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 18 of May 2023, and is a 371 application of PCT/US2021/058313 filed on 5th of November 2021, Applicants claim for priority to a provisional application 63/116,447 filed 11th of November 2020 is acknowledged.
Election/Restrictions
Applicant’s election without traverse of Group I (claims 51-63) drawn to a multicellular spheroid in the reply filed on 18th of December 2025 is acknowledged. Election was made without traverse in the reply filed on 18th of December 2025.
Status of Claims
In the reply on 18th of December 2025, Applicant has filed new claims 71-77.
Claims 51-63 and 71-77 are under examination in this Office Action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 21 of February 2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Applicant is reminded that the listing of references in the specification 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 Objections
The numbering of claims is not in accordance with 37 CFR 1.126 which requires the original numbering of the claims to be preserved throughout the prosecution. When claims are canceled, the remaining claims must not be renumbered. When new claims are presented, they must be numbered consecutively beginning with the number next following the highest numbered claims previously presented (whether entered or not), such as the misnumbered claims 76 and 75 (see page 4).
Claim 75 is objected to because of the following informalities: acronym a-CNCs. Claim 75 recites “a-CNCs”, where “aldehyde-functionalized cellulose nanocrystals” needs to be spelled out for the first recitation of the acronym a-CNCs. Appropriate correction is required.
Specification
The disclosure is objected to because of the following informalities: trademarks and typos.
The use of the term “PrestoBlue”(page 7 and 9), “Dulbecco's Modified Eagle Medium (DMEM), Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12) and/or Minimum Essential Medium (MEM)” (see page 16, 27), “CLARIOstar” (page 33) which is a trade name, or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore, the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, requires the specification to be written in “full, clear, concise, and exact terms.” The specification is replete with terms which are not clear, concise and exact. The specification should be revised carefully in order to comply with 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112. Examples of some unclear, inexact or verbose terms used in the specification are: “the first aqueous culture medium may be conFIG.d to induce contraction of the cell-laden droplets”(see Spec. e.g. pages 5, 15, 17, and 26). For compact prosecution the word will be interpreted as meaning the word “configured”. Appropriate correction is required.
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 63 and 73 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 63, the claim recites “wherein each of the plurality of multicellular spheroids has an average diameter that is within about +/- 1 μm to about +/-10 μm of each other”. Further, claim 51 recites “the core has an average diameter of about 10 μm to about 900 μm”. Therefore, if the diameter of the multicellular spheroids is about 10 μm (i.e. 9 μm) than the plurality of multicellular spheroids cannot have an average diameter of -10 μm of each other, which would read on a plurality of multicellular spheroids having a negative diameter of each other. Therefore, the parameter of “about -10 μm of each other” in the claim has been rendered indefinite because the multicellular spheroid having a diameter of 10 μm would result in a zero or negative diameter.
Claim 74 recites “the multicellular spheroid of claim 60, further comprising a tight cell junction, the tight cell junction forming a skin barrier in the shell.” Claim 60 recites “wherein the core comprises laminin 5 and the shell comprises claudin 1”. Therefore, there is no recitation of “a tight cell junction” in claim 60. Further, it is unclear what “a tight cell junction” is referring to like if it is referring to a structural piece that is a part of the multicellular spheroid or if it is referring to the “tight junction” of claudin 1. Thus, there is insufficient antecedent basis for this limitation in the claim.
Further, where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “tight cell junction” in claim 74 is used by the claim to mean the “tight junction” of claudin 1, while the accepted meaning is “tight junction.” The term is indefinite because the specification does not clearly redefine the term.
Appropriate correction is required.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 51-58, 61, and 71 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bibette et al., (US20150017676 A1, published 2015).
Regarding claim 51, Bibette discloses a multicellular spheroid (see e.g. title abstract, fig. 5, Example 7), comprising: a core comprising a first hydrogel and first skin cells (see e.g. claims 17-21, fig. 5, Example 7), wherein the core has an average diameter of about 10 μm to about 900 μm (e.g. 150 μm)(see e.g. para. 186, 454, page 25, Example 7) and the first skin cells comprise dermis cells (see e.g. fig. 5, Example 7); a shell overlaying the core, the shell comprising second skin cells, wherein the second skin cells comprise epidermis cells (see e.g. claim 21, fig. 5, Example 7); and an epidermal-dermal junction formed at an interface of the core and the shell (see e.g. para. 254, 458, fig. 5, Example 7).
Regarding claim 52, Bibette discloses wherein the epidermis cells in the shell provide a skin barrier (see e.g. para. 458, Example 7).
Regarding claim 53, Bibette discloses wherein the dermis cells comprise one or more of dermal fibroblasts and wherein the epidermis cells comprise keratinocytes or melanocytes (see e.g. Example 5, claim 21).
Regarding claim 54, as stated supra, Bibette discloses wherein the first skin cells comprise human dermal fibroblasts and the second skin cells comprise keratinocytes (see e.g. claims 17-21, fig. 5, Example 7).
Regarding claim 55, Bibette discloses wherein the shell has an average thickness of about 1 μm to about 30 μm (see e.g. page para. 300, 361, fig. 9, 13, Example 5).
Regarding claim 56, Bibette discloses wherein the first skin cells form an aggregate (i.e. spheroids as cell aggregates)(see e.g. para. 403).
Regarding claim 57, Bibette discloses wherein the second skin cells are within a second hydrogel (i.e. gel)(see e.g. para. 77, 123, and 179, page 10-12, Fig. 5, Examples 2, and 5-7).
Regarding claim 58, Bibette discloses wherein the shell is adhered to the core (see e.g. pg. 26, Example 5 and 7).
Regarding claim 61, Bibette discloses a system, comprising: a plurality of microwells on a substrate (i.e. plate)(see e.g. para. 347-348); and a plurality of multicellular spheroids, each in one of the plurality of microwells (see e.g. para. 347-348), wherein the plurality of multicellular spheroids comprises at least one multicellular spheroid comprising: a core comprising a first hydrogel and first skin cells (see e.g. claims 17-21, fig. 5, Example 7), wherein the core has an average diameter of about 10 μm to about 900 μm (see e.g. para. 186, 454, page 25, Example 7) and the first skin cells comprise dermis cells (see e.g. fig. 5, Example 7); a shell overlaying the core, the shell comprising second skin cells, wherein the second skin cells comprise epidermis cells (see e.g. claim 21, fig. 5, Example 7); and an epidermal-dermal junction formed at an interface of the core and the shell (see e.g. para. 254, 458, fig. 5, Example 7)(see e.g. section: I.G. Imaging the Growth of Spheroids in the Long Run and of the Deformation of the Capsules.).
Regarding claim 71, Bibette discloses wherein the multicellular spheroid has a spherical shape, a cylindrical shape (see e.g. Example 5).
Thus, Bibette anticipates the instant claims.
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 59, and 72-73 are rejected under 35 U.S.C. 103 as being unpatentable over Bibette et al., (US20150017676 A1, published 2015), as applied to claims 51-58, 61, and 71 above, and further view of Kim, Eun Mi, et al. (ACS applied materials & interfaces 11.3: 2802-2813, published 2018), Zuo, et al. (Research, published Feb. 2020).
The teachings of Bibette apply here as indicated above.
Regarding claim 59, as stated supra, Bibette discloses multicellular spheroids with keratinocytes, fibroblasts, or melanocytes (see e.g. para. 253). Further, Bibette discloses that confocal microscopy confirmed the formation of spheroids as aggregates (i.e. cell aggregates)(see e.g. para. 403).
Bibette does not explicitly disclose wherein the first skin cells (i.e. fibroblasts) are contracted.
However, the prior art of Kim discloses that fibroblast contraction is a key factor in the fabrication cell spheroids (see e.g. page 2807).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have combined the multicellular spheroid (as taught by Bibette) with contracted fibroblasts as taught by Kim because Kim discloses that contracted fibroblasts are important for uniformly sized spheroids (see e.g. abstract). Further, Kim discloses that a uniformly cell spheroid culture can be an effective approach for providing a microenvironment similar to an in vivo environment (see e.g. abstract). Bibette is directed to obtaining an improved physiological three-dimensional multicellular spheroid models for screening active ingredients (i.e. drugs)(see e.g. col. 22-23). Thus, a person of ordinary skill in the art would have had predictable results with a reasonable expectation of success because both Bibette and Kim are directed to improved multicellular spheroid models, as discussed above. Furthermore, an artisan of ordinary skill in the art of (i.e. multicellular spheroid methods) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 72-73, as stated supra, Bibette discloses multicellular spheroids with keratinocytes, fibroblasts, or melanocytes (see e.g. para. 253).
Bibette does not explicitly teach wherein the second skin cells further comprise hypodermis cells, such as smooth muscle cells.
However, the prior art of Zuo discloses multicellular spheroids wherein the second skin cells further comprise hypodermis cells, such as smooth muscle cells (see e.g. abstract, sec. 2.2 and fig. 4).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the multicellular spheroid (as taught by Bibette) and incorporate the hypodermis cells (as taught by Zuo) because Zuo discloses that multicellular spheroids with endothelial cells (EC) and vascular smooth muscle cells (SMC)(i.e. EC-SMC) provide an improved model for studying wound healing and tissue regeneration (see e.g. page 9-10). Further, Zuo discloses that both EC-SMC spheroids are able to promote angiogenesis compared to a spheroid with just EC or SMC spheroids (see page 11). Thus, a person of ordinary skill in the art would have predictable results with a reasonable expectation of success of incorporating hypodermis cells with multicellular spheroids because both Bibette and Zuo teach methods involving multicellular spheroids, as discussed above. Furthermore, an artisan of ordinary skill in the art of (i.e. spheroid methods) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 60 and 74 are rejected under 35 U.S.C. 103 as being unpatentable over Bibette et al., (US20150017676 A1, published 2015), as applied to claims 51-55, 57-58, 61, and 71 above, and further view of Nishiyama, et al. (Journal of dermatological science 24: S51-S59, published 2000), and Tao, et al. (Scientific Reports 10.1: 6567, April 16, 2020).
The teachings of Bibette apply here as indicated above.
Regarding claim 60, Bibette discloses wherein the core comprises laminin (see e.g. para. 59 and 257).
Bibette does not explicitly state the core comprising laminin-5.
However, the prior art of Nishiyama discloses that laminin-5 is one of the key components of the basement membrane, which is responsible for epidermal-dermal communication (see e.g. abstract).
Accordingly, it would have been obvious for one of ordinary skill in the art to use a type of laminin in the core of the multicellular spheroid as taught by Bibette and choose laminin-5 as taught by Nishiyama because Nishiyama discloses that laminin-5 is important for epidermal-dermal communication of the basement membrane (i.e. extracellular matrix)(see e.g. abstract). Further, Bibette discloses biopolymers (i.e. laminin) are intended to model extracellular biological matrices (see e.g. para. 115). Since Bibette is directed to obtaining an improved physiological three-dimensional multicellular spheroid models for screening active ingredients (i.e. drugs)(see e.g. col. 22-23) it would have been obvious for a person of ordinary skill in the art to substitute laminin-5 as taught by Nishiyama in place of the laminin as taught by Bibette to make an improved multicellular spheroid that models extracellular biological matrices. Thus, one of ordinary skill could have substituted one element for another with predictable results and a reasonable expectation of success, since both laminins are readily available and are deliverable using similar techniques. Furthermore, an artisan of ordinary skill in the art of (i.e. multicellular spheroids) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claim 60 and 74, as stated supra, Bibette discloses wherein the multicellular spheroid core comprises biopolymers, such as laminin (see e.g. para. 59 and 257).
Bibette is silent regarding a tight junction biopolymer, and wherein the tight junction is claudin-1.
However, the prior art Tao discloses extracellular matrix (ECM) components (i.e. biopolymer), such as laminin and Claudin-1, into multicellular spheroids (see e.g. abstract, page 2,6, and 10; fig. 7).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the multicellular spheroid as taught by Bibette and incorporate Claudin-1 as taught by Tao because Tao discloses that the addition of ECM components (i.e. biopolymers) into spheroids provides a high-performance three-dimensional tissue fabricated for increasing the efficiency of drug screening and applications related to regenerative medicine (see e.g. abstract). Tao discloses that tight junction proteins (i.e. Claudin-1) are important for studying extracellular matrices (ECM)(see e.g. page 6). Further, Bibette discloses that additionally biopolymers are needed to accurately model extracellular biological matrices (see e.g. para. 115). Since Bibette is directed to obtaining an improved physiological three-dimensional multicellular spheroid models for screening active ingredients (i.e. drugs)(see e.g. col. 22-23), it would have been obvious for a person of ordinary skill in the art to add additional biopolymers (i.e. claudin-1) in the shell forming a skin barrier in order to provide a more accurate extracellular matrices (ECM) model. A person of ordinary skill in the art would have predictable results with a reasonable expectation of success because both Bibette and Tao disclose method using extracellular matrix (ECM) components (i.e. biopolymers) with multicellular spheroids, as discussed above. Furthermore, an artisan of ordinary skill in the art of (i.e. spheroid methods) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Hence, the claimed invention as a whole was prima facie obvious in the absence of evidence to the contrary.
Claims 62-63 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Bibette et al., (US20150017676 A1, published 2015), as applied to claims 51-58, 61, and 71 above, and further view of Kumacheva and Prince (WO2019010587A1, published 2019, hereinafter as “Kumacheva”).
The teachings of Bibette apply here as indicated above.
Regarding claim 62-63, as stated supra, Bibette discloses a system, comprising: a plurality of microwells on a substrate (i.e. plate)(see e.g. para. 347-348); and a plurality of multicellular spheroids, each in one of the plurality of microwells (see e.g. para. 347-348), Bibette discloses a microfluid platform that consists of an external fluid injection system and a co-extrusion microdevice (see e.g. para. 297, fig. 6, 15). Further, Bibette discloses that the expected that the size of the droplets be closely associated with the diameter (D) of the orifice of the system (see e.g. para. 381).
Bibette does not explicitly disclose a plurality of microwells form an array and are connected with a supplying channel, and the plurality of multicellular spheroids has an average diameter that is within about ±1 μm to about ±10 μm of each other.
However, the prior art of Kumacheva discloses a microfluidic device for multi-cellular spheroids (see e.g. abstract, claim 1). Further, Kumacheva discloses a plurality of microwells forming an array and are connected with a supplying channel (see e.g. page 5, 8, 11, 15, 17-23, 25-26, and 42, Fig. 1-2). Additionally, Kumacheva discloses wherein each of the plurality of multicellular spheroids are uniform, which reads on the claim limitation of having an average diameter that is within about ±1 μm of each other (see e.g. page 8, 26-30, claim 27).
Further, the following is noted from the MPEP: MPEP 2144.05: “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990).” 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 regards to overlapping ranges, MPEP 2144.05(I) states, “In the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”, continuing in regards to ranges are close, “Similarly, 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, 783, 227 USPQ 773, 779 (Fed. Cir. 1985)”.
In the instant case, Kumacheva discloses generating a large array of uniformly-sized multicellular spheroids (i.e. has an average diameter that is within about ±1 μm to about ±10 μm of each other) that can have diameters ranging from at least 40 μm to about 1000 μm under continuous close-to-physiological flow conditions in microfluidic devices (see e.g. pages 4-8, 17, 37, 52, and claim 27).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have combined the multicellular spheroid system as taught by Bibette with a plurality of microwells that form an array of uniformly multicellular spheroids that are connected with a supplying channel as taught by Kumacheva because Kumacheva teaches that uniformed multicellular spheroids are more efficient for drug screenings and therapeutic treatments (see e.g. page 45). Thus, incorporating the plurality of microwells and supply channel as taught by Kumacheva would have led to predictable results with a reasonable expectation of success because both Kumacheva and Bibette teach using microfluidic methods for obtaining multicellular spheroids, as discussed above. Furthermore, an artisan of ordinary skill in the art of (e.g. multicellular spheroid and microfluidics) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Regarding claims 75-77, Bibette discloses where the multicellular spheroids comprise hydrogel (e.g. first or second hydrogel)(i.e. gelled capsules)(see e.g. para. 77, 118, 123, 201, 232, 380, fig. 6, Examples 1 and 6), made of gelatin (see e.g. para. 59, 201, 249-257).
Bibette does not explicitly disclose a hydrogel shell with an amount of aldehyde-functionalized cellulose nanocrystals (a-CNCs) or the amount of gelatin.
However, the prior art of Kumacheva discloses hydrogels( see e.g. page 42-43, 47-49) discloses of aldehyde-functionalized cellulose nanocrystals (i.e. a-CNCs) in an amount of 0.3 wt% to 2 wt% (see e.g. pages 7, 11-14, 30-33, and fig. 5-6, and 14) and gelatin in an amount of in an amount of about 0.6 wt% to about 4 wt %. (see e.g. pages 11-14, fig. 7, 11, 14, and 25-26).
Accordingly, it would have been obvious for a person of ordinary skill in the art to have modified the hydrogel-based multicellular spheroid as taught by Bibette and incorporated a hydrogel comprising aldehyde-functionalized cellulose nanocrystals (a-CNCs) and gelatin as taught by Kumacheva because Kumacheva discloses that a-CNCs derived hydrogels may be used in hydrogel-based multicellular spheroids to more accurately resemble the structure of extracellular matrices (ECM)(see e.g. page 30). Further, a person of ordinary skill in the art would have incorporated the a-CNCs and gelatin hydrogel as taught by Kumacheva because Bibette is directed to obtaining an improved physiological three-dimensional multicellular spheroid models for screening active ingredients (i.e. drugs)(see e.g. col. 22-23). Since both Bibette and Kumacheva teach methods for obtaining multicellular spheroids with hydrogels a person of ordinary skill in the art would have obtained predictable results with a reasonable expectation of success. Moreover, an artisan of ordinary skill in the art of (i.e. multicellular spheroids) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
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 double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 51-63 and 71-77 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-4, 6, and 8-11 of U.S. Patent No. US11466240B2 (Application Number 16/630,965, hereinafter as “the ‘240 patent”), in view of Bibette et al., (US2015/0017676 A1, published 2015), Zuo, et al. (Research, published Feb. 2020), Nishiyama, et al. (Journal of dermatological science 24: S51-S59, published 2000), Tao, et al. (Scientific Reports 10.1: 6567, April 16, 2020), and Kumacheva and Prince (WO2019/010587A1, published 2019, hereinafter as “Kumacheva”).
The instant claims are directed to:
“A multicellular spheroid, comprising: a core comprising a first hydrogel and first skin cells, wherein the core has an average diameter of about 10 μm to about 900 μm and the first skin cells comprise dermis cells; a shell overlaying the core, the shell comprising second skin cells, wherein the second skin cells comprise epidermis cells; and an epidermal-dermal junction formed at an interface of the core and the shell” (see claim 51), and “A system, comprising: a plurality of microwells on a substrate; and a plurality of multicellular spheroids, each in one of the plurality of microwells, wherein the plurality of multicellular spheroids comprise at least one multicellular spheroid, comprising: a core comprising a first hydrogel and first skin cells, wherein the core has an average diameter of about 10 μm to about 900 μm and the first skin cells comprise dermis cells; a shell overlaying the core, the shell comprising second skin cells, wherein the second skin cells comprise epidermis cells; and an epidermal-dermal junction formed at an interface of the core and the shell (see claim 61).
The ‘240 patented claims are directed to:
“A method for producing multicellular aggregates, in a microfluidic device comprising at least one row having at least one microwell, for each row, a supplying channel spanning along a length of the row and each microwell is in flow connection with the supplying channel, the method comprising the steps of: introducing a first wetting agent into the supplying channel and corresponding microwells of at least one row of the microfluidic device; introducing a solution comprising an aqueous suspension of cells and a hydrogel precursor into the supplying channel and corresponding at least one microwell of the at least one row of the microfluidic device to replace the first wetting agent within the supplying channel and the at least one microwell with the solution; introducing a second wetting agent into the supplying channel of the at least one row of the microfluidic device to replace the solution within the supplying channel with the second wetting agent, wherein replacing the solution in the supplying channel with the second wetting agent induces the formation of droplets containing the aqueous suspension of cells and the hydrogel precursor within the at least one microwell of the at least one row of the microfluidic device, wherein the formation of the droplets is confined in the microwell; inducing the gelation of the hydrogel precursor within the droplets to form a hydrogel seeded with the suspension of cells; and introducing a cell culture medium into the supplying channel of the at least one row of the microfluidic device to replace the second wetting agent in the supplying channel, to form multicellular aggregates within the hydrogel” (see claims 1-4, 6, and 8-11).
Although the conflicting claims are not identical, they are not patentably distinct from each other because both claim sets are directed to multicellular spheroids (i.e. aggregates) and a microfluidic system, which are thus considered a species of the present claims, and would be obvious over the present claims if available as prior art.
The ’240 patent does not recite all the details of the multicellular spheroid and/or the system (i.e. hypodermis cell layers, laminin-5, claudin-1, and aldehyde-functionalized cellulose nanocrystals (a-CNCs), and gelatin.
However, all of those limitation were known in the art for producing multicellular spheroids and microfluidic system, see the prior art of: Bibette et al. teaches the multicellular spheroid and laminin (see e.g. para. 77, 123, and 179, page 10-12, Fig. 5, Examples 2, and 5-7), Nishiyama, et al. teaches laminin-5 (see e.g. abstract), Tao, et al. teaches claudin-1 (see e.g. abstract, page 2,6, and 10; fig. 7), and Kumacheva teaches a multicellular spheroid and/or the system (see e.g. page 8, 45 26-30, claim 27) with hydrogels (see e.g. page 42-43, 47-49) comprising aldehyde-functionalized cellulose nanocrystals (a-CNCs), and gelatin (see e.g. pages 11-14, fig. 7, 11, 14, and 25-26).
Providing guidance on instances where the method steps of the prior art and instant claims are the same, Ex parte Marhold, 231 USPQ 904, 905 (Bd. Pat. App. & Int. 1986) relying on In re Sussman, 141 F.2d 267, 269-70, 60 USPQ 538, 540-41 (CCPA 1944) states “[T]hat since the steps are the same, the results must inherently be the same unless they are due to conditions not recited in the claims.”
Accordingly, it would have been obvious for a person of ordinary skill in the art to have used the multicellular spheroid system (as taught by the ‘240 patent) and modify it with the modifications of the hydrogel as taught by Kumacheva, the hypodermis cells as taught by Bibette et al., laminin-5 as taught by Nishiyama, and claudin-1 as taught by Tao, et al. for the benefit of optimizing multicellular spheroids that are particularly useful drug screenings and useful for drug efficacy of therapeutic treatments, such as anticancer drugs (see e.g. page 45 of Kumacheva). One could have been motivated to do so with a reasonable expectation of success because the cited prior art teaches benefits of making those medication. Furthermore, an artisan of ordinary skill in the art of (e.g. multicellular spheroid and microfluidics) has good reason to pursue the known options within his or her technical grasp (KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (US 2007).
Therefore, all the limitation of the instant claims would have been obvious in view of the patented ’240 claims and Bibette et al., Nishiyama, et al., Tao, et al., and Kumacheva.
Conclusion
No claim is allowed.
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/JOSEPHINE GONZALES/Examiner, Art Unit 1631
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631