DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
This application was filed Nov. 30, 2023, and is a 371 application of PCT/EP2022/025245 filed on May 26, 2022, which claims benefit to the foreign application EP21305722.7 filed on May 31, 2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 1-10) drawn to a method for preparing cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel by 3D bioprinting, in the reply filed on April 9, 2026 is acknowledged.
Claims 10-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention (i.e. composition), there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 9, 2026.
It is noted that claim 10 was inadvertently added to both Group I (i.e. drawn to the method) and Group II (i.e. drawn to the composition). However, claim 10 recites a 3D bio-printed cell-laden collagen-gellan gum IPN hydrogel comprising stem cell-laden collagen, thus is directed to a composition and not a method. Attorney Megerditchian was contacted via telephone on June 3, 2026, and a provisional election was made without traverse to prosecute the invention drawn to a method for preparing cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel by 3D bioprinting, Claims 1-9. Affirmation of this election must be made by applicant in replying to this Office action. Claims 10-15 are withdrawn from further consideration by the examiner, 37 CFR 1.142(b), as being drawn to a non-elected invention.
Claim Status
Claims 1-15 are pending in this application. Claims 10-15 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 9, 2026.
Claims 1-9 are under examination in this application.
Claim Objections
Claims 1-2, 4, 6, and 8 are objected to because of the following informalities: grammar, formatting, and clarity (e.g. symbols, spacing, and missing articles).
Regarding claim 1, it is suggested that claim 1 recites: b) preparing a second bioink by suspending stem cells in a collagen solution, preferably in a neutralized type I collagen solution.” Further, claim 1 recites “f) adding an ionic crosslinking agent, preferably MgCl 2 solution,” which should recite “MgCl2” and with no space between the “Cl” and the number two. Appropriate correction is required.
Regarding claims 2, 4, and 6, the claims recite percentages, however some percentages have a spaced between the number and the percent sign and some parts of the claims do not. For example, claim 2 recites “between 0.1 and 10 % (w/v), preferably about 0.8% (w/v) of gellan gum”. It is suggested that all claims remove the spacing between the number and the percent sign in all of pending claims.
Regarding claim 8, there is a little “c” recited after the degree symbol, however a capital “C” is appropriate because the letter “C” it is an abbreviation. Further, it is suggested that claim 8 be amended to recite: by heating the bio-printed product to a temperature of 37°C or above.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on August 30, 2023, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
However, Applicant is reminded that the listing of references in the specification (e.g. “Przekora A; et al. Cells. 20 2020, 9(7): 1622”) is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “A method for preparing cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel by 3D bioprinting, the method comprising: a) preparing a first bioink by dissolving gellan gum with a viscosity enhancer in a solvent, preferably by heating the solution at a temperature above hydration temperature and by lowering the temperature; b) preparing a second bioink by suspending stem cells in collagen solution, preferably in neutralized type I collagen solution; c) depositing the first bioink on a support media; d) depositing the second bioink into the first bioink; e) heating the bioprinted product obtained from the deposition of the first and second bioinks of step c) and d) to achieve collagen fibrillogenesis; and, f) adding an ionic crosslinking agent, preferably MgCl 2 solution to cross-link gellan gum to obtain a cell-laden collagen-gellan gum IPN hydrogel”.
Regarding claims 1-6, the phrase "preferably" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. As recited supra, claim 1 recites: “preferably by heating the solution”, preferably in neutralized type I collagen solution,” and “preferably MgCl 2 solution.” Claim 3 recites “preferably a pregelatinized starch derived from a potato”. Claim 5 recites “preferably with sodium trimetaphosphate”. Further, claims 2, 4, and 6 recite the term “preferably” and then a claimed range. The term “preferably” in claims 1-6 are regarding as relative terms, which renders the claim indefinite because the term “preferably” is not defined by the claim, and the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonable apprised of the scope of the invention. Thus, parameter of “preferably” in the claim has been rendered indefinite. See MPEP § 2173.05(d). Furthermore, It is noted that the term “preferably” does not have special definitions in the specification, therefore the term “preferably” will be treated as “optionally” because it is just one version of which is “preferable.” This affects the scope of all depending claims. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claims 1-2, and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al., (WO2020/225336 A1, published Nov. 2020, hereinafter as “Zhang”, cited IDS 11/30/2023), Levato et al., (Biofabrication 6.3: 035020, published 2014, hereinafter as “Levato”), and Kadziński, Leszek, et al. (Journal of pharmaceutical sciences 104.4: 1275-1281, published 2015, hereinafter as “Kadzinski”), as evidence by Darvish DM. (Mater Today Bio. 2022 Jun 14;15:100322).
Claim Interpretation: It is noted that the term “preferably” does not have special definitions in the specification. Features preceded by expressions such as "preferably'' are to be interpreted as entirely optional and do not restrict the scope of the claims containing these expressions. Thus, the term “preferably” will be treated as “optionally” because it is just one version of the claims that is “preferable” and not required.
Regarding claims 1, Zhang discloses a method for preparing cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel (see e.g. abstract, Examples section, page 14-23, Tables 1-2, fig. 2, and claims 1-15), the method comprising: a) preparing a solution (i.e. first bioink) by dissolving gellan gum with a solvent (see e.g. claims 4-6, page 9-10, and 14-15), preferably by heating the solution at a temperature above hydration temperature and by lowering the temperature (see e.g. pages Examples section, 14-15); b) preparing a second solution (i.e. second bioink) by suspending stem cells in collagen solution (e.g. adipose-derived stem cells or mesenchymal stem cells), preferably in neutralized type I collagen solution (see e.g. page Examples section 14-15, 21); c) depositing the first solution (i.e. first bioink) on a support media (see e.g. Examples section, pages 14-15); d) depositing the second solution (i.e. second bioink) into the first solution (i.e. first bioink)(see e.g. Examples section, pages 14-15); e) heating the product obtained from the deposition of the first and second solution (i.e. bioinks) of step c) and d) to achieve collagen fibrillogenesis (see e.g. Examples section, pages 14); and, f) adding an ionic crosslinking agent, preferably MgCl2 solution to cross-link gellan gum to obtain a cell-laden collagen-gellan gum IPN hydrogel (see e.g. Examples section, pages 14-15).
Zhang does not explicitly disclose the method involving 3D bioprinting and a viscosity enhancer that is starch from potato.
However, the prior art of Levato discloses methods involving 3D bioprinting and viscosity enhancers.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Zhang to incorporate 3D bioprinting and viscosity enhances as taught by Levato because Levato discloses that bioprinting allows for the deposit of the multiple bioinks to be spatially controlled (see e.g. abstract) which would have improved the cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel as taught by Zhang. A person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Zhang and Levato disclose methods that combine multiple bioinks (see e.g. abstracts, respectively). Further, Levato discloses that viscosity enhancers are important to incorporate into bioinks solutions because they improve properties of the bioinks when bioprinting a complex structures that has multiple solutions (i.e. bioinks)(see e.g. page 2). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 2, Zhang discloses wherein said first bioink comprises between 0.1 and 10% (w/v), preferably about 0.8% (w/v) of gellan gum (i.e. 0.762%)(see e.g. page 15).
Regarding claim 7, Zhang discloses wherein the bioink comprises about 1 mg/mL of collagen.
Zhang does not explicitly state wherein said second bioink comprises less than 0.2 mg/mL of collagen.
However, the prior art of Kadziński discloses using collagen at concentrations less than 0.2 mg/ml (e.g. 0.1mg/ml) to achieve collagen fibrillogenesis (see e.g. page 1276 and table 1).
MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” Further, MPEP § 2144.05 (II) states, “Generally, differences in time, concentration and/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 reAller, 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 reHoeschele, 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.). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration of collagen is critical, thus the teaching of 0.1mg/ml of collagen as taught by Kadzinski renders the claimed concentration of collagen as obvious.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Zhang and combine the concentration of collagen as being less than 0.2 mg/ml as taught by Kadzinski because Kadzinski discloses achieving collagen fibrillogenesis at concentrations less than 0.2mg/ml. Additionally, since Zhang discloses methods of adding a second bioink to achieve collagen fibrillogenesis (see e.g. Examples section, pages 14), the amount of collagen would have been able to be optimized by one of ordinary skill in the art. A person of ordinary skill in the art would have had predictable results because both Zhang and Kadzinski disclose using collagen type I to achieve fibrillogenesis, as discussed above. Moreover, Kadzinsk discloses the stability of collagen type I at concentrations less than 0.2mg/ml (see e.g. table 1), as evidence by Darvish which discloses that collagen type I concentrations in the range from 0.023 to 0.94 mg/ml were known in the prior art and that the low concentration of collagen solutions were able to form gels and have the appearance of fibrils (see e.g. page 6-7). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 8, Zhang discloses wherein said fibrillogenesis of collagen is achieved by heating the bioprinted product to 37°C or above (see e.g. page 15).
Regarding claim 9, Zhang discloses wherein said stem cells are adipose derived stem cells (see e.g. pages 13-15 and 21-22).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al., (WO2020/225336 A1, published Nov. 2020, hereinafter as “Zhang,” cited IDS 11/30/2023), Levato et al., (Biofabrication 6.3: 035020, published 2014, hereinafter as “Levato”), and Kadziński, Leszek, et al. (Journal of pharmaceutical sciences 104.4: 1275-1281, published 2015, hereinafter as “Kadzinski”), as applied to claims 1-2, and 7-9 above, and further in view of Carvalho, Antonio Jose Felix, et al. (Carbohydrate Polymers 53.1: 95-99, published 2003, hereinafter as “Carvalho”), Kang, Hyun-Wook, et al. (Nature biotechnology 34.3: 312-319, published 2016, hereinafter as “Kang”), Shahbazi, Mahdiyar, and Henry Jäger. (ACS Applied Biomaterials 4.1: 325-369, published 2020, hereinafter as “Shahbazi”), Lefnaoui, Sonia, and Nadji Moulai-Mostefa. (Colloids and Surfaces A: Physicochemical and Engineering Aspects 458: 117-125, published 2014, hereinafter as “Lefnaoui”), and Ojogbo, et al., (Materials today sustainability 7: 100028, published 2020, hereinafter as “Ojogbo”).
The teachings of Zhang et al., apply here as indicated above.
Regarding claims 3-4 and 6, as stated supra, Zhang et al., does not explicitly disclose the wherein said first bioink comprises between 1 and 20% (w/v) of a pregelatinized starch and the wherein said first bioink comprises glycerol between 1 and 30 % (v/v) glycerol.
However, the prior art of Carvalho discloses blends of glycerol-to-starch proportions varying from 20 to 50% (see e.g. page 96). Moreover, the prior art of Kang discloses wherein optimal bioinks comprises 10% (v/v) of glycerol (see e.g. table 1). Additionally, the prior art of Shahbazi discloses using starch as a cost-effective polymer for bioprinting, such as potato starch at 15-20% (see e.g. sec. 3.2.2. starch). Although Shahbazi does not explicitly state “pregelatinized starch”, the prior art of Lefinaoui discloses that pregelatinized starch is an optimal factor for hydrogels (see e.g. abstract).
MPEP § 2144.05 (II) states, “Generally, differences in time, concentration and/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 reAller, 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 reHoeschele, 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.). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”). Further, the MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration percentage of pregelatinized starch and glycerol is critical, thus the teaching of Carvalho discloses blends of glycerol-to-starch proportions varying from 20 to 50% as taught by Carvalho (see e.g. page 96), renders the claimed concentration as obvious.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Zhang to incorporate 1 and 20% (w/v) of a pregelatinized starch and 1 and 30 % (v/v) glycerol in the first bioink as taught by Carvalho, Kang, Shahbazi, and Lefinaoui because Kang discloses that the optimal bioink comprises 10% (v/v) of glycerol (see e.g. table 1), and Shahbazi discloses that potato starch is a cost-effective polymer for bioprinting(see e.g. sec. 3.2.2. starch). Further, a person of ordinary skill in the art would have done so because both Zhang and Shahbazi disclose methods for polysaccharide-based hydrogels scaffolds for wound care (see e.g. abstract and sec. 4.3.2, respectively). Additionally, both Zhang and Kang disclose methods involving cell-laden hydrogels (see e.g. abstract and page 312, respectively). Further, Kang discloses that cell-laden hydrogels with 10% glycerol were known for optimal 3D bioprinting tissue constructs (see e.g. table 1, page 313). Additionally, Kang teaches that gelatin and glycerol are important cell carriers for bioprinting because they provide adequate mechanical support, cell-specific cues and negligible cytotoxicity (see e.g. page 317). Moreover, a person of ordinary skill in the arts would have done so because the prior art of Carvalho discloses that blends of glycerol-to-starch proportions varying from 20 to 50% (see e.g. page 96) were known polymer blends (see e.g. abstract, and page 96), and Lefnaoui discloses that optimal hydrogel factors involved pregelatinized starch and glycerol blends (see e.g. abstract and conclusion sections). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 5, as stated supra, Zhang discloses adding an ionic crosslinking agent (see e.g. Examples section, pages 14-15).
Zhang does not explicitly disclose wherein said pregelatinized starch is crosslinked, preferably with sodium trimetaphosphate.
However, the prior art of Ojogbo discloses pregelatinized starch (PGS) (see e.g. pages 5-7) and starch when crosslinked with sodium trimetaphosphate (see e.g. pages 8-9, table 6).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Zhang to incorporate pregelatinized starch crosslinked with sodium trimetaphosphate as taught by Ojogbo because Ojogbo discloses pregelatinized starch (PGS) improves swelling capacity (see e.g. page 5-6) and that starch when crosslinked with sodium trimetaphosphate has enhances stability, hardness, and adhesiveness of gels (see e.g. pages 8-9). A person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Zhang and Ojogbo disclose methods involving bio-polymer material applications (e.g. hydrogels or gels)(see e.g. abstracts, respectively).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 1-2, and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Boyer et al., (US2021/0069964A1, published March 2021, hereinafter as “Boyer”; cited IDS 11/30/2023), Chen, Hong, et al. (ACS Applied BioMaterials 1.5: 1408-1415, published 2018, hereinafter as “Chen”; cited IDS 11/30/2023), Williams, Barbara R., et al. (The Journal of biological chemistry 253.18: 6578-6585, published 1978, hereinafter as “Williams”), and Tang, Juming, Marvin A. Tung, and Yanyin Zeng. (Carbohydrate polymers 29.1: 11-16, published 1996, hereinafter as “Tang”).
Regarding claim 1-2, and 7-9, Boyer discloses a method for preparing cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel (i.e. double-network bioink) by 3D bioprinting (see e.g. para. 101-117, Examples 1-3), the method comprising: a) preparing a first bioink by dissolving gellan gum with a viscosity enhancer in a solvent (i.e. thickener)(see e.g. para. 101-107, Examples 1-3, fig. 1-5), preferably by heating the solution at a temperature above hydration temperature and by lowering the temperature (see e.g. para. 97, fig. 2-3, fig. 1); b) preparing a second bioink by suspending stem cells in collagen solution, preferably in neutralized type I collagen solution (see e.g. para. 101-107, Example 1, table 1); c) depositing the first bioink on a support media (See e.g. para. 126, table 1, Example 1, fig. 1-4); d) depositing the second bioink into the first bioink (See e.g. para. 59-70, table 1, Example 1-3, claim 14); e) heating the bioprinted product obtained from the deposition of the first and second bioinks of step c) and d)(see e.g. para. 97, 116-118, fig. 2, Example 1-3). Further, Boyer discloses wherein said first bioink comprises between 0.1 and 10% (w/v) of gellan gum (see e.g. para. 107). Further, Boyer discloses wherein said stem cells may be adipose derived stem cells (e.g. mesenchymal stem cells)(see e.g. para. 82, 107, 113)
Boyer does not explicitly discloses achieving collagen fibrillogenesis, the second bioink having less than 0.2 mg/ml of collagen and adding an ionic crosslinking agent, such as MgCl2 solution to cross-link gellan gum.
However, the prior art of Chen discloses using at 1 or 2 mg/ml of collagen in hydrogels. Further, the prior art of Williams discloses amounts of collage from a range of 0.023 to 0.94 mg/ml that were proportional to the rate of fibril formation (see e.g. page 6584-6585).
MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).” Further, MPEP § 2144.05 (II) states, “Generally, differences in time, concentration and/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 reAller, 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 reHoeschele, 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.). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”).
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration of collagen is critical, thus the teaching of about 1 mg/ml of collagen as taught by Chen renders the claimed concentration of collagen as obvious.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of the cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel as taught by Boyer and incorporate the concentration of collagen as being less than 0.2 mg/ml as taught by Chen and Williams because Chen discloses achieving optimal conditions between gellan gum and collagen in hydrogels (see e.g. abstract). Further, the prior art of Williams discloses that it was well known to a person of ordinary skill in the art that collagen fibrillogenesis occurred at concentrations less than 0.2mg/ml (see e.g. abstract, page 6583). Further, Boyer discloses that the method may be used with hydrogels that contain nanofibrils (see e.g. para. 105). Thus, a person of ordinary skill in the art would have optimize the amount of collagen as taught by Chen to achieve fibrillogenesis as taught by Williams in order to optimize the concentration of collagen in cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel (i.e. double-network bioink) for 3D bioprinting as taught by Boyer. Moreover, hydrogels with low concentration of collagen type I were known in the prior art, as discussed above. Furthermore, both Boyer and Chen disclose hydrogel methods with type I collagen (see e.g. para. 107, and abstract, respectively). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
As discussed above, Boyer does not explicitly discloses adding an ionic crosslinking agent, such as MgCl2 solution to cross-link gellan gum.
However, the prior art of Tang discloses adding an ionic crosslinking agent (e.g. divalent cation), such as MgCl2 solution to cross-link gellan gum gels (see e.g. abstract).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of the cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel as taught by Boyer and incorporate the addition of ionic crosslinking agent (i.e. MgCl2 solution) to cross-link gellan gum as taught by Tang because Tang discloses that gellan gels that were cross-linked with divalent cations like MgCl were the strongest gels obtained (see e.g. abstract and page 12). Thus, a person of ordinary skill in the art would add an ionic crosslinking agent to the gellan gum gels in order to obtain the strongest gellan gum gel (as taught by Tang)(see e.g. abstract). A person of ordinary skill in the art would have predictable results with a reasonable expectation of success because both Boyer and Tang disclose methods for obtaining gellan-gum hydrogels (see e.g. abstracts, respectively).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 3-6 are rejected under 35 U.S.C. 103 as being unpatentable over Boyer et al., (US2021/0069964A1, published March 2021, hereinafter as “Boyer”; cited IDS 11/30/2023), Chen, Hong, et al. (ACS Applied Biomaterials 1.5: 1408-1415, published 2018, hereinafter as “Chen”; cited IDS 11/30/2023), Williams, Barbara R., et al. (The Journal of biological chemistry 253.18: 6578-6585, published 1978, hereinafter as “Williams”), and Tang, Juming, Marvin A. Tung, and Yanyin Zeng. (Carbohydrate polymers 29.1: 11-16, published 1996, hereinafter as “Tang”), as applied to claims 1-2 and 7-9 above, and further in view of Carvalho, Antonio Jose Felix, et al. (Carbohydrate Polymers 53.1: 95-99, published 2003, hereinafter as “Carvalho”), Kang, Hyun-Wook, et al. (Nature biotechnology 34.3: 312-319, published 2016, hereinafter as “Kang”), Shahbazi, Mahdiyar, and Henry Jäger. (ACS Applied Biomaterials 4.1: 325-369, published 2020, hereinafter as “Shahbazi”), Lefnaoui, Sonia, and Nadji Moulai-Mostefa. (Colloids and Surfaces A: Physicochemical and Engineering Aspects 458: 117-125, published 2014, hereinafter as “Lefnaoui”), and Ojogbo, et al., (Materials today sustainability 7: 100028, published 2020, hereinafter as “Ojogbo”).
The teachings of Boyer et al., apply here as indicated above.
Regarding claims 3-4 and 6, Boyer discloses one or more bioink comprises a viscosity agent (i.e. thickening agent) that is starch (see e.g. para. 101).
Boyer et al., does not explicitly disclose the wherein said first bioink comprises between 1 and 20% (w/v) of a pregelatinized starch and the wherein said first bioink comprises glycerol between 1 and 30 % (v/v) glycerol.
However, the prior art of Carvalho discloses blends of glycerol-to-starch proportions varying from 20 to 50% (see e.g. page 96). Moreover, the prior art of Kang discloses wherein optimal bioinks comprises 10% (v/v) of glycerol (see e.g. table 1). Additionally, the prior art of Shahbazi discloses using starch as a cost-effective polymer for bioprinting, such as potato starch at 15-20% (see e.g. sec. 3.2.2. starch). Although Shahbazi does not explicitly state “pregelatinized starch”, the prior art of Lefinaoui discloses that pregelatinized starch is an optimal factor for hydrogels (see e.g. abstract).
MPEP § 2144.05 (II) states, “Generally, differences in time, concentration and/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 reAller, 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 reHoeschele, 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.). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (identifying “the need for caution in granting a patent based on the combination of elements found in the prior art.”). Further, the MPEP 2144.05(I) teaches “a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.” Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985).”
In the instant case, neither the specification nor Applicant have provided evidence of that the claimed concentration percentage of pregelatinized starch and glycerol is critical, thus the teaching of Carvalho discloses blends of glycerol-to-starch proportions varying from 20 to 50% as taught by Carvalho (see e.g. page 96), renders the claimed concentration as obvious.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Boyer to incorporate 1 and 20% (w/v) of a pregelatinized starch and 1 and 30 % (v/v) glycerol in the first bioink as taught by Carvalho, Kang, Shahbazi, and Lefinaoui because Kang discloses that the optimal bioink comprises 10% (v/v) of glycerol (see e.g. table 1), and Shahbazi discloses that potato starch is a cost-effective polymer for bioprinting(see e.g. sec. 3.2.2. starch). Additionally, both Boyer and Kang disclose methods involving cell-laden hydrogels (see e.g. abstract and page 312, respectively). Further, Kang discloses that cell-laden hydrogels with 10% glycerol were known for optimal 3D bioprinting tissue constructs (see e.g. table 1, page 313). Additionally, Kang teaches that gelatin and glycerol are important cell carriers for bioprinting because they provide adequate mechanical support, cell-specific cues and negligible cytotoxicity (see e.g. page 317). Moreover, a person of ordinary skill in the arts would have done so because the prior art of Carvalho discloses that blends of glycerol-to-starch proportions varying from 20 to 50% (see e.g. page 96) were known polymer blends (see e.g. abstract, and page 96), and Lefnaoui discloses that optimal hydrogel factors involved pregelatinized starch and glycerol blends (see e.g. abstract and conclusion sections). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success.
Regarding claim 5, as stated supra, Boyer does not explicitly disclose wherein said pregelatinized starch is crosslinked, preferably with sodium trimetaphosphate.
However, the prior art of Ojogbo discloses pregelatinized starch (PGS) (see e.g. pages 5-7) and that PGS is crosslinked with sodium trimetaphosphate (see e.g. pages 8-9, table 6).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the methods of Boyer to incorporate pregelatinized starch crosslinked with sodium trimetaphosphate as taught by Ojogbo because Ojogbo discloses pregelatinized starch (PGS) improves the swelling capacity (see e.g. page 5-6) and that starch when crosslinked with sodium trimetaphosphate enhances the stability, hardness, and adhesiveness of gels (see e.g. pages 8-9). Thus, person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Boyer and Ojogbo disclose methods involving bio-polymer material applications (e.g. hydrogels) with starch (see e.g. para. 101 and abstract, respectively).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Claims 1-9 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 17, 19, 21-25 and 33 of co-pending Application No. 17/594935 in view of Levato et al., (Biofabrication 6.3: 035020, published 2014, hereinafter as “Levato”).
Although the patent and instant claims are not identical, they are not patentably distinct from each other. Although the patent and instant claims are not identical, they are not patentably distinct from each other because claims in both applications are drawn to the same composition. As such the composition of the reference application could be used in the method of the instant application.
The instant claims are directed to a method for preparing cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel by 3D bioprinting, the method comprising: a) preparing a first bioink by dissolving gellan gum with a viscosity enhancer in a solvent, preferably by heating the solution at a temperature above hydration temperature and by lowering the temperature; b) preparing a second bioink by suspending stem cells in collagen solution, preferably in neutralized type I collagen solution; c) depositing the first bioink on a support media; d) depositing the second bioink into the first bioink; e) heating the bioprinted product obtained from the deposition of the first and second bioinks of step c) and d) to achieve collagen fibrillogenesis; and, f) adding an ionic crosslinking agent, preferably MgCl2 solution to cross-link gellan gum to obtain a cell-laden collagen-gellan gum IPN hydrogel (claims 1-9).
The co-pending ‘935 application’s claims are directed to a hydrogel comprising a gellan gum polymer networks and collagen for use in the wound treatment in a subject in need thereof, wherein said hydrogel comprises a full interpenetrating polymer network comprising: a thermally crosslinked collagen, and a ionically crosslinked gellan gum, wherein the hydrogel comprises 0.1% (w/v) to 1% (w/v) gellan gum and greater than 0% (w/v) and less than 0.2%(w/v) of collagen, and wherein the full interpenetrating polymer network is obtained by ionically crosslinking the gellan gum using a divalent cation as ionic cross-linking agent in the presence of the thermally crosslinked collagen and wherein the hydrogel has a storage modulus (G’) of 2000 to 3000 Pa as measured at 1 Hz at 25°C (claims 17, 19, 21-25 and 33).
Both claims are direct to a cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel and adding a solution to cross-link gellan gum to obtain a cell-laden collagen-gellan gum IPN hydrogel.
The co-pending claims do not recite 3D bioprinting.
However, 3D bioprinting would have been obvious in view of the prior art in view of Levato which discloses methods involving 3D bioprinting.
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the ‘935 application to incorporate 3D bioprinting and viscosity enhances as taught by Levato because Levato discloses that bioprinting allows for the deposit of the multiple bioinks to be spatially controlled (see e.g. abstract) which would have improved the cell-laden collagen-gellan gum interpenetrating network (IPN) hydrogel as taught by ‘935 application. A person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both the ‘935 application and Levato disclose methods that combine multiple bioinks (see e.g. abstracts, respectively). Further, Levato discloses that viscosity enhancers are important to incorporate into bioinks solutions because they improve properties of the bioinks when bioprinting a complex structures that has multiple solutions (i.e. bioinks)(see e.g. page 2). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success. Therefore, the instant claims would have been obvious in view of the co-pending claims and the cited prior art. In addition, it would not be possible to use the instant claims without the compositions of the co-pending claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/JOSEPHINE GONZALES/Examiner, Art Unit 1631 /JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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