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 .
Claim Status
Claims1-14 are pending.
Claims 3-4,8,9,10-11, and 14 are amended.
Claims 15-18 are new.
Claims 1-18 are under examination.
Withdrawn Rejections
Rejections – under 35 USC § 112
The rejections of claims 3-4, and 8-11 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of claims amendment.
The rejection of claim 14 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of claims amendment.
Edited rejections necessitated by claims amendment
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-18 are rejected under 35 U.S.C. 103 as being unpatentable over Mooney et al (WO 98/12228), in view of Enobakhare ( Journal of Applied Biomaterials and Biomechanics, 2006), Kong et al (Biomacromolecules, 2004), and Yu et al ( Biomaterials, 2009), as evidenced by ThermoFisher product sheet ( Medium 200, ThermoFisher, 2025).
Regarding claims 1, 3, 15 and 17 , Mooney et al disclose a method of producing a modified alginate polymer. The method involves the covalent bonding of biologically active molecule for cell adhesion, such as RGD, to the alginate molecule. According to Mooney et al “The modification of the crosslinked alginates with the biologically active molecules can provide a further three-dimensional environment which is particularly advantageous for cell adhesion, thus making such alginates useful as cell transplantation matrices”. (See page 2, lines 12-30, example 1, and claims 1-8). Furthermore, Mooney et al disclose “ that the distribution of M and G units (i.e. M/G ratio) provides a controllability feature of the invention, with a higher ratio of G units generally providing a stiffer alginate material which will hold its shape better”. According to Mooney et al “an alginate chain having a percentage of G units based on the total of M and G units from 10 to 100% is particularly preferred”. Converting the percentage to ratio reveals that Mooney et al suggest using Alginate with G/M of 0.1-1, which corresponds to an M/G ratio of 0-0.9, when a stiffer hydrogel is desired. (See page 11, lines 9-12). Mooney et al further suggest utilizing an alginate or a modified alginate with a low molecular weight, possibly less than 50,000 Kda, when the hydrogel is desired to provide a temporary matrix. (See page 31, lines 23-30, and claims 23,25). Mooney et al disclose that a polymeric backbone with a low molecular weight can be cleared through the kidneys and by other normal metabolic routes, and suggest to use it in application where its removal by kidney is desired.(See page 8, lines 7-9, and page 11 lines 4-8). Taken together, Mooney et al suggest that the molecular weight and the M/G ratio of alginate can be adjusted to meet the requirements for a certain application.
Enobakhare et al also demonstrate that the concentration and M/G ratio influence the physiochemical and mechanical properties of alginate constructs. Enobakhare et al utilized four types of alginates with either a high or low molecular weight and an M/G ratio of 1.5 or 0.6. (See table 1, page 88). Enobakhare et al. show that the uptake/diffusion of the large molecules into high guluronic acid (i.e. high G) content gels appears to be significantly more efficient than in the low guluronic acid content gels (i.e. low G). ( See Fig.4). Enobakhare et al explain that such an event occurs when the Alginate hydrogel has a higher G content than M, resulting in a gel with a large pore size; however, increasing the M content and hence the M/G ratio leads to a decrease in network size and reduce diffusion of solute. ( See Discussion, page 94, 1st column).
Kong et al disclose that the molecular weight (MW) and chemical structure of alginate can be modified via γ-irradiation and oxidation reaction. Kong et al demonstrate that decreasing alginate MW upon irradiation and oxidation significantly reduces the viscosity of pre-gelled solutions, due to the weaker physical interactions between the smaller polymers. Kong et al show that oxidized low MW alginate has a degradation rate constant that is 3 times higher than that of the high MW alginate.(See Fig.2). Kong et al. suggest that “one can readily modulate the degradation rate of the gels by mixing oxidized low and high MW MVGs at different weight fractions”.
Taken together, it would have been prima facie obvious to one with ordinary skill in the art at the time the invention was filed to combine the teachings of Mooney, Enobakhare, and Kong’s to optimize an alginate with a specific molecular weight and M/G ratio, and conjugate it with one or more cell-adhesion peptides. Mooney et al teach a method for producing alginate conjugated with cell-adhesion peptide and suggest that the molecular weight and the M/G ratio of alginate can be adjusted to meet the requirements for a certain application. Enobakhare and Kong demonstrate that the selected molecular weight and the M/G ratio influence the physiochemical and mechanical properties of alginate construct, and provide motivation and expectation of success for optimizing the two parameters to fulfill the desired application. Thus one would have been motivated to utilize an alginate with low molecular weight and an M/G ration of 0.8 to 1.5 and conjugate it with a cell-adhesion molecules, as per the teachings of Mooney. There is a reasonable expectation of success in doing so because using a low molecular weight of alginate allows for increased biodegradability, which may be beneficial for removal through metabolic functions e.g. the kidneys. Furthermore, utilizing an alginate with a specified M/G ratio would provide a tool to adjust the stiffness, gelation rate, and the pore size within the hydrogel, serving the required purpose. Some Teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention. See MPEP 2143 (I)(G).
Mooney et al do not disclose the use of the modified alginate in cultured meat application. However, this is considered to be an intended use and not an actual limitation of the
claimed invention. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim, and the disclosure of use of the prior art product in said intended use is not necessary. See MPEP 2144.07. In the instant case, the modified hydrogel must be suitable for tissue engineering/cell culturing.
Regarding claim 2, Mooney et al state that “Particularly preferred as the cell adhesion molecule bonded to the alginate chain are synthetic peptides containing the amino acid sequence arginine-glycine-aspartic acid (RGD) which is known as a cell attachment ligand and found in various natural extracellular matrix molecules. Further of interest is GREDVY (endothelial cell specific) peptide”. It should be noted that the usage of synthetic peptides implies that the cell adhesion molecules are not animal-derived (i.e. they are animal-free).
Regarding claims 4, 16 and 18, Mooney et al disclose that the modified alginate can be gelled (i.e. crosslinked) in the presence of divalent metal cations such as ca++ or Ba++ in aqueous systems. ( See page 6, lines 14-18).
Regarding claims 7-8, and 12, Mooney et al disclose a variety of cell attachment peptides that can be used to generate a modified alginate, as recited in table 1 ( See page 26-Table 1). According to Mooney et al, the modified alginate may comprises combinations of cell adhesion peptides with differing cell adhesion ligands. ( See page 29, lines 8-12).
Regarding claims 5-6, and 11, Mooney et al teach that the modified alginate can be modified with cell adhesion active molecules using amide chemistry. Mooney et al, also teach that alginate can be gelled (i.e. crosslinked) in the presence of divalent metal cations such as ca++. However, Mooney et al do not disclose the specific concentration of the cation required for the crosslinking and culturing steps.
Yu et al demonstrate that culturing the human umbilical vein endothelial cell (HUVEC) on commercially RGD conjugated alginate improves cells proliferation and adhesion when
compared to the non-modified alginate group.(See abstract). The method of Yu et al involves preparing the peptide-modified alginate solutions by mixing high-density peptide-alginate complex to pure alginate in a ratio of 1:4. For hydrogel formation, Yu et al teach the use of 102 mM CaCl2 to allow solidification. This reads on claim 5. Yu et al disclose that after complete gelation, the CaCl2 solution was removed by washing with PBS for 3 times, and the cells ( i.e. HUVEC) were then cultured on alginate with medium and incubated in humanified 37C environment. ( See Material and Methods, sections 2.1 and 2.2, page 752).
Yu et al do not disclose the cation concentration in the culturing media. However, the range recited in claim 6 (e.g. 0-50 mM) allows for culturing cells in the absence of cation (e.g. 0 mM). Furthermore, Yu et al disclose culturing HUVEC on alginate with the addition of a culturing medium, but do not specify the type of the culturing media. However, it is well known in the art that cell culturing medium contains inorganic salts, including CaCl2, at the appropriate concentration for the cell type. For example, the M200 medium, which is one of the recommended mediums for HUVEC, contains CaCl2, as evidenced by the Thermofisher product sheet, but the actual concentration is not disclosed. Because the cation is involved in the crosslinking step, their constant supply or absence is also an optimizable step. It is well recognized that it is prima facie obvious for one of ordinary skill in the art to use routine experimentation to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05.
Regrading claims 9-10, and 13, following the discussion of claim 1, Mooney et al also disclose a method of producing a modified alginate, particularly by the utilization of carbodiimide chemical reaction. (See examples 1-2).
Regarding claim 14, following the discussion above, Mooney et al do not explicitly state that the modified alginate is sacrificial. However, Mooney et al in view of Enobakhare and Kong render obvious the method of making the modified alginate of claim 1. Therefore, the combined teachings of Mooney, Enobakhare, and Kong render obvious a modified alginate that is sacrificial.
Response to Arguments
Applicant's arguments filed 08/20/2025 have been fully considered but they are not
persuasive.
Applicants argue that the primary reference used in the rejection i.e. Mooney et al
relates to a different chemistry than the hydrogels of the presently claimed invention. As such, the alginates in Mooney are used as sidechains for various polymeric backbones. ( See Applicant’s remarks on page 6).
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because Applicants appear to be focusing on one of the embodiments recited in Mooney’s disclosure. While the office agrees that one of embodiments in Mooney et al teach the making of a hydrogel composed of two different polymers, for example, wherein the modified hydrogel is generated with a backbone derived from one polymer and the side chain from another ; however, the disclosure of Mooney et al also demonstrate the generation of an RGD- and GRGDY-modified hydrogel wherein the backbone of the modified hydrogel is alginate itself. ( See examples 1-2 on pages 33-35, and page 14 lines 2-4).
Applicants also argue that none of the aforementioned references teach a meaningful preference for the M/G ratio in combination with the molecular weight ranges of the instant claim 1. In particular, Applicants argue that Mooney et al teach an alginate with an M/G ratio and a molecular weight that is outside the recited ranges of claim 1. Applicants also assert that ,while Enobakhare teaches an alginate with M/G ratio of 1.5 and 0.6, their respective molecular weights fall outside the presently claimed range of 10 to 50 Kda. Applicants further argue that, even though Kong’s et al demonstrate the effect of modifying the molecular weight of an alginate on the degradation rate of said alginate, an ordinary skill in the art in reading Mooney, Enobakhare, and Kong would not have the motivation to optimize these parameters to arrive at a modified hydrogel comprising the alginate of claim 1. ( See Applicant’s remarks on pages 6-7).
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). In this case, Mooney et al clearly suggest that the molecular weight and the M/G ratio of alginate can be adjusted to meet specific application. Enobakhare et al, demonstrate that the diffusion of molecules into and out of an alginate hydrogel can be controlled by adjusting the M/G ratio, which controls the pore size within the hydrogel. Similarly, Kong et al also show that the degradability of an alginate hydrogel can be controlled by adjusting the molecular weight of the alginate. Clearly, the combined teachings of Mooney, Enobakhare, and Kong suggest that the M/G ratio and the molecular weight are optimizable parameters, and that an ordinary skill in the art can use routine experimentation to discover an optimum value of a result effective variable.
As per the MPEP “ "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272,276,205 USPQ 215, 218-219 (C.C.P.A. 1980). See MPEP 2144.05.
Applicants further argue unexpected results. In particular, Applicants submit that the M/G ratio and molecular weight ranges of the instant claim 1 are not arbitrary, but rather provide unexpectedly improved properties, as shown in Figure 6, that could not have been predicted from the teachings of the art of record.
Examiner’s Response to Traversal: Applicant’s arguments have been carefully considered but are not found persuasive. This is because, the office disagrees that Fig. 6 provides evidence of unexpected results . This is because, based on the error bars in the left-hand bar graph in Fig.6, the difference between L3 and L3G appears to be negligible. Furthermore, the lines for L3 and L3G nearly overlap in the right-hand graph of Fig.6, indicating that there is no significant differences in the swelling percentage between L3 and LG3.
Conclusion
No claim is 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 FATIMAH KHALAF MATALKAH whose telephone number is (703)756-5652. The examiner can normally be reached Monday-Friday,7:30 am-4:30 pm EST.
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/FATIMAH KHALAF MATALKAH/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638