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 .
DETAILED ACTION
Amendments
In the reply filed on 12/19/2025, Applicant has amended claim 46, newly canceled claims 30-45 and 48, and added new claims 49-66.
Election/Restriction
Applicant’s election, without traverse, of Group II, claims 46-47 and 49-66, drawn to a method of making a transwell with 3D printing, in the reply filed on 12/19/2025 is acknowledged.
Claim Status
Claims 46-47 and 49-66 are pending and are considered on the merits.
Priority
This application claims benefit from application 63/392,724 (filed on 07/27/2022). The priority claim of the instant application has been granted and the earliest benefit date is 07/27/2022 from the application 63/392,724.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/16/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner. The corresponding signed and initialed PTO form 1449 has been mailed with this action.
Specification Objections
The disclosure is objected to because it contains typographic errors in, e.g., [0023] and other paragraphs, by reciting “DPBS Ca+/Mn+”, in which the “Mn+” seems to refer to “Mg+” (i.e., magnesium rather than manganese).
Claim Objections
Claims 47, 49, 51-53, 58 and 64 are objected to because of the following informalities:
Claim 47 recites the term “sterolithography” in line 2, which contains a typographic error. It should be changed to “stereolithography”.
Claim 49 recites the phrase “digital light printing (DLP) printing technique”, which seems to contain a typographic error as compared to claim 48 reciting the phrase “digital light projection printing (DLP)”.
Claims 51-53, 58 and 64 each recite abbreviations, such as “DPBS +/+” in claim 51, “DPBS -I-” in claims 52 and 53, and “HPA”, “PEGDA”, “PEGTAC”, “PEO”, “NAP”, “LAP” in claims 58 and 64. An abbreviation should be preceded in its first occurrence by the specific identity of the entity which said abbreviation is intended to represent. Thereafter, the use of the abbreviation in the claims will be understood.
Furthermore, claim 51 recites two “d)”.
Claim 64 recites the term “HP A” in (1), which seems to refer to “HPA”.
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 46-47 and 49-66 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 46 recites the limitation “an advanced manufactured transwell (AM-transwell)”. A claim may be rendered indefinite by reference to term of an object that is variable (see MPEP 2173.05(b), II; see, e.g., Ex parte Miyazaki, 89 USPQ2d 1207 (Bd. Pat. App. & Inter. 2008) (precedential) and Ex parte Brummer, 12 USPQ2d 1653 (Bd. Pat. App. & Inter. 1989). In instant case, the recited “advanced” is a relative term that renders the claim indefinite, because neither the claims nor the specification specifies what reference transwell this “advanced manufactured transwell” is compared to so as to be “advanced”. Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. It is examined as a transwell. Claims 47 and 49-66 are rejected as being dependent from claim 46 but not resolving the ambiguity.
Claim 60 recites “0.1 M HEPES in water and 1X PBS”. It is not clear whether the diluent of HEPES is water or 1X PBS. It is examined as “0.1 M HEPES in 1X PBS”.
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.
Claims 46, 47 and 65 are rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024).
With respect to claim 46, Maoz teaches an insert chip (i.e., a transwell. See e.g., Fig 1A in the front page) and teaches a method of making such a transwell (see [0058] and Fig 4).
In regard to the transwell, Maoz teaches the insert chip comprises (i) a lower chamber (i.e., the space between the well-plate and the insert membrane, see e.g., Fig 9 the space pointed by 210A); (ii) an upper chamber (i.e., the space of the hollow scaffold, see e.g., Fig 9 the space pointed by 204); (iii) a membrane disposed between the lower chamber and the upper chamber (i.e., a porous membrane, see e.g., claim 1 and Fig 9); and (iv) one or more legs (see e.g., claim 1 and Fig 9).
In regard to the method, Maoz teaches the method comprises printing the base/hollow scaffold in a stereolithography Form 2 3D printer using a dental long-term (LT) clear resin (e.g., [00107], [00131] and Fig 4), thus teaches step a) printing one or more of the lower chamber (by printing the legs in the base/hollow scaffold), the upper chamber (i.e., in the hollow scaffold), and the one or more legs (part of the base scaffold) using a synthetic bioink (e.g., a dental long-term clear resin) via a 3D printing technique (a stereolithography 3D printing technique). Maoz teaches the components of the ring and the membrane are aligned and inserted into the 3D-printed insert-chip to form the ready-to-use assembled chip ([00108]-[00111]), thus teaches step b) assembling the transwell to form assembled transwells.
With respect to claim 47, as stated supra, Maoz teaches the 3D printing technique is a stereolithography (SLA) 3D printing technique (e.g., [00107]).
With respect to claim 65, Maoz teaches the transwell is a cylinder (see e.g., Fig 1A).
Accordingly, Maoz anticipates 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 50-56 and 66 are rejected under 35 U.S.C. 103 as being unpatentable over Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024).
With respect to claim 50 directed to a step c) of storing the transwell at 4 °C until needed, however, Maoz does not specifically teach storing the transwell at 4 °C.
Nevertheless, Maoz teaches the transwell can be used for neuronal culture on multi-electrode array (MEA) system (e.g., [0062]) and teaches “prior to cell seeding, the MEA substrates were treated with polyethyleneimine in borate buffer overnight at 4 °C” ([00119]), thus suggests the transwell can be stored at 4 °C until needed for cell seeding.
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method by combining a step of storing the assembled transwell at 4 °C until needed as suggested by Maoz with a reasonable expectation of success. Since Maoz teaches the assembled transwell can sustain the temperature of 4 °C and can be store at 4 °C prior to cell seeding, one of ordinary skill in the art would have had a reason to store the assembled transwell at 4 °C until needed in order to prepare the transwell for analytical experiment.
With respect to claim 51 directed to washing the transwells with PBS, Maoz teaches after assembling the chip, the ready-to-use assembled chip was then washed with phosphate-buffered saline (PBS) 3 times and sterilized under a UV lamp for 20 minutes (e.g., [00111]).
Although Maoz does not specifically teach the transwells are transferred into DPBS +/+ (Dulbecco's phosphate-buffered saline with calcium and magnesium) and washed for about 5 minutes and then transfer to sterile 50 mL tubes, one of ordinary skill in the art would have immediately chosen Dulbecco's phosphate-buffered saline with calcium and magnesium to wash the transwells because the DPBS +/+ is a well-known balanced buffer solution used for cell culture applications, such as washing cells before dissociation and transporting cells or tissue samples. One of ordinary skill in the art would also have transferred the transwells to a sterile tube after washing because Maoz teaches the transwells are to be used in cell culture thus it would have been obvious to keep the transwells in a sterile container, such as a 50 mL tube.
With respect to claim 52 directed to the transwells being sterilized by incubating in DPBS -/- (Dulbecco's phosphate-buffered saline without calcium or magnesium) supplemented with antibiotic/antimycotic (anti-anti) overnight, as stated supra, Maoz teaches after assembling the chip, the ready-to-use assembled chip was then washed with phosphate-buffered saline (PBS) 3 times and sterilized under a UV lamp for 20 minutes (e.g., [00111]). Maoz also teaches “the so-formed ready-to-use assembled insert chip may be further sterilized (for example, by ethanol wash and/or UV) (p. 17, para 1), suggesting other means of sterilization. Maoz teaches cells and the transwells are incubated in a medium containing 1% Penicillin-Streptomycin-Amphotericin B (PSA) solution (p. 26, para 1), in which Penicillin and Streptomycin are antibiotics and Amphotericin B is antimycotic, thus suggest a solution supplemented with antibiotic/antimycotic (anti-anti).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the sterilization method of UV exposure with incubating in a DPBS -/- supplemented with antibiotic/antimycotic (anti-anti) as suggested by Maoz with a reasonable expectation of success. Since the UV exposure (or ethanol wash) and incubating in a DPBS -/- anti-anti are for the same purpose (i.e., to sterilize the transwells), these methods are art-recognized obvious equivalents to each other. Therefore, it would have been obvious for one of ordinary skill in the art to have substituted incubating in a DPBS -/- anti-anti overnight for UV exposure in order to form sterilized transwells. See MPEP 2144.06.
With respect to claim 53 directed to g) the transwells being washed in 35 mL PBS/0.1 M HEPES anti-anti buffer for about 4 hours and h) the transwells being incubated in 35 mL cell culture media in 50 mL tubes for about 2 days, as stated supra, Maoz teaches the transwells are washed in PBS and the cell-seeded transwells are incubated in cell culture media for an extended period of time, e.g., for 9-11 days (e.g., [00111] and [00115]).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have combined washing the transwells in 35 mL PBS/0.1 M HEPES anti-anti buffer for about 4 hours and incubating the transwells in 35 mL cell culture media in 50 mL tubes for about 2 days with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so because a skilled artisan would have understood that addition of HEPES to the wash buffer solution would provide extra buffering capacity and ensure the pH remains stable, and that incubating the transwell in cell culture media would equilibrate the transwells with culture media to facilitate cell seeding.
With respect to claims 54-56 directed to printing at least 3, 20 and 50 assembled transwells, Maoz teaches a plurality of insert chips (e.g., [0023]) that are placed in separate wells of cell culture containers such as 6, 12, and 24 well-plates (e.g., [0023], [0057] and Fig 3A). Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have printed at least 3, 20 or 50 assembled transwells as suggested by Maoz with a reasonable expectation of success. One of ordinary skill in the art would have had a reason to do so in order to apply the transwells in culturing a plurality of different cell types (e.g., [0006]) and in various high-throughput experiments (e.g., [0007]).
With respect to claim 66 directed to the dimensions of the transwell, Maoz teaches the transwells are made in different sizes in order to be associated with commercially available cell culture plates (e.g., [0057], [0074]). Maoz teaches exemplary leg heights of the transwells being 1mm, 2mm and 4mm in Fig 2A, in which one exemplary transwell (the rightmost one, 50C) has a height of about 10 mm to about 16 mm (comparing the transwell to the scale bar of 2 mm) and a thickness from about 1 mm to about 3 mm (see the inlet and the outlet above the transwell that have a diameter/thickness about the same as the scale bar of 2 mm).
Accordingly, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen the claimed height and thickness of the transwells as suggested by Maoz with a reasonable expectation of success. Since Maoz suggests to make the transwells in different sizes in order to be associated with commercially available cell culture plates (e.g., [0057], [0074]) and reduces to practice the claimed height and thickness, one of ordinary skill in the art would have had a reason to choose the claimed height and thickness in order to associate the transwells with different cell culture containers.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 49 is rejected under 35 U.S.C. 103 as being unpatentable over Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024) in view of Lu et al., (J Biomed Mater Res. 2006; 77A: 396-405).
Claim 49 is directed to the 3D printing technique being a digital light projection (DLP) printing technique.
However, Maoz teaches a stereolithography (SLA) 3D printing technique (e.g., [00107]), but is silent on a digital light projection (DLP) technique.
It is noted that the difference between a SLA and a DLP technique is that SLA uses laser to scan and cure resin point-by-point, while DLP projects the light to the entire layer at once. Lu develops the DLP technique and teaches that this layer-by-layer technique is simple and fast and allows fabrication of complex internal features along with precise spatial distribution inside a single scaffold (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the SLA technique with a DLP technique as taught by Lu with a reasonable expectation of success. Since Lu teaches the DLP technique is simple and fast that allows fabrication of complex features along with precise spatial distribution of biological factors inside a single scaffold (e.g., abstract), one of ordinary skill in the art would have had a reason to make this substitution in order to take advantage of this simple and fast technique to make the transwells.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 58, 59 and 64 are rejected under 35 U.S.C. 103 as being unpatentable over Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024) in view of Keilsohn et al., (US Patent No: 12,384,935, effectively filed on 07/15/2022 as provisional application 63/389,459).
Claims 58, 59 and 64 are directed to the compositions of the synthetic bioink.
However, Maoz is silent on the synthetic bioink comprising compositions recited in claims 58, 59 or 64.
Keilsohn, in provisional application 63/389,459 filed on 07/15/2022, teaches ink compositions for production of biocompatible hydrogel articles having high resolution features (see e.g., [0001]). Keilsohn teaches the ink comprises a polyethylene glycol diacrylate (PEGDA) component, sulfonated quinoline yellow, a photoinitiator component, and water (e.g., [0004], related to claims 58 and 59), and further comprises an acrylate component (e.g., [0017]) and one or more UV-absorbers/light stabilizers (e.g., [0028]). Keilsohn teaches the PEGDA component has an average molecular weight of 0.1 kDa to 20 kDa ([0014] and Table 1, encompassing claimed PEGDA3400, PEGDA6000, PEGDA575 and PEGDA700), and is present in an amount of 1-20% or 5-20% ([0015]), related to claim 58 and claim 64 (2). Keilsohn teaches the acrylate component is in addition to the PEGDA component, including hydroxypropylacrylate (HPA) being present in an amount of 1-40 wt.% ([0017]-[0018]), related to claim 58 and claim 64 (1). Keilsohn teaches photoinitiators such as anthraquinone ([0022], it is noted that anthraquinone is a similar quinone compound as the claimed NAP naphthoquinone, thus they are art-recognized obvious equivalents to each other. See MPEP 2144.06) being present in an amount of 0.1% to 5%, related to claim 58 and claim 64 (3). Keilsohn teaches UV-absorbers/light stabilizers including UV386 in an amount of 0.1-2% ([0028]), related to claim 58 and claim 64 (4).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the synthetic bioink of Maoz with the ink comprising the claimed components in the claimed amounts as taught by Keilsohn with a reasonable expectation of success. Since Keilsohn reduces to practice the claimed synthetic bioink comprising the claimed components in the claimed amounts (see above and Table II), and teaches the ink compositions can be used to print biocompatible hydrogel articles having high resolution features ([0001]), one of ordinary skill in the art would have had a reason to substitute with the synthetic bioink taught by Keilsohn in the method of Maoz in order to make a biocompatible transwell having high resolution features.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claim 60 is rejected under 35 U.S.C. 103 as being unpatentable over Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024) in view of Keilsohn et al., (US Patent No: 12,384,935, effectively filed on 07/15/2022 as provisional application 63/389,459), as applied to claims 58 and 46 above, and further in view of Shiwarski et al., (APL Bioeng. 2021; 5: 010904, p. 1-15).
Claim 60 is directed to the synthetic bioink further comprising a buffer solution comprising 0.1 M HEPES in 1X PBS at pH of 7.2.
Keilsohn teaches the pH of the water environment containing the leached sulfonated quinoline can have a pH of 7-7.5, which marks a fundamental departure from other hydrogel inks having highly acidic aqueous environments (e.g., [0006]).
However, Maoz and Keilsohn are silent on the synthetic bioink comprising a buffer solution comprising 0.1 M HEPES in 1X PBS.
Shiwarski summarizes 3D printing as a platform for advanced tissue biofabrication (e.g., abstract). Shiwarski teaches a buffer solution such as HEPES can be added to allow cell survival in a CO2 independent environment and to neutralize acidified bioinks (p. 5, right col, para 1), and teaches a bioink comprising a buffer solution comprising 50mM HEPES in PBS (see Table I, row 3 and row 4).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the synthetic bioink that have a pH of 7-7.5 suggested by Maoz in view of Keilsohn, by combining a buffer solution comprising HEPES in 1X PBS as suggested by Shiwarski with a reasonable expectation of success. Since Keilsohn aims to keep the pH of the bioink between 7 and 7.5 (e.g., [0006]), and since Shiwarski teaches a buffer solution HEPES can be added to neutralize acidified bioinks (p. 5, right col, para 1) and reduces to practice a bioink comprising a buffer solution comprising 50mM HEPES in PBS (see Table I, row 3 and row 4), one of ordinary skill in the art would have had a reason to combine a buffer solution comprising HEPES in PBS as suggested by Shiwarski in order to neutralize the bioinks to keep the pH of 7-7.5.
Furthermore, regarding the differences in concentration from Shiwarski (50 mM HEPES, i.e., 0.05 M HEPES) and the instant invention (0.1 M HEPES), MPEP states “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” and “where 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”. See MPEP 2144.05(II)(A). In the instant case, Shiwarski teaches a buffer solution HEPES can be added to neutralize acidified bioinks (p. 5, right col, para 1, thus being a results effective variable), and exemplifies a bioink comprising a buffer solution comprising 50mM HEPES in PBS (see Table I, row 3 and row 4). Therefore, it would have been obvious for one ordinary skill in the art before the effective filing date of the claimed invention to apply the claimed working concentrations because they are the result of “routine optimization”.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Claims 57 and 61-63 are rejected under 35 U.S.C. 103 as being unpatentable over Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024) in view of Keilsohn et al., (US Patent No: 12,384,935, effectively filed on 07/15/2022 as provisional application 63/389,459), as applied to claims 58 and 46 above, and further in view of Lutolf et al., (Nat Biotechnol. 2003;21(5):513-518).
With respect to claim 63, Maoz teaches the transwell is seeded with cells (see Example 2 “Cell culture” and see Fig 9 for the membrane being seeded with cells), thus teaches claim 63 the membrane is seeded with cells.
However, Maoz and Keilsohn are silent on the synthetic bioink comprising a degradable peptide in claim 57, nor teach the bioink further comprising mono-cysteine peptide RGDS and dicysteine peptide in claims 61 and 62.
Lutolf teaches engineering synthetic poly(ethylene glycol) (PEG)–based hydrogels (comprising the base material PEG taught in Keilsohn) as cell-ingrowth matrices (e.g., abstract). Lutolf teaches the PEG-based hydrogel contains a combination of pendant oligopeptide ligands for cell adhesion (C-RGDSP, i.e., a mono-cysteine peptide comprising RGDS, related to claim 61 and claim 62) and substrates for matrix metalloproteinase (MMP) as linkers between PEG chains (Ac-GCRD-GPQGIWGQ-DRCG-NH2, see p. 517, left col, para 1 and Fig 1, i.e., a degradable peptide and a dicysteine peptide, related to claim 57 and claim 61). Lutolf teaches 10 μl of 1 mM RGD is added to 20 μl triethanolamine buffer and 10 μl dicysteine peptide (i.e., about 0.25 mM RGD) (p. 517, para 1). Lutolf teaches cells are shown to migrate within the matrices by integrin- and MMP-dependent mechanisms, and thus demonstrates cell-mediated proteolytic invasiveness of the gels (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the synthetic bioink suggested by Maoz in view of Keilsohn, by combining a mono-cysteine peptide RGDS and a degradable dicysteine peptide as taught by Lutolf with a reasonable expectation of success. Since Maoz aims to use the transwell to study cell-cell interactions (e.g., [0007]), such as co-culturing three different cell types/populations on top of the membrane, on the bottom of the membrane, and on the bottom of the well (shown in Fig 9 and [0063]), and since Lutolf teaches a combination of a mono-cysteine peptide for cell adhesion (C-RGDSP) and a MMP-degradable dicysteine peptide enables cells to migrate within the matrices by integrin- and MMP-dependent mechanisms, and demonstrates cell-mediated proteolytic invasiveness (e.g., abstract), one of ordinary skill in the art would have had a reason to combine a mono-cysteine peptide comprising RGDS and a MMP-degradable dicysteine peptide as suggested by Lutolf in the bioink of Maoz in view of Keilsohn in order to enhance cell adhesion and to enable cell-mediated proteolytic migration to study cell-cell interactions.
Furthermore, regarding the differences in concentration from Lutolf (about 0.25 mM RGD) and the instant invention (from 0.5 mM to 20 mM of mono- and di-cysteine peptides), MPEP states “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” and “where 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”. See MPEP 2144.05(II)(A). In the instant case, Lutolf teaches a mono- and a di-cysteine peptides are added to the hydrogel (i.e., bioink) to enable cell migration via integrin- and MMP-dependent mechanisms (thus being a results effective variable), and exemplifies an amount of about 0.25 mM RGD. Therefore, it would have been obvious for one ordinary skill in the art before the effective filing date of the claimed invention to apply the claimed working concentrations because they are the result of “routine optimization”.
Hence, the claimed invention as a whole was prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention in the absence of evidence to the contrary.
Provisional Double Patenting Rejections
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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 46-47 and 49-66 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over copending claims 1-3 and 22 of copending Application No. 18/226,635 in view of Maoz et al., (WO 2022/097150, published 05/12/2022, cited in IDS 01/16/2024), Lu et al., (J Biomed Mater Res. 2006; 77A: 396-405), Shiwarski et al., (APL Bioeng. 2021; 5: 010904, p. 1-15) and Lutolf et al., (Nat Biotechnol. 2003;21(5):513-518). Although the claims at issue are not identical, they are not patentably distinct from each other.
Copending claims recite a method of making an advanced manufactured interpenetrating polymer network comprising printing the network using a synthetic bioink and a 3D printing technique and assembling and/or printing the network to form an assembled network (reference claim 22), wherein the synthetic bioink comprises one or more of HPA in an amount from about 0.5% to about 20%, PEGDA6000 in an amount from 0.5% to about 20%, NAP in an amount of about 0.05% to about 3%, UV386A in an amount from about 0.0001% to about 0.5%, water in an amount as a balance (reference claim 2) and further comprising PEO (reference claim 3).
However, copending claims are silent on printing a transwell, the 3D printing technique, storing, washing and sterilizing the transwells, the number, shape or dimensions of transwells, a buffer solution in the bioink, or mono- and di- cysteine peptides in the bioink.
Maoz teaches 3D printing an insert chip (i.e., a transwell. See e.g., Fig 1A in the front page) using a synthetic bioink ([00107]). Maoz teaches the insert chip comprises (i) a lower chamber (i.e., the space between the well-plate and the insert membrane, see e.g., Fig 9 210A); (ii) an upper chamber (i.e., the space of the hollow scaffold, see e.g., Fig 9 204); (iii) a membrane disposed between the lower chamber and the upper chamber; and (iv) one or more legs (see e.g., claim 1 and Fig 9). Maoz teaches the 3D printing technique is a stereolithography (SLA) 3D printing technique (e.g., [00107]). Maoz teaches the transwell is a cylinder (see e.g., Fig 1A). Maoz teaches the transwell can be used for neuronal culture on multi-electrode array (MEA) system (e.g., [0062]) and teaches “prior to cell seeding, the MEA substrates were treated with polyethyleneimine in borate buffer overnight at 4 °C” ([00119]), thus suggests the transwell can be stored at 4 °C until needed for cell seeding. Maoz teaches after assembling the chip, the ready-to-use assembled chip was then washed with phosphate-buffered saline (PBS) 3 times and sterilized under a UV lamp for 20 minutes (e.g., [00111]). Maoz also teaches “the so-formed ready-to-use assembled insert chip may be further sterilized (for example, by ethanol wash and/or UV) (p. 17, para 1), suggesting other means of sterilization. Maoz teaches cells and the transwells are incubated in a medium containing 1% Penicillin-Streptomycin-Amphotericin B (PSA) solution (p. 26, para 1), in which Penicillin and Streptomycin are antibiotics and Amphotericin B is antimycotic, thus suggest a solution supplemented with antibiotic/antimycotic (anti-anti). Maoz teaches a plurality of insert chips, i.e., transwells (e.g., [0023]) that are placed in separate wells of cell culture containers such as 6, 12, and 24 well-plates (e.g., [0023], [0057] and Fig 3A). Maoz teaches the transwells are made in different sizes in order to be associated with commercially available cell culture plates (e.g., [0057], [0074]). Maoz suggests one exemplary transwell (the rightmost one, 50C) has a height of about 10 mm to about 16 mm (comparing the transwell to the scale bar of 2 mm) and a thickness from about 1 mm to about 3 mm (see the inlet and the outlet above the transwell that have a diameter/thickness about the same as the scale bar of 2 mm). Maoz teaches the transwell is seeded with cells (see Example 2 “Cell culture” and see Fig 9 for the membrane being seeded with cells).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have used the recited synthetic bioink and the recited 3D bioprinting technique in the copending claims, in making a transwell with the components, shape, number and dimensions as suggested by Maoz and to have combined steps of storing, washing and sterilizing the transwells with a reasonable expectation of success. Since Maoz teaches the transwells can be used in various applications such as studying cell-cell interactions ([0007]), one of ordinary skill in the art would have had a reason to make a transwell as suggested by Maoz using the recited method and bioink in the copending claims in order to use in various applications such as studying cell-cell interactions.
In regard to a DLP 3D printing technique, Lu develops the DLP technique and teaches that this layer-by-layer technique is simple and fast and allows fabrication of complex internal features along with precise spatial distribution inside a single scaffold (e.g., abstract).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have chosen a DLP technique as taught by Lu with a reasonable expectation of success. Since Lu teaches the DLP technique is simple and fast that allows fabrication of complex features along with precise spatial distribution of biological factors inside a single scaffold (e.g., abstract), one of ordinary skill in the art would have had a reason to choose DLP in order to take advantage of this simple and fast technique to make the scaffold.
In regard to a buffer solution, Shiwarski summarizes 3D printing as a platform for advanced tissue biofabrication (e.g., abstract). Shiwarski teaches a buffer solution such as HEPES can be added to allow cell survival in a CO2 independent environment and to neutralize acidified bioinks (p. 5, right col, para 1), and teaches a bioink comprising a buffer solution comprising 50mM HEPES in PBS (see Table I, row 3 and row 4).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the synthetic bioink by combining a buffer solution comprising HEPES in 1X PBS at a physiological pH as suggested by Shiwarski with a reasonable expectation of success. Since Shiwarski teaches a buffer solution HEPES can be added to neutralize acidified bioinks (p. 5, right col, para 1) and reduces to practice a bioink comprising a buffer solution comprising 50mM HEPES in PBS (see Table I, row 3 and row 4), one of ordinary skill in the art would have had a reason to combine a buffer solution comprising HEPES in PBS as suggested by Shiwarski in order to neutralize the bioinks to maintain a physiological pH.
Furthermore, regarding the differences in concentration from Shiwarski (50 mM HEPES) and the instant invention (0.1 M HEPES), it would have been obvious for one ordinary skill in the art to apply the claimed working concentrations because they are the result of “routine optimization”. See MPEP 2144.05(II)(A).
In regard to mono- and di- cysteine peptides in the bioink, Lutolf teaches engineering synthetic poly(ethylene glycol) (PEG)–based hydrogels as cell-ingrowth matrices (e.g., abstract). Lutolf teaches the PEG-based hydrogel contains a combination of pendant oligopeptide ligands for cell adhesion (C-RGDSP, i.e., a mono-cysteine peptide comprising RGDS) and substrates for matrix metalloproteinase (MMP) (Ac-GCRD-GPQGIWGQ-DRCG-NH2, see p. 517, left col, para 1 and Fig 1, i.e., a degradable peptide and a dicysteine peptide). Lutolf teaches about 0.25 mM RGD in the hydrogel (p. 517, para 1).
Therefore, it would have been obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the synthetic bioink by combining a mono-cysteine peptide RGDS and a degradable dicysteine peptide as taught by Lutolf with a reasonable expectation of success. Since Lutolf teaches a combination of a mono-cysteine peptide for cell adhesion (C-RGDSP) and a MMP-degradable dicysteine peptide enables cells to migrate within the matrices by integrin- and MMP-dependent mechanisms, and demonstrates cell-mediated proteolytic invasiveness (e.g., abstract), one of ordinary skill in the art would have had a reason to combine a mono-cysteine peptide comprising RGDS and a MMP-degradable dicysteine peptide as suggested by Lutolf in the bioink in order to enhance cell adhesion and to enable cell-mediated proteolytic migration to study cell-cell interactions.
Furthermore, regarding the differences in concentration from Lutolf (about 0.25 mM RGD) and the instant invention (from 0.5 mM to 20 mM of mono- and di-cysteine peptides), it would have been obvious for one ordinary skill in the art before the effective filing date of the claimed invention to apply the claimed working concentrations because they are the result of “routine optimization”. See MPEP 2144.05(II)(A).
Since the instant application claims are obvious over cited application claims, in view of Maoz, Lu, Shiwarski and Lutolf, said claims are not patentably distinct.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims in the copending application have not in fact been patented.
Conclusion
No claims are allowed.
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/JIANJIAN ZHU/Examiner, Art Unit 1631