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 Interpretation
The term organoid as used in claim 1 is defined in the Specification as supplied by the Applicant as “a three-dimensional structure composed of various cells of a specific human organ and tissue and can implement complicated interactions among them”. (0002) Applicant further narrows the definition of “organoid” in paragraphs 0093-0094 by defining it as “an ultraminiature body organ prepared in the form of an artificial organ by culturing cells derived from tissues or pluripotent stem cells in a 3D form” and “a three-dimensional tissue analog that contains organ-specific cells which originate from stem cells and self-organize”
Therefore, any instance of three-dimensional culture that demonstrates self-organization or differentiation will satisfy the definition of “organoid” as supplied by the Applicant.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 2 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Christman et al. (US 2012/0264190 A1).
Regarding claims 1 and 3: Christman discloses a decellularized and delipidized extracellular matrix derived from adipose or loose connective tissue. (0009) Christman further teaches that the AEM scaffold of the claimed invention is well-suited for cell transplantation in the adipose or loose connective tissue as it better approximates the in vivo environment as opposed to currently available materials. (0058) This reads on claim 1 regarding a scaffold suitable for transplantation made of adipose extracellular matrix. In addition to this, Christman discloses various compositions for the ACM to be present in the scaffold, including 1-100 mg/mL, 2-8 mg/mL, and specifically, 10 mg/mL. (0044)
Christman further teaches that the present invention is designed for the migration and infiltration of native cell types (0110) and that the AEM may be adjusted to the desired concentration. (0043) As such, the intended use of the invention taught by Christman is that of any of the cell types mentioned in claim 1. It would be within the scope of routine optimization for a person skilled in the art to determine the ideal concentration for the intended organoid type, and furthermore each range presented in claim 1 is within the range as taught by Christman of 2-8 mg/mL.
Regarding claim 2: As claim 2 refers to a product-by-process which is not limited to the manipulation of the recited steps and only by the structure implied by the steps (see MPEP 2113.1), Christman teaching use of a scaffold made from ACM (0009) further satisfies claim 2, as the process involved in the manufacture of the scaffold, be it decellularization via Triton X-100 alone or in conjunction with ammonium hydroxide, does not change the end result product of a decellularized ACM scaffold.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 kU.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.
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 4-8 are rejected under 35 U.S.C. 103 as being unpatentable over Uriel et al. (The role of adipose protein derived hydrogels in adipogenesis, 2008) in view of Gilpin et al. (Decellularization Strategies for Regenerative Medicine: From Processing Techniques to Applications, 2017), Christman et al. (US 2012/0264190 A1), and Badylak et al. (US 9,814,744 B2).
Regarding claim 1: Uriel teaches use of biomaterials used in hydrogels which induce adipogenesis both in vitro and in vivo with use of adipose-derived hydrogels. (Pg 3712, Abstract) Specifically, subcutaneous fat was isolated from rats and subjected to an enzymatic digestion and mechanical breakdown by mortar and pestle. The mixture was centrifuged repeatedly and the extracts were texted via Western blot to contain adipose-derived basement membrane (BM) proteins. Kinetic readings were also taken to judge the ability of the extracts to form gels. (Pg 3713, Materials and Methods). The adipose-derived hydrogels were determined to contain collagen IV, fibronectin, laminin, and nidogen (BM proteins) and were able to gel either via incubation or by reduction of pH. (Pg 3714, Results)
Uriel demonstrates differentiation of preadipocytes on the adipose-derived matrices which aggregated into large colonies which were not seen when the same process was carried out with commercially-available Matrigel. When used in vivo, adipose-derived matrices demonstrated large areas of growth of adipose tissue and after 6 weeks, blood vessel formation appeared within the areas of fat tissue forming on the matrices. (Pg 3714, Results) As this demonstrates both the differentiation and organization of three dimensional tissue aggregates within the hydrogel, this satisfies the requirements of claim 1 of a scaffold for culture and transplantation of an organoid using an adipose extracellular matrix. Uriel fails to disclose use of a solution comprising both Triton X-100 and ammonium hydroxide, define a concentration for AEM in the scaffold, lyophilization of the tissue, or use of pepsin to adjust the pH of the scaffold.
Regarding claim 2: Gilpin teaches a need for decellularized scaffolds for the generation of organoids and tissues due to an epidemic of patients on waiting lists for organ transplants. (Pg 1, Introduction) Gilpin further teaches a variety of differentiation strategies, including use of Triton X-100 alone in comparison to its use in conjunction with ammonium hydroxide. When used together, Triton X-100 and ammonium hydroxide completely removed all DNA and maintained a greater amount of collagen I when compared to other decellularization treatments. (Pg 4, Decellularization Strategies)
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the decellularization strategy as taught by Gilpin with the AEM scaffold generation as taught by Uriel to create a decellularized scaffold. One would have been motivated and had a reasonable expectation of success at doing so based on the teachings of Gilpin, who demonstrate more complete decellularization when using Triton X-100 and ammonium hydroxide in combination.
Regarding claim 3: Christman teaches compositions comprising decellularized and delipidized extracellular matrix derived from adipose or connective tissue. (57) Christman further teaches a method of preparation of taking adipose tissue, either freeze-drying or lyophilizing it, and milling it to form a powder. (0042) it is then mixed with a gel to form a hydrogel in various concentrations including 10 mg/mL. (0044) The formation of the hydrogel in the recommended concentrations allows for the hydrogel to be injected through a needle into a subject. (0044) This reads on the claimed concentration range of claim 3 of 1-10 mg/mL of AEM in the scaffold.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the concentration of 10 mg/mL as taught by Christman for the concentration of AEM in the scaffold with the teachings of Uriel to create a hydrogel with 10 mg/mL AEM. One would have been motivated to do so and had a reasonable expectation of success due to the teachings of Christman, who state that use of the hydrogel at the given concentrations allows for the hydrogel to be injectable.
Regarding claims 4-6: Badylak teaches methods of making a cell growth scaffold from adipose tissue. (57) Importantly, Badylak differs from Christman in the way that Badylak specifies to crush, pulverize, roll, chop, etc the tissue prior to treatment with a protease or decellularization steps. The reason for this is that it allows the tissue to be broken up, therefore allowing the cells within the tissue to be processed more efficiently in later steps and it also allows for the lysing of cells prior to the decellularization step. Furthermore, it allows larger pieces of tissue to be broken up and sinew to be removed prior to processing. (Col 6, ln 21-37) Due to this teaching, a person skilled in the art would be motivated to perform the crushing step prior to any further processing of the adipose tissue; therefore this reads on step 1 of claim 4. Badylak fails to teach use of both Triton X-100 and ammonium hydroxide for decellularization.
As discussed above, Gilpin teaches decellularization strategies. In particular, when used together, Triton X-100 and ammonium hydroxide completely removed all DNA and maintained a greater amount of collagen I when compared to other decellularization treatments. (Pg 4, Decellularization Strategies) This reads on step 2 of the method of claim 4 of using both Triton X-100 and ammonium hydroxide for decellularization in the preparation of an AEM.
Following the steps of crushing and decellularization as taught by Badylak and Gilpin respectively, Badylak further teaches an example of the invention in which the AEM is subjected to lyophilization after being digested and decellularized. (Pg 21, Example 1, Method B) Christman also teaches a method of processing the tissue that involves, in order, decellularization and delipidization of the adipose tissue prior to lyophilization. (0092) This reads on the method of claim 5 of lyophilizing the decellularized AEM after the method of claim 4. Christman further teaches that it is necessary to decellularize and delipidize the adipose tissue prior to lyophilization due to residual lipids in the tissue preventing complete lyophilization and efficient solubilization. (0092) Therefore, one skilled in the art would be motivated to perform the lyophilization step after decellularization and crushing of the tissue, as is required by the method of claims 4 and 5.
Christman further teaches that after lyophilization, the matrix can be solubilized at a low pH and (in some embodiments) digested with pepsin prior to rehydrating the ECM in an aqueous solution prior to injection or implantation. (0042) As discussed above, Uriel also teaches implantation in vivo and use of the AEM scaffolds in a culture setting. (Pg 3714, Results) This reads on the method of claim 6 of the formation of a scaffold for culture and transplantation of an organoid in the form of a hydrogel with the lyophilized AEM. Christman further teaches that the present invention is designed for the migration and infiltration of native cell types (0110) and that the AEM may be adjusted to the desired concentration. (0043) As such, the intended use of the invention taught by Christman is that of any of the cell types mentioned in claim 1. It would be within the scope of routine optimization for a person skilled in the art to determine the ideal concentration for the intended organoid type, and furthermore each range presented in claim 1 is within the range as taught by Christman of 2-8 mg/mL.
It would have been obvious to a person of ordinary skill in the art to, in order, pulverize the tissue prior to decellularization prior to lyophilization prior to forming a scaffold by combining the teachings of Badylak, Christman, Gilpin, and Uriel. One would have been motivated and had a reasonable expectation of success at doing so based on the following, in order:
Badylak teaches that pulverization or crushing of tissue prior to further processing allows for bigger tissue pieces to be broken up, sinew removed, and more efficient processing. (Col 6, ln 21-37)
Decellularization with both Triton X-100 and ammonium hydroxide resulted in the complete removal of DNA and preservation of collagen I within the ECM, as taught by Gilpin (Pg 4, Decellularization Strategies)
Christman teaches that it is necessary to decellularize the tissue prior to lyophilization to remove residual lipids and prevent incomplete lyophilization (0092) and that the invention is intended to be used for native cell types to infiltrate. In addition, the invention is designed to be adjustable regarding AEM concentration, as discussed above.
Uriel teaches implantation in vivo and in vitro culture using the AEM hydrogel, demonstrating differentiation of preadipocytes in vitro and formation of organized vasculature and fat tissue in vivo (Pg 3714, Results)
Regarding claim 7: Christman teaches digestion of the decellularized AEM with pepsin at a low pH. (0018) Christman further teaches an example of the invention where adipose matrix that had been dried and milled was further processed with pepsin to digest the matrix and then the pH was raised. This process allowed for the gelling of the hydrogel when warmed to 37°C. (0080) This reads on the claimed method of dissolving the AEM in a pepsin solution and then adjusting the pH of the solution to form the hydrogel.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the use of pepsin and pH adjustment as taught by Christman with the adipose derived scaffold as taught by Uriel to generate a liquid solution that can be gelled to form the hydrogel. One would have been motivated and had a reasonable expectation of success based on the teachings of Christman, who detail a process of dissolving of the AEM with pepsin and raising the pH to induce gelling when subjected to heat.
Regarding claims 8 and 9: Christman teaches that the disclosed invention, after processing via decellularization, delipidization, solubilization, and gelation may be suitable for an in situ scaffold for cellular transplantation. The construct may also be shaped or gelled ex vivo, and since an adipose-derived ECM mimics the natural adipose or loose connective tissue environment, it improves cell survival and retention at the scaffold site, thereby encouraging loose connective tissue and/or adipose regeneration. (0038) Furthermore, Uriel teaches use of the adipose derived scaffolds to culture preadipocytes which differentiated into adipocytes and formed large colonies within the AEM (Pg 3714, Results), thus reading on the method of claim 8 of culturing an organoid in the scaffold of claim 1 and an organoid in the scaffold made by the method of claim 4, reading on claim 9.
Response to Arguments
Applicant's arguments filed 02/18/2026 have been fully considered but they are not persuasive. Applicant argues regarding both the 35 U.S.C. 102(a)(1) and 35 U.S.C. 103 rejections that claims 1 and 4 as amended lists specific parameters for each organoid type that the AEM is intended for. In response to applicant's argument that the broad range recited in Christman regarding the matrix concentration fails to satisfy the newly amended ranges as presented by the Applicant, 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. Christman states that the present invention is designed for the migration and infiltration of native cell types (0110) and that the AEM may be adjusted to the desired concentration. (0043) While Examiner acknowledges and appreciates that Applicant has devoted years of trial and error regarding developing optimal concentrations for the invention based on each organoid type (as referenced in the Mode for Carrying Out the Invention section of the Specification), it would also be routine optimization for one skilled in the art to determine the optimal concentration of AEM to use for the respective tissue or organoid being studied.
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.")
Conclusion
THIS ACTION IS MADE FINAL. 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 HANNA M THUESON whose telephone number is (571) 272-3680. The examiner can normally be reached M-F 7:30-5 EST. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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/HANNA MARIE THUESON/ Examiner, Art Unit 1638
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633
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