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 .
Claim Status
Claims 1-11 are pending.
Claims 8-11 are withdrawn.
Claims 1-7 are under examination. Applicant’s amendment has necessitated modification of the existing rejections. Accordingly, this Action is FINAL.
Nucleotide and/or Amino Acid Sequence Disclosures
Applicants’ amendment appears to have fixed the Examiner’s concerns. The application appears compliant.
Withdrawn rejections
Applicants’ amendments and arguments filed 9/14/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 are rejected under 35 U.S.C. 103 as being unpatentable over Ramshaw et al. (US10155793) and Morita et al. (US5116552) and Chuang et al. (Artif Cells Nanomed Biotechnol. 2018; 46(SUP3): S434–S447) and Harden et al. (WO2019046943) and Sarrigiannidis et al. (Materials Today Bio 2021;10:100098; 22 pages) as evidenced by Millipore Sigma ([online] retrieved on 6/10/26 from: https://www.sigmaaldrich.com/US/en/products/chemistry-and-biochemicals/biochemicals/biological-buffers/phosphate-buffer-saline; 1 page).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims:
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Claim interpretation: The term “collagen-like” is a term of the art and not indefinite. Please note that optional steps do not need to be performed. “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure.” See M.P.E.P § 2111.04; see also MPEP §§ 2103(C) and 2173.05(h).
Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a tissue engineering research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from the tissue engineering art including methods and materials for medical applications and scaffolds such as collagen and collagen based materials1 as well as bacterial collagen-like proteins2 and in the form of lyophilized chemically crosslinked sponges3— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1, 3 and 4, Ramshaw et al. teach modified bacterial collagen-like proteins (Abstract; title; claims 1-11), in the form of a sponge (column 11, lines 50-55; column 23, lines 4-6) and produced by a method of:
crosslinking a modified bacterial collagen solution using glutaraldehyde to provide a hydrogel, which reads on claimed steps i) and ii) by providing a solution comprising at least one collagen-like protein and crosslinking the at least one collagen-like protein with at least one cross-linker with an implicit incubation period to obtain a hydrogel;
that is then freeze-dried to form a sponge that is stable at > 37°C (Example 21, column 30, lines 45-57), which reads on lyophilization step iv).
Ramshaw et al. teach that the solutions of collagen are aqueous buffer systems (Examples 17-20). Regarding claim 6, Ramshaw et al. teach washing with phosphate buffered saline (PBS, which has a pH of 7-7.44)(Column 29, lines 5-6). Ramshaw et al. also teach adding additives: “Persons skilled in the art will be aware of certain agents or additives that may be added during the processing of the collagen-like protein which assist in maintaining the thermal stability of the triple-helical collagen-like protein.” (Column 15, lines 44-48).
Regarding claim 2, Ramshaw et al. teach using a 2 fold molar excess of crosslinking agent (Example 14) and a 5 fold excess of crosslinking agent (Example 15), thereby having the functional groups of the at least one collagen-like protein to the functional groups of the at least one cross-linker, which undergo a reaction with each other present in a ratio of 1:0.1 to 1:5. Ramshaw et al. also teach: “by increasing the extent of crosslinking, it is possible to generate hydrogels which have various uses in medical and non-medical applications, as well as cosmetic applications.” (Column 6, lines 50-53).
Regarding claim 6, Ramshaw et al. teach performing the crosslinking reactions at pH values of 6.8 (Example 13), 7.2 (Examples 11-12) and 8.0 (Example 14), thereby rendering obvious pH values to perform any washing away of excess crosslinking reagent.
Regarding claims 1-7, Morita et al. teach methods of crosslinking collagen 0.3 w/v%, which is equivalent to 3 mg/ml, with glutaraldehyde at 4° C for 24 hours, washed to remove excess glutaraldehyde and then rapidly frozen to -80° C or -135° C and dried by vacuum lyophilization (Column 4, lines 8-32). Morita et al. teach sterilization of the sponge (Column 3, lines 60-68). Morita et teach other useful crosslinking agents: “Examples of useful crosslinking agents are various and include conventional ones such as formaldehyde, hexamethylene diisocyanate, glutaraldehyde and the like.” (Column 2, lines 63-66). Morita et al. also teach: “Subsequently the atelocollagen solution is placed into a suit able mold, frozen and dried to give microporous sponge. The freezing and drying may be conducted under conventional conditions. The sponge is frozen at a low temperature of about -20° to about -50° C and vacuum-dried at a temperature of about -30° to about 40° C in a vacuum of about 0.01 to about 0.2 mmHg.” (Column 2, lines 42-50).
Regarding claims 1, 4 and 6, Harden et al. guide the artisan to DMTMM in PBS and EDC/NHS in MES for use as crosslinking agents with collagen like polypeptides (Page 25, lines 13-16; page 29, lines 6-12; page 39, lines 20-28). Harden et al. also teach: “For example, by varying the molar equivalent ratio of a chemical crosslinker such as EDC or DMTMM to the lysine groups the user can tune the physical properties (e.g. tensile strength, modulus) of the crosslinked hydrogel.” (Page 25, lines 13-16). Chuang et al. teach using Dulbecco’s PBS, HEPES and MES in methods of physically crosslinking collagen hydrogels with EDC and NHS (Title; Abstract and Page 4, Self-assemble collagen hydrogel formation and Synthesis and characterization of collagen-phenolic (collagen-Ph) conjugates). The Examiner also notes that Morita et al. teach formaldehyde which has a MW of 30.03 g/ml. In addition, the art of Sarrigiannidis et al. guides the artisan to multi-arm PEG succinimidyl glutarate, glutaraldehyde, carbodiimide/hydroxysuccinimide ester, diisocyanate and transglutaminase for modifying hydrogels (Page 7, figure 3); Page 9 2.1.2. Chemical and enzymatic cross-linking through page 11, left column 2.1.2.7.).
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Ramshaw et al. is that Ramshaw et al. do not expressly teach the concentration of the bacterial collagen like protein is from 2.5 to 100 mg/ml or an incubation with glutaraldehyde crosslinking agent that is performed for 5 minutes to 48 hours and/or at 4 to 37 °C and that the lyophilization is performed at -40 to -60 °C; and/or the obtained hydro gel is cooled to -20 to -80 °C before the lyophilization is performed. However, not only is the concentration of the bacterial collagen like protein readily optimized by the ordinary artisan to obtain the desired sponge, but also the analogous art of Morita et al. teaches a concentration of collagen within the claimed range. From MPEP 2144.05 (II) (A): “[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). Thus, having from 2.5 to 100 mg/ml of the bacterial collagen-like protein in a ratio of 1:0.1 to 1:5 of the crosslinker is merely an optimization of the teachings of the combined references. Ramshaw et al. teach in a photo-crosslinking example, an incubation of at least 1 hour at 37° C (Column 21, lines 15-19) and Morita et al. teach an incubation at 4° C for 24 hours. It is then merely routine optimization to incubate the glutaraldehyde crosslinked example of Ramshaw et al. for 5 minutes to 48 hours and/or at 4-37°C with a reasonable expectation of success. Regarding the lyophilization limitations, Morita et al. provide guidance for the artisan to first freeze the hydrogel before lyophilization to about -20° to about -50° C, and preferably -80°C or lower, and Morita et al. teach lyophilization at a temperature of about -30° to about 40° C. Consequently, it is merely routine optimization of the lyophilization conditions where the lyophilization is performed at -40 to -60 °C; and/or the obtained hydrogel is cooled to -20 to -80 °C before the lyophilization is performed. The result is the same: a collagen-like sponge is obtained. Furthermore, the optional steps of adding an additive, washing the hydrogel and sterilizing are obvious over the combined references.
The difference between the combined references of Ramshaw et al. and Morita et al. is that Ramshaw et al. and Morita et al. do not expressly teach crosslinkers with two succinimidyl groups, DMTMM, transglutaminase, diisocyanate and the combination of EDC and NHS or employing a buffer selected from 2-[ 4-(2-hydroxyethyl)piperazin-l-yl]ethane-l-sulfonic acid buffer (HEPES) and 2-morpholin-4-ylethanesulfonic acid buffer (MES) for washing the hydrogel. However, Harden et al. guide the artisan to DMTMM in PBS and EDC/NHS in MES for use as crosslinking agents with collagen like polypeptides (Page 25, lines 13-16; page 29, lines 6-12; page 39, lines 20-28). Harden et al. also teach: “For example, by varying the molar equivalent ratio of a chemical crosslinker such as EDC or DMTMM to the lysine groups the user can tune the physical properties (e.g. tensile strength, modulus) of the crosslinked hydrogel.” (Page 25, lines 13-16). Chuang et al. teach using Dulbecco’s PBS, HEPES and MES in methods of physically crosslinking collagen hydrogels with EDC and NHS (Title; Abstract and Page 4, Self-assemble collagen hydrogel formation and Synthesis and characterization of collagen-phenolic (collagen-Ph) conjugates). The Examiner also notes that Morita et al. teach formaldehyde which has a MW of 30.03 g/ml. In addition, the art of Sarrigiannidis et al. guides the artisan to multi-arm PEG succinimidyl glutarate, glutaraldehyde, carbodiimide/hydroxysuccinimide ester, diisocyanate and transglutaminase for modifying hydrogels (Page 7, figure 3); Page 9 2.1.2. Chemical and enzymatic cross-linking through page 11, left column 2.1.2.7.). Consequently, it is merely judicious selection of conventional buffering agents such as HEPES and MES at a pH from 5.5 to 8.2 to wash the hydrogel and conventional crosslinking agents such as crosslinkers with two succinimidyl groups, DMTMM, transglutaminase, diisocyanate and the combination of EDC and NHS and formaldehyde by the ordinary artisan to employ in the method of Ramshaw et al., as modified by Morita et al., with a reasonable expectation of success.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicant’s arguments filed on 9/14/26 have been carefully considered but are not persuasive.
Applicant asserts that the “claim limitation of a bacterial collagen-like protein is neither disclosed nor suggested by the collagen from pig tendon of Morita et al.” However, Morita et al. is not relied upon for that limitation but rather Ramshaw et al. teaches modified bacterial collagen-like proteins (Abstract; title; claims 1-11), in the form of a sponge (column 11, lines 50-55; column 23, lines 4-6). It is impermissible to attack references singly when the Examiner relies upon the combined teachings of the references, nor may they attack a reference for not teaching a limitation of the claim when the Examiner has explicitly relied upon another reference as teaching that limitation. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000).
On page 8 of remarks, Applicant contends that: “the reference discloses modification of a collagen-like protein to express specific reactive amino acids such as Cys and Tyr which may be chemically cross-linked with glutaraldehyde. There is no disclosure or suggestion of a cross-linker comprising at least two succinimidyl groups, 4-( 4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methyl-morpholinium chloride, transglutaminase, diisocyanate, and a combination of l-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide.” Respectfully, the Examiner has a different perspective. The reference of Ramshaw et al. is not limited to glutaraldehyde. In fact, Ramshaw et al. teach: “collagen-like proteins could, for example, be crosslinked through formation of disulfide bonds between Cys residues on different molecules, or through cross-linking agent that link one Cys to another…In addition, or alternatively, a wide variety of suitable stabilisation strategies are possible.” (Column 21 lines 40-51). And: “the collagen-like protein material(s) can be stabilised, either by chemical fixation, e.g., glutaraldehyde, or by a physical method e.g., dehydrothermal cross-linking.” (Column 22, lines 54-57). It is clear from this disclosure that glutaraldehyde is just an example (“e.g.” for example) from a list of possible chemical fixation agents to achieve stabilization. In fact, Ramshaw et al. also teach cross-linking with bis-maleimidyl-PEG (Column 4, lines 43-52; column 12, lines 39-40), which is a crosslinking agent with at least 2 functional groups that are able to undergo a reaction with functional groups of at least one bacterial collagen-like protein. The crosslinking agents claimed are conventional crosslinking agents known to the ordinary artisan as taught by the secondary references.
On page 9 of remarks, Applicant asserts that: “there is no suggestion to have used such cross-linkers with the modified bacterial collagen-like protein of Ramshaw et al. which is modified with specific amino acids which are reactive with glutaraldehyde. There is no disclosure or suggestion of in the cited art, of the claimed cross-linkers or their reactivity with a bacterial collagen-like protein to provide cross-linking.” Respectfully, the Examiner has a different perspective. The art of Ramshaw et al. is open to other chemical fixation agents for stabilization other than glutaraldehyde (Column 22, lines 55-57) and, for example, Harden et al. guide the artisan to DMTMM in PBS and EDC/NHS in MES for use as crosslinking agents with collagen like polypeptides. Consequently, it is obvious to employ the claimed crosslinking agents in the method of Ramshaw et al. with a reasonable expectation of success. "The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 417 (2007). Moreover, “Where two known alternatives are interchangeable for a desired function, an express suggestion to substitute one for the other is not needed to render a substitution obvious." In re Fout 675 F.2d 297, 301 (CCPA 1982). In the present case, the crosslinking agents function as crosslinking agents. The secondary references provide conventional crosslinking agent stabilization strategies. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). Especially when Ramshaw et al. teaches that “a wide variety of suitable stabilization strategies are possible.” (Column 21, lines 47-48). Here, the combined references teach and suggest the claimed subject matter and render it obvious to the ordinary artisan. Respectfully, Applicant’s arguments are not persuasive.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after review of all the facts, Applicant’s arguments are not persuasive. The Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts, which is more convincing than the evidence which has been offered in opposition to it.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Y Kwon can be reached at 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613
1 See for example Shekhter et al. (Current Medicinal Chemistry, 2019:26:506-516).
2 See for example Peng et al. (Biomaterials, 2010;31(10):2755-2761).
3 See for example Chattopadhyay et a. (Biopolymers, 2014;101(8):821-833).
4 As evidenced by Millipore Sigma, PBS has a pH from 7-7.4.
Prosecution Insights