, since this is a known and routine technique for using injectable hydrogel compositions to generate implantable hydrogels that deliver cells and bioactive agents to the body. Since the combined composition is an injectable shear-thinning and self-healing composition, a green body would have necessarily been formed during the injection step. The combination of such prior art elements would have yielded the predictable result of forming a cross-linked hydrogel (i.e., object) at the injection site.
Regarding the properties of the above composition, since the structural elements appear to be the same as the instantly claimed composition, the combined composition should necessarily have the same properties as instantly claimed (i.e., selective adsorption, self-healing, and inability to form a hydrogel alone). When the composition taught by the prior art is identical to the composition claimed, the composition must necessarily have the characteristics claimed as an inherent property. It is noted that In re Best (195 USPQ 430) and In re Fitzgerald (205 USPQ 594) discuss the support of rejections wherein the prior art discloses subject matter, which there is reason to believe inherently includes functions that are newly cited, or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to “prove that subject matter to be shown in the prior art does not possess the characteristic relied on” (205 USPQ 594). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference.
Response to Arguments and Declaration
Applicant’s arguments with respect to the rejection of the claims as obvious over Appel in view of Alsberg, have been considered but are moot because the new ground of rejection does not rely on any references applied in the prior rejection of record for any teaching or matter specifically challenged in the arguments.
Applicant has also provided a Declaration under Rule 132 that is dated 12/05/2025. The Declaration details the non-obviousness of adding the OMA of Alsberg into the hydrogel of Appel. However, since Alsberg is no longer relied on in the above rejections, the inability of a composition containing 2% HPMC, 10% OMA, and 5% NPs to form a hydrogel is moot.
Conclusion
No claims are allowed.
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/SUSANNAH S ARMSTRONG/Examiner, Art Unit 1616
/Mina Haghighatian/Primary Examiner, Art Unit 1616