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
Claims 1-20 are pending following the Reply filed 01/28/2026. Claims 21-30 are cancelled. Claims 18-20 are withdrawn. Claims 1-17 are presently considered.
Election/Restrictions
Applicant's election with traverse of Group I, claims 1-17, in the reply filed on 01/28/2026 is acknowledged.
The traversal is on the ground(s) that the “presently claimed assay is directed to a dedicated microfluidic potency platform in which the encapsulated cells are analyzed specifically to generate a potency readout suitable for cell-therapy product characterization, whereas Williams is a research-focused tissue-on-a-chip study that explores immunomodulatory biology and feasibility rather than defining a potency assay framework for manufacturing”.
This is not found persuasive because: the Williams reference (cited in the IDS filed 10/30/2023 at Cite No. 2) used in the restriction requirement (lack of unity of invention) anticipates the product claims of Applicant’s invention (see Claim Rejections – 35 U.S.C. 102), including the technical features of claim 1 (i.e., a microfluidic potency assay), which are the only technical feature required by both groups. This technical feature does not make a contribution over the prior art, because Williams teaches an assay platform comprising the same recited structure as claim 1. Therefore, the claimed inventions still lack unity of invention a posteriori. Furthermore, the intended uses argued by Applicant (i.e., “to generate a potency readout” or “for manufacturing”) are not recited by the claims, nor do they alter the structure of the claimed product.
The requirement is still deemed proper and is therefore made FINAL.
Claims 18-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 01/28/2026.
Priority
The present application claims status as a 371 (National Stage) of PCT/US2022/027056 filed on 04/29/2022. Applicant’s claim for benefit under 35 U.S.C. 119 (e) of Provisional application No. 63/182,075 filed on 04/30/2021 is acknowledged. The present application and all claims are being examined with the earliest effective filing date of 04/30/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed 10/30/2023, 03/13/2024, and 05/07/2025 have been considered by the examiner.
Claim Objections
Claim 14 is objected to because of the following informalities: for clarity, please amend “system comprised of” in line 2 to “system is comprised of”. Appropriate correction is required.
Claim Interpretation
Claim 1 recites a “microfluidic potency assay comprising living cells, wherein the cells are encapsulated in a synthetic hydrogel, and further wherein the hydrogel is incorporated into a closed system which is perfused with liquid media and/or disease-relevant chemical stimuli”. While an “assay” can be interpreted to refer to a process (e.g., method of testing), the assay of claim 1 is interpreted to be directed to a product. While the claim uses active language, e.g., “encapsulated”, “perfused”, and “incorporated”, these limitations can also be interpreted as defining the structure of the product (i.e., they describe how the elements are disposed within the composition with respect to one another). Further, the method claims (i.e., claims 18-20, presently withdrawn) are clearly directed to a method, requiring a first step of “providing” the structure of claim 1, and the instant specification (see pg. 17, “Compositions and Methods”) appears to distinguish the “assay” composition from methods of using said assay. Therefore, claims 1-17 are directed to a composition of matter (product).
Claim 15 recites, “A platform comprising the assay of claim 1.” In view of the instant specification, there is no special definition for the term “platform”. In view of the prior art, an “assay platform” is defined as the technology used to measure response or output (see Devanarayan et al., cited on Form 892, at pg. 4, lines 3-4). Hence, “a platform” merely refers to the technological basis (i.e., methodology) used in the design of the assay. In view of Williams, et al. (previously cited), these terms (assay, platform) can be used interchangeably. For example, in one section of the disclosure, Williams discusses microfluidic platforms and refers back to these elements as “such assays” (see pg. 3, para. 1). Therefore, with respect to the prior art, there is no patentable distinction between a composition referred to as “an assay” and a composition referred to as “a platform” when each composition comprises the same structure. Hence, the “platform” of claim 15 is interpreted to be the same composition as the “assay” of claim 1.
Because claims 16 and 17 depend from claim 15 and recite functional limitations (i.e., wherein the platform is “high-throughput” or “scalable”) without reciting any additional structure, rejections under 112(a), written description, were contemplated. However, in view of the prior art of record, these functional limitations appear to be largely satisfied by the structure recited in claim 1. Specifically, “scalable” tissue-on-a-chip microfluidic platforms are known in the art (see Williams at pg. 3, para. 1), and the type of platform described by Williams enables higher throughput potency analysis as well as scalability (see pg. 8, para. 2). In view of the specification, the claimed invention appears to achieve these functions in the same manner, using an on-chip, high-throughput system as a basis for the platform (see specification at pg. 30, para. 2). Furthermore, Low, et al. (cited in the IDS filed 03/13/2024) teach there are a wide diversity of platform designs for microfluidic potency assays (see Fig. 1) and discusses the increasing scalability and higher-throughput of these designs in the art (see pg. 12, para. 3). Hence, a person of skill would have been able to envisage which prior art structures correspond to these functional limitations. For at least these reasons, the written description requirement is considered to have been met regarding these claims. Note that these conclusions are dependent on the interpretation of the claims in their present form and may be reevaluated in response to amendment.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 15 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 15 recites, “A platform comprising the assay of claim 1.” As discussed under Claim Interpretation, there is no patentable distinction between a composition referred to as “an assay” and a composition referred to as “a platform” when each composition comprises the same structure. Thus, the claim does not recite or reasonably imply any further limitation to the product of claim 1, and therefore fails to further limit the subject matter of claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
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(s) 1-17 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Williams, et al. (cited in the IDS filed 10/30/2023 at Cite No. 2). “Enabling Mesenchymal Stromal Cell Immunomodulatory Analysis using Scalable Platforms”. Integr Biol (Camb). Pubmed. 01 April 2019; 11(4): 154-162. Hereafter, “Williams”.
Regarding claim 1, Williams discloses a microfluidic platform for analyzing the response of human mesenchymal stromal cells (hMSCs) to factors such as inflammatory stimuli for potential use in potency analyses (see Abstract). Williams teaches the hMSCs are encapsulated in synthetic polyethylene glycol (PEG)-based hydrogels (see pg. 3, para. 1; pg. 5, para. 3).
Regarding the limitation, “living cells”, Williams discloses the hMSCs were screened for colony forming units, cell growth, and differentiation into fat and bone using standard assays (see pg. 3, para. 3). Hence, Williams teaches the cells were capable of growth and differentiation, which requires them to be living cells, which meets the limitation.
Regarding the limitation, “wherein the hydrogel is incorporated into a closed system”, Williams discloses that a hole was punched through polydimethylsiloxane (PDMS), generating a channel through which inflammatory stimuli could be perfused, and the hole was then filled with PEG-4MAL hydrogel containing hMSCs and enclosed via plasma-bonded glass coverslip (see pg. 4, para. 3). Hence, Williams teaches the hydrogel was incorporated into an enclosed structure, which meets the limitation.
Regarding the limitation, wherein the closed system “is perfused with liquid media and/or disease-relevant chemical stimuli”, Williams discloses that the channel filled with PEG-4MAL hydrogel was perfused with growth media containing inflammatory stimuli, IFN-gamma and TNF-alpha (see pg. 8, para. 4). Further, Williams teaches that IFN-gamma is an important licensing cytokine at sites of inflammation (see pg. 3, para. 2), and the instant specification identifies TNF-alpha as a “tumor necrosis factor” (see instant specification at pg. 41, Table 3). Hence, the inflammatory stimuli taught by Williams meet the limitation of “disease-relevant chemical stimuli”, which are perfused into the closed system.
In Summary, Williams teaches a microfluidic potency assay (microfluidic platform for potency analysis) comprising living cells (hMSCs), wherein the cells are encapsulated in a synthetic hydrogel (PEG-4MAL), and further wherein the hydrogel is incorporated into a closed system (PDMS channel) which is perfused with media containing disease-relevant chemical stimuli (IFN-gamma and TNF-alpha in a growth medium).
Regarding claim 2, Williams teaches the hMSCs have differentiation capacities (see pg. 2, para. 2) and were screened for differentiation prior to being used in the platform (see pg. 3, para. 3). Hence, the cells (hMSCs) of Williams are “differentiating cells”.
Regarding claim 3, Williams teaches the differentiating cells are human mesenchymal stromal cells (hMSCs), as discussed above.
Regarding claim 4, Williams teaches the synthetic hydrogel comprises PEG-4MAL, as discussed above.
Regarding claim 5, Williams teaches the hydrogels used for hMSC culture were prepared by combining the cross-linkers VPM and dithiothreitol (DTT) to provide a crosslinking solution, which was mixed with the PEG-4MAL/RGD solution (hydrogel) and hMSCs (see pg. 4, para. 2). The cross-linker, “VPM”, meets the limitation of a “protease-degradable peptide” in view of instant claim 6.
Regarding claim 6, Williams teaches the hydrogel is mixed with the cross-linker, VPM, as discussed above.
Regarding claim 7, Williams discloses VPM as “GCRDVPMS↓MRGGDRCG” (see pg. 4, para. 2), which is identical to instant SEQ ID NO: 1.
Regarding claim 8, Williams teaches the hydrogels used for hMSC culture were prepared by combining the cross-linkers VPM and dithiothreitol (DTT) to provide a crosslinking solution, which was mixed with the PEG-4MAL/RGD solution and hMSCs, as discussed above. The cross-linker, “dithiothreitol (DTT)” meets the limitation of a dithiolated molecule in view of instant claim 9.
Regarding claim 9, Williams teaches the dithiolated molecule comprises dithiothreitol (DTT), as discussed above.
Regarding claim 10, Williams teaches the hydrogels were prepared by adding the hMSCs to a solution comprising PEG-4MAL and the adhesive peptide GRGDSPC (RGD), which was then combined with the crosslinkers (see pg. 4, para. 2).
Regarding claim 11, Williams teaches the adhesive peptide comprises RGD, as discussed above.
Regarding claim 12, Williams discloses RGD as GRGDSPC, as discussed above. This sequence is identical to instant SEQ ID NO: 2.
Regarding claim 13, Williams teaches the hydrogel is perfused with a medium containing IFN-gamma and TNF-alpha, as discussed above. While Williams does not explicitly refer to the medium as “liquid media”, it is clear from Williams’ disclosure that the perfused media must be in the form of a liquid. For example:
-Williams teaches microfluidic platforms, wherein “soluble factors”, such as inflammatory stimuli, are perfused into the structure containing the hydrogel (see Abstract);
-Williams discloses that time-dependent diffusion through the hydrogel was evaluated using the transport of diluted species (see pg. 5, para. 2);
-Williams discloses that an effective diffusion coefficient relative to that of water was used to model diffusion through the hydrogel (see pg. 5, para. 2);
-Williams teaches that the media and inflammatory stimuli are delivered through “fluidic channels” for generating gradients in the hydrogel (See FIG. 4A); and
-Williams teaches the media with inflammatory cytokines is perfused through one end of the closed system containing the hydrogel and the “effluent” with secreted cytokines is collected from the opposite end (see FIG. 1).
Therefore, the only reasonable interpretation of the perfused media taught by Williams is that this feature must have been in the form of a “liquid”, because its activities and properties (i.e., perfusion, diffusion, dilution, excretion of effluent containing cytokines) could not have reasonably been present when in another state of matter (e.g., solid or gas).
Regarding claim 14, Williams discloses that a hole was punched through polydimethylsiloxane (PDMS), generating a channel through which inflammatory stimuli could be perfused, and the hole was then filled with PEG-4MAL hydrogel containing hMSCs and enclosed via plasma-bonded glass coverslip (see pg. 4, para. 3). Hence, Williams teaches the hydrogel is incorporated into a closed system comprised of PDMS.
Regarding claim 15, Williams discloses a microfluidic platform for potency analyses, as discussed above. As discussed under 35 U.S.C. 112(d), claim 15 does not recite any further structural limitation, and is therefore anticipated for the same reasons as claim 1.
Regarding claim 16, Williams discloses that to demonstrate the feasibility of evaluating hMSC response while cultured in hydrogels in a high-throughput and scalable manner, the platform was developed to reduce the amount of sample required for dose-response testing, and could enable higher throughput potency analysis (see pg. 8, para. 2). Williams also teaches a device based on the platform was developed to demonstrate the feasibility of using microfluidics for high throughput potency testing. Hence, Williams teaches the platform is high-throughput.
Regarding claim 17, Williams teaches the platform is “scalable”, as discussed above. See also, e.g., Title, Abstract, and page 3, paragraph 1.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651