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
Applicant’s claim for the benefit of a prior-filed application provisional application 62/511,743 filed on July 13, 2023 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/511,743 filed on July 13, 2023 fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Regarding claims 1 and 16, ‘743 fails to provide support for a copolymer comprising a stimulus-responsive polymer and an ionic polymer. The closest support for this limitation can be found on pg. 2 of ‘743, which recites:
“The resist may include chemical groups to regulate adsorption of proteins or biological molecules to enhance cell adhesion prior to release. For example, copolymerization with a cation (e.g., 3-aminopropylmethacrylate) enhances increases adsorption of serum proteins including fibronectin and enhances adhesion strength on the texture. (data can be provided).” However, this recitation is generic.
“Resist” is interpreted to be referring to a “photoresist”, defined as:
“a photocrosslinking polymer that forms an insoluble network when exposed to light…The photoresist is composed of a stimuli-responsive polymer or co-polymer system such as PNIPAAm, OEGMA, etc., copolymerized with a benzophenone derivative monomer” on pg. 1.
As such, the term “cation” is only mentioned in the context of a photoresist, not with a stimuli-responsive polymer alone, and the photoresist requires a benzophenone derivative monomer, which is not required in the instant claims. Further, a cation polymer is not explicitly disclosed, and the species “cation” does not provide support for the genus of “ions” (e.g., ionic).
Accordingly, the effective priority date of the claims 1-20 is granted as the filing date of the instant application, 07/03/2024.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/05/2024 is considered by the examiner.
Drawings
The drawings are objected to because Figure 6 is too small/blurry to read. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The specification filed 07/03/2024 is accepted.
Claim Rejections - 35 USC § 112(a)- Written Description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to a cell culture substrate comprising a support and a copolymer comprising a stimulus-responsive polymer and an ionic polymer, where the copolymer is patterned on the support.
Claim 1 recites the structure of the cell culture substrate having the function of upon exposure to a stimulus, decreasing adhesion strength between the cell culture substrate and a plurality of cells seeded on the cell culture substrate, thereby releasing the plurality of cells from the cell culture substrate.
The cell culture substrate may also have the function of the copolymer increasing in surface area and/or volume upon exposure to the stimulus, thereby decreasing adhesion strength between the cell culture substrate and the plurality of cells (claim 10).
The method of cell culturing using the cell culture substrate may result in releasing from about 50% to about 100% of the plurality of cells in from about 1 second to about 300 seconds (claim 19).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The cell culture substrate is recited at a high level of generality, e.g., no % of the polymers, patterning of copolymer, etc. The method steps of claim 16 are recited at a high level of generality, e.g., no culture period.
The claim is considered to lack adequate written description for failing to recite the structure (e.g., copolymer; active method steps) that is necessary and sufficient to cause the recited functional language (e.g., exposure to a stimulus decreasing adhesion strength between the cell culture substrate and a plurality of cells seeded on the cell culture substrate, thereby releasing the plurality of cells from the cell culture substrate; releasing from about 50% to about 100% of the plurality of cells in from about 1 second to about 300 seconds). The specification fails to disclose what structural changes/components of a cell culture substrate/method of cell culture is/are necessary and sufficient to aid in releasing the plurality of cells from the cell culture substrate when exposed to a stimulus (e.g., how would an artisan conduct the protocol such that from about 50% to about 100% of the plurality of cells in from about 1 second to about 300 seconds are released from the cell substrate? how long must the cells be seeded on the cell culture substrate?), and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The specification offers little guidance on what copolymers on a support result in decreased adhesion strength when exposed to a stimulus. Only two cell culture substrates are disclosed in the working examples, one of which does not read on the claimed substrate (e.g., NIPAAm-benzophenone copolymer in [0105] is not a polyNIPAAm, nor does it comprise an ionic polymer). [0110] discloses UV-crosslinkable PNIPAAm copolymerized with 0%, 1%, or 5% APMA (e.g., an ionic polymer), which were combined with MABP, a photoactivatable crosslinker. The copolymer was then square patterned onto spin coated polymer films. No cell culture particulars such as length of time or temperature are disclosed. Additionally, temperature was the only stimulus tested.
Additionally, the specification fails to describe or provide evidence of possessing a cell culture substrate that does not also comprise a photoactivatable crosslinker. Dependent claim 6 further limits the copolymer to comprise one of the three recited photoactivatable crosslinkers.
The prior art teaches a variety of stimulus-responsive polymers that may be used to create a cell culture substrate. For example, Mueller et al. (US20220186179A1, published 6/16/2022) teaches a stimulus-responsive polymer layer comprised of (meth)acrylate or (meth)acrylamide homo- or copolymers, preferably polymers of (meth)acrylates modified (esterified) with alkylene glycols, particularly preferably poly(di(ethylene glycol)methyl ether methacrylate) polymers, in particular the homopolymers thereof (e.g., [0032]). While the instant specification does not teach poly(di(ethylene glycol)methyl ether methacrylate) (PDEGMA) as part of the copolymer. Mueller et al. lists a variety of suitable synthetic polymers, including those recited in the instant claims (e.g., PNIPAM, POEGMA, PDMAEMA). Only PDEGMA is found in the working examples of Mueller et al. Mueller et al. also teaches polymers not claimed, such as OEGMA and PTEGMA-EE (e.g., [0091]), and does not teach polyethylene oxide (PEO) as a stimulus-responsive polymer. Additionally, Mueller et al. does not teach a copolymer comprising a stimulus-responsive polymer and an ionic polymer.
Rubinsztajn et al. (US20100330674A1, published 12/30/2010) teaches cell culture substrates comprising dual stimuli responsive block copolymer immobilized on the substrate. Examples taught by Rubinsztajn et al. include PDEGMA-co-PAA (acrylic acid, an ionic polymer) and poly (di(ethylene glycol)methylether methacrylate)-co-poly(diethylaminoethyl acrylate) and poly (N-isopropyl acrylamide)-co-poly(vinylpyridine) (e.g., [0036]). Rubinsztajn et al. notes poly N-isopropyl acrylamide (PNIPAM) has been used as coating for cell culture supports to provide a gentle mechanism for releasing cultured cells, as well as multilayers supports comprising alternative layers of negatively charged polystyrene sulfonate-co-poly N-isopropyl acrylamide (PSS-co-PNIPAM) and positively charged polyallylamine hydrochloride-co-poly N-isopropyl acrylamide (PAH-co-PNIPAM) copolymers (e.g., [0004]). However, only PDEGMEMA-co-PAA is used in the working examples (e.g., [0059]). Rubinsztajn et al. does not teach any of the other claimed polymers.
Akintewe, Olukemi O., et al. "Shape-changing hydrogel surfaces trigger rapid release of patterned tissue modules." Acta biomaterialia 11 (2015): 96-103. (by Applicant) is considered relevant prior art for teaching cell culture supports comprising PNIPAAm. Akintewe et al. demonstrates that it was well known in the art that pNIAPAAm is a thermoresponsive polymer that swells during thermal activation due to thermally mediated changes in the hydrophilic and hydrophobic interactions around its lower critical solution temperature (LCST) of 32 C (e.g., pg. 9., col 2, paras 1 and 2). Following pNIPAAm crosslinking with MBAm, Akintewe et al. found that the degree of swelling of pNIPAAm hydrogels is dependent on the extent of available network crosslinks; increasing crosslinks reduces swelling (e.g., pg. 99, col 2, para 1). Further, release of tissue modules from pNIPAAm hydrogel microbeams occurred within seconds and was completed within 3 min after lowering the culture temperature to 27 C (e.g., pg. 100, col 2, para 2). Importantly, the thermal stimulus used to actuate the pNIPAAm hydrogel was not the key factor in achieving rapid cell release from the shape-changing microbeams. When the amount of crosslinker was varied in the hydrogel network, the extent of bulk swelling and therefore surface expansion was modulated (e.g., pg. 100, col 2, last para- pg. 101). In summary, Akintewe et al. teaches the importance of the composition of the cell culture substrate, e.g., crosslinker amount present and that varying amounts will result in differing functional outcomes.
Claim Rejections - 35 USC § 112(b)
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 9 and 11-13 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 9 recites “the stimulus is a change in temperature of from about 1 C to about 20 C.” As written, it is unclear whether the temperature value is changing (e.g., starts at 1C, ends at 20C), or whether the temperature is required to change by about 1C to about 20C (e.g., temperature starts at 15C, and is increased by 5C). For examination purposes, the claim language is interpreted to read on either the temperature or the amount the temperature is changed. It would be remedial to clarify whether the change is referring to the resulting temperature or the amount by which the temperature is changed.
Claim 11 recites “the copolymer pattern comprises a plurality of elements comprising circles, squares, rectangles, hexagons, triangles, or any array or combination thereof.” It is unclear whether the plurality of elements must all be the same shape, e.g., circles, or whether the plurality of elements may be a mixture of circles, squares, triangles, etc. For examination purposes, a pattern comprising any assortment of these shapes reads on the claim language. It would be remedial to clarify whether the pattern must be uniform in shape.
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.
Claims 8, 9, 14, and 15 are 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.
Claims 8 and 9 further limit the stimulus. However, the claimed invention is directed to a cell culture substrate. While a component of the substrate is a stimulus-responsive polymer, the stimulus itself is not part of the structure of the claimed cell culture substrate. Therefore, claims 8 and 9 fail to further limit the claimed subject matter of claim 1.
In kind, claim 15 is similarly rejected, as claim 15 further limits the plurality of cells, which are not a part of the claimed substrate.
Claim 14 recites “the copolymer covers from about 1% to about 100% of the support.”. Because the copolymer is already known to be present in the base claim 1, as the copolymer is a component of the cell culture substrate, reciting that the copolymer covers from about 1% to 100% of the support fails to further limit the cell culture substrate. The specification does not provide a specific/definite value for what the term “about” encompasses. As such, reciting “about 1%” encompasses the copolymer being present, even in negligible amounts. Additionally, the other end of the range, 100% is the max amount possible that the copolymer can cover of the support. Therefore, claim 14 fails to further limit the claimed subject matter on which it is based.
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) 1-5 and 8-20 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Brady-Mine et al. (Enhancing Switchable Cell Adhesion to PNIPAAm Through Incorporation of Cationic Monomers Alexandria Brady-Mine, Ryan Toomey, PhD, Nathan Gallant, PhD, University of South Florida, Tampa, FL, USA P2009, presented to the public 04/20/2023 at the 2023 Society for Biomaterials Research Conference) (by Applicant).
Regarding claims 1-4 and 11, Brady-Mine et al. discloses a cell culture substrate, comprising:
a support (e.g., glass coverslips- claim 2); and
a copolymer comprising a stimulus-responsive polymer (e.g., PNIPAAm- claim 3) and an ionic polymer (e.g., APMA- claim 4);
wherein the copolymer is patterned on the support (e.g., uniform or square- claim 11); and
wherein exposure to a stimulus (e.g., temperature) decreases adhesion strength between the cell culture substrate and a plurality of cells seeded on the cell culture substrate, thereby releasing the plurality of cells from the cell culture substrate (e.g., “Methods”).
Regarding claim 5, Brady-Mine discloses the copolymer comprising 1 or 5% APMA (ionic polymer) (e.g., “Methods”).
As discussed above in the 112(d) rejection, claims 1-15 are directed to a cell culture substrate. As such, further limiting the stimulus, as recited in claims 8 and 9, does not further limit the structure of the claimed product. Similarly, further limiting the type of cells, as recited in claim 15, does not further limit the structure of the cell culture substrate. Thus, Brady-Mine discloses all the structures of claims 8, 9, and 15.
Regarding claim 10, Brady-Mine et al. discloses the copolymer increasing in surface area and/or volume upon exposure to the stimulus (e.g., swelling), thereby decreasing adhesion strength between the cell culture substrate and the plurality of cells (e.g., col 1, para 1).
Regarding claims 12 and 13, Brady-Mine et al. discloses the surface being crosslinked through a mask to create 20 µm “square pattern” textures (e.g., 20 µm “square pattern” reads on each element being 20 µm and elements being spaced apart by 20 µm) (e.g., “Methods”).
Regarding claim 14, while Brady-Mine et al. does not explicitly disclose the copolymer covering from about 1% to about 100% of the support, the copolymer is present on the support (e.g., the presence of the copolymer means the copolymer covers about 1% or more of the support) (e.g., “Methods”). Thus, Brady-Mine et al. discloses the claimed structure.
Regarding claims 16-18, Brady-Mine et al. discloses seeding cells on the claimed cell culture substrate, followed by exposing the substrate to a stimulus (e.g., change in temperature by 12 degrees C- claims 17 and 18) and then collecting the cells.
Regarding claim 19, Brady-Mine et al. does not explicitly disclose from about 50% to about 100% of the plurality of cells are released in from about 1 second to about 300 seconds. However, Brady-Mine et al. discloses the same active method steps as base claim 16. Thus, absent evidence to the contrary, an Artisan would expect the method disclosed by Brady-Mine et al. to result in the functional outcome of from about 50% to about 100% of the plurality of cells are released in from about 1 second to about 300 seconds.
Regarding claim 20, while Brady-Mine et al. doesn’t explicitly disclose the method step of reseeding the cells on a different substrate following detachment, Brady-Mine et al. discloses the detached cells being used to 3D print tissues and to develop smart cell culture vessels (e.g., col 1, para 1). As such, these purposes read on reseeding the cells on a different substrate.
Claim(s) 1-10 and 15 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sanden (Sanden, G. (2014). Quantification of Protein Adhesion Strength to Surface Attached Poly(N-isopropylacrylamide)(PNIPAAm) Networks by Hydrodynamic Detachment Shear Stresses)).
Regarding claims 1-4 and 11, Ruiz et al. discloses a cell culture substrate, comprising:
a support (e.g., polymer film, quartz crystal resonator, glass coverslips- claim 2); and
a copolymer comprising a stimulus-responsive polymer (e.g., PNIPAAm- claim 3;) and an ionic polymer (e.g., APMA- claim 4);
wherein the copolymer is patterned on the support (e.g., uniform; hydrogel fabrication through photochemical technique); and
wherein exposure to a stimulus (e.g., temperature, ionic conc.) decreases adhesion strength between the cell culture substrate and a plurality of cells seeded on the cell culture substrate, thereby releasing the plurality of cells from the cell culture substrate (e.g., pg. 23-24, “3.2 Surface Attached Hydrogel Fabrication”)
Regarding claim 5, Sanden discloses the copolymer comprising 3.5mol% APMA (ionic polymer) (e.g., pg. 24,“3.3 Synthesis of Poly(NIPAAm-co-3-APMA) and Poly(NIPAAm) Hydrogels”; pg. 25, para 1).
Regarding claims 6 and 7, Sanden discloses the copolymer comprising 2 mol% MBAm as a crosslinker (e.g., pg. 24,“3.3 Synthesis of Poly(NIPAAm-co-3-APMA) and Poly(NIPAAm) Hydrogels”).
As discussed above in the 112(d) rejection, claims 1-15 are directed to a cell culture substrate. As such, further limiting the stimulus, as recited in claims 8 and 9, does not further limit the structure of the claimed product. Similarly, further limiting the type of cells, as recited in claim 15, does not further limit the structure of the cell culture substrate. Thus, Brady-Mine discloses all the structures of claims 8, 9, and 15.
Regarding claim 10, Sanden discloses the copolymer increasing in surface area and/or volume (e.g., swelling) upon exposure to the stimulus, thereby decreasing adhesion strength between the cell culture substrate and the plurality of cells (as discussed above in the 112(a) rejection, decreasing adhesion strength between the cell culture substrate and the plurality of cells is a functional property. Because Sanden discloses the copolymer increasing in surface area/volume, Sanden discloses the claimed structure) (e.g., Fig. 6.1, 6.2, 6.3).
Conclusion
No claims are allowed.
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ALLISON M. JOHNSON
Examiner
Art Unit 1638
/ALLISON MARIE JOHNSON/ Examiner, Art Unit 1638
/ROBERT M KELLY/ Primary Examiner, Art Unit 1638
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