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 1-3, 5, 7-12, 14-19, 21-22, 37 and 40 are currently pending in this application.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-5, 7-12 and 14-21, in the reply filed on Sept. 17, 2025 is acknowledged. Claim 22 is withdrawn for being directed to non-elected subject matter, and claims 1-3, 5, 7-12, 14-19, 21, 37, and 40 have been considered on the merits.
Benefit of Priority Claim
Acknowledgement is made of applicant’s claim for the benefit of the prior-filed application US 63/004,537 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c). 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. 63/004,537, 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. Entitlement to priority to April 3, 2020 based on 63/004,537 does not apply to the subject matter of claims 5 and 12, therefore the earliest effective filing date of claims 5 and 12 is April 5, 2021 based on PCT/US2021/025471.
Previous Rejections
Status of the rejections: the previous claim rejections under sections 112(a), 112(b), 112(d), 102(a)(1), 103 and double patenting are withdrawn in view of the claim amendments.
Claim Objections
Claim 5 is objected to because of the following informalities: while not insolubly ambiguous, it would be clearer to add the term “bacterium” or “bacteria” after each of the terms Akkermansia muciniphila, Bifidobacterium spp., and Lactobacillus spp. Appropriate correction is requested.
Claim Interpretation
In claim 1, the phrases “configured to be in contact with” regarding a surface of a cell support structure is not interpreted as limiting and, thus, the first and second surfaces may be of any shape that provides support to the cells (including flat, tubular, ellipsoid, etc. (see instant [0087])).
In claim 1, the phrase “induce luminal fluid secretion” is interpreted as meaning secretion, on the apical side of a cell layer, of a liquid of any minimal amount, such as forming an aqueous viscous colloid suspension or aqueous solution at the first surface.
In claim 5, the “adding” is interpreted as requiring contacting the differentiating stem cells and/or EEC-enriched monolayer with said recited agent, e.g., via contacting cells or the first and/or second surface with a aqueous solution or medium comprising said agent.
In claims 14-16, the respective phrases reciting “induces,” “blocks,” or “potentiates” “secretion of hormones from EECs” is interpreted as limiting the one or more “drug, metabolite, foodstuff and/or compound” to ones already known to “induce,” “block,” or “potentiate,” respectively, a secretion of hormones from EECs.
In claim 15, the term “blocks” is interpreted as encompassing both a partial block and a complete block of secretion.
In claim 17, the phrase “stem cells comprise gastrointestinal epithelial cells” is interpreted to require the gastrointestinal epithelial cells to be stem cells, i.e., capable of differentiating into enteroendocrine (EEC) cells as well as capable of self-renewal into more undifferentiated cells having said EEC-differentiating capability. However, this limitation does not require all stem cells to be gastrointestinal epithelial stem cells.
In claim 21, the “adding” is interpreted as contacting the any of the final cell construct, stem cells, EECs, subtypes of EECs, cells of the first surface with a Wnt signaling activator or Wnt signaling enhancer.
Claim 37 requires exposing the stem cells in step (b) to serotonin and/or gastrin (e.g., whether exogenously added or naturally produced), which is interpreted as anytime during the “differentiating” step (b) meaning as matter of logic as occurring after step (a) but prior to the completion of step (b) to produce EEC and subtypes of EEC, such as prior, during and/or after exposing the stem cells to VIP.
35 USC § 112(a) – Scope of Enablement (new)
Claims 1-3, 5, 7-12, 14-19, 21, 37, and 40 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because while enabled for wherein the stem cell is gastrointestinal, the amount of VIP sufficient to induce luminal fluid secretion is between 10-100 nM, and there is an initial exposure of the luminal side to air interface (i.e., VIP-assisted ALI format); the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, for any stem cell, any type of maintaining a fluid layer at the first surface, and without using an air interface (e.g., a liquid interface).
Enablement is considered in view of the Wands factors (MPEP 2164.01 (a)). The court in Wands states that "Enablement is not precluded by the necessity for some experimentation such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is 'undue.' Not 'experimentation;" (Wands, 8 USPQ2d 104). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighting many factual considerations." (Wands, 8 USPQ2d 1404).
The factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation required is “undue” include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Furthermore, the USPTO does not have laboratory facilities to test if an invention will function as claimed when working examples are not disclosed in the specification. Therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention. And thus, skepticism raised in the enablement rejections are those raised in the art by artisans of expertise.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature and breadth of the invention:
In the instant case, claim 1 is broad in several aspects, at least regarding:
(1) the functionally defined amount of VIP “sufficient to induce luminal fluid secretion,”
(2) the scope of “maintaining” a layer of fluid at the first surface and “configured to” be in contact with a liquid or an air-liquid interface, and
(3) the genus of stem cells.
All the claims encompass any means of maintaining a layer of fluid at the first surface during the differentiating step of about 0.1-1.0 mm, such as by intentionally adding exogenous fluid or by removing fluid in excess of about 1.0 mm.
All the claims require an amount of VIP defined merely functionally as sufficient to induce luminal fluid secretion. This amount seems to encompass amounts of VIP already shown to induce luminal fluid secretion in any situation, e.g., in vitro, in vivo or in explant cultures.
Claims 1-3, 5, 7-12, 14-16, 21, 37 and 40 encompass wherein the stem cell is any stem cell defined merely functionally as “capable of differentiating into EECs.” This genus of stem cells encompasses primary stem cells, mesenchymal stem cells, pluripotent stem cells, embryonic stem cells and immortalized cell line cells (e.g., Caco-2) under certain culture conditions; however the culture conditions are unlimited by the claims and left to the discretion of the ordinary artisan in view of the guidance in the written description. However the instant specification fails to provide any clear description of a representative number species for this genus beyond mammalian intestinal epithelial stem cells.
All the claims encompass wherein the culturing of the stem cells is under a liquid or an air interface (or alternating combination thereof) but the differentiating stem cell step requires a liquid interface at the first surface of at least about 0.1 mm to about 1.0 mm. Thus, the claims are broad in that neither an air interface at the first surface is required but may be optionally be applied outside of the differentiating step.
The prior art teaches culturing human intestinal organoid-derived or mouse intestinal-derived crypt cells comprising stem cells (e.g., Lgr5+ EEC stem cells) as a monolayer confluently covering a permeable membrane in a Transwell® support structure will spontaneously differentiate into EEC lineages, e.g., chromogranin A+ EECs (Kozuka et al., Stem Cell Reports 9: 1976-90 (2017); IDS ref., at Figs. 1B-C, 3A-B, 4B, 4G and 5; pg. 1978, right col., last para., to pg. 1979, left col., 2nd para.). The prior art teaches adding cytokines like BMP-4 can increase EEC Chga marker expression (FIG. 2, pg. 1980, left col., 2nd para. to right col., 2nd para.). The prior art teaches setups for in vitro mucosal cell monolayer maintenance (e.g., using cells dissociated from gut organoids) having an air-mucus (liquid) interface, and that Notch inhibitor may induce mucus production in some models (Lock et al., Adv Drug Deliv Rev 124: 34-49. (2018) at Fig. 4; pg. 40, left col., 2nd para.) or an adjustable, dynamic air-liquid interface (Wang et al., Cell 179: 1144-59 (2019) at e4 (ALI culture), pg. 1147, right col., Fig. 2 and 4, Graphical abstract).
Regarding VIP effective amounts, the prior art teaches VIP may cause secretion in a 0.1-100 nM range and VIP signals via its receptor VPAC in nanomolar concentrations (e.g., between 1-10 nM or at 10-7 M), at least in an immortalized colon cancer cell lines under certain conditions (HT-29-Cl.16E or HM3M2) (Laburthe et al., Am J Physiol 256: G443-50 (1989) at abstract, Fig. 3, 5; Hokari et al., Am J Physiol Gastrointest Liver Physiol 289: G949-59 (2005), IDS ref; at Fig. 1B, 3, G950, right col.).
The disclosure provided by the applicant, in view of prior art, must encompass a wide area of knowledge to a reasonably comprehensive extent. In other words, each of these aspects must be shown to a reasonable extent so that one of the ordinary skills in the art would be able to practice the invention without any undue burden being on such Artisan.
The only working embodiments in the instant application are limited specifically to human colonic stem cells (transverse colon) and “ALI” culture relying on an initial exposure to air before a sufficient apical/luminal fluid layer is formed, i.e., due to mucus secretions (Examples 1-8). Importantly the instant application is silent as to the type of MSC used in any embodiment or skipping the air interface step and progressing from submerged culture directly to the differentiating step under at least about 0.1 mm surface liquid. Thus, there is no evidence in the art or the instant application that the method recited in claim 1 would predictably produce the claimed live cell construct having a continuous cell monolayer comprising many EECs and subtypes thereof, such as having the requisite characteristics of any of dependent claims 8-12. There is no evidence in the instant application or the prior art for possession of all stem cells capable of differentiating into EECs can be made into the claimed live cell construct, such as with the requisite characteristics of any of dependent claims 8-12. Further, there is no evidence in the instant application or the prior art for possession when no air interface at some point during the differentiating step, e.g., at the beginning before a significant number of cells have finished differentiating into mucus-secreting cells.
By reciting “amount sufficient” of VIP in claim 1, applicant admits there are amounts that may be administered which are not effective to induce luminal fluid secretion and/or maintain a layer of 0.1 to 1.0 mm of fluid at the first surface, and thus, there exists a definable boundary between effective and ineffective amounts. While routine experimentation may allow identification of effective amounts of VIP, one needs guidance as to a starting amount to test and then routinely vary the amount from there with luminal secretion from the cell construct as a results-effective variable. The only guidance in the instant application is VIP+ condition without any specific amount described.
Thus, the effective amount must be determined without guidance while varying three other parameters: stem cell type, air or liquid interface configuration, and fluid maintaining method (i.e., via secretion and/or intentional fluid addition/removal).
From the empirical data, it is not predictable that a sufficient amount of VIP exists across the scope of stem cells and non-air interface configurations. Further, nnowhere does the specification provide any working example for different methods of maintaining the fluid layer at the first surface. Furthermore, the term “sufficient amount” has been held to be indefinite when the claim fails to state the function which is to be achieved and more than one effect can be implied from the specification or the relevant art. In re Fredericksen, 213 F.2d 547, 102 USPQ 35 (CCPA 1954). MPEP 2173.05(c). Thus, the claims may be indefinite by reference to an amount to “induce luminal fluid secretion” instead of causing actual secretion and/or producing a fluid layer of at least 0.1 mm (MPEP §2173.05(b)) depending on other parameters simultaneously as discussed above. The dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim.
The skilled artisan could not rely upon the combination of the prior art and the disclosure in the specification such that the specification would sufficiently describe that Applicant has enabled the full scope of the broad method of claim 1 as discussed above based on such limited guidance.
Moreover, nothing in any individual dependent claim alone cures this deficiency. Regarding claim 8, nothing in claim 1 ensures this claim limitation is predictably met as in the working example at Example 2-3 (FIG. 4D), i.e., an apparent permeability coefficient (Papp) of at least 4 x 10-7 cm/s. This result is dependent on the culture conditions (stimulants added), the air interface (complete drying and/or liquid layer height and oxygenation), and an amount of VIP sufficient to alter barrier impermeability not to induce a minimal luminal secretion in some context. Regarding claims 14-16, a method comprising a step of screening of a drug, metabolite, foodstuff, or compound already known to “induce,” “block,” or “potentiate” “secretion of hormones from EECs is not sufficiently described in the instant specification. Instead the specification implies agents having unknown properties are “screened” in search for ones having such activating or potentiating properties.
In conclusion, given the lack of working examples, the limited guidance provided in the specification, the lack of guidance in the prior art, and the broad scope of the claims, the skilled artisan could not rely upon the disclosure at the filing date such that the specification sufficiently describes how to make and use without undue/unreasonable experimentation the full scope of methods recited in any one of claims 1-3, 5, 7-12, 14-19, 21, 37, and 40.
Claim Rejections - 35 USC § 112(b) (new)
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 14-16 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.
The claims are interpreted as set forth in a previous section.
Claims 14-16 recite the process step of “screening” a drug, metabolite, food or compound “that” respectively “induces,” “blocks,” or “potentiates” secretion of hormones.” As noted above, this agent is one already known to “induce,” “block,” or “potentiate,” respectively, a secretion of hormones from EECs, and thus it is incoherent and unclear as to how/what “screening” is performed on such agents. Are the agents being screened for any specific effect, e.g., related to obesity, metabolism, infection, EEC formation, secretion levels, 5HT, GLP-1, PYY, cholecystokinin, motilin, neurotensin, leptin, secretin, or dose-effect (see instant pg. 10, line 30, to pg. 13, line 22; pg. 16, lines 6-14, Example 5 and 6, FIG. 10)? Are the agents being screened alongside other agents that have an unknown effect or to compare relative effects? It would be remedial to add a type of screening, such as a readout of detecting X or identifying Y among a pool of agents.
Claim Rejections - 35 USC § 112(d) (new)
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 3 and 8 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.
Claim 3 recites the layer of fluid at the first surface is maintained in a range of about 0.001-10 mm above the cell monolayer; however claim 1 already limits the layer of fluid at the first surface be in a narrower subrange of about 0.1-1.0 mm. Thus, claim 3 attempts to broaden the scope of claim 1 from which it depends.
Claim 8 recites the cell monolayer maintains an apparent permeability coefficient (Papp) of at least 4 x 10-7 cm/s but does not recite any active process step or limitation to any step or structure used therein of claim 1. Thus, claim 8 fails to narrow the subject matter of claim 1. To the extent applicant argues otherwise, see 112(a) rejection above.
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 § 103 (new)
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 1-2, 5, 8-12, 14-19, 21, 37 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Boccellato (WO2019/141824A1; IDS ref.) in view of Iwasaki (Iwasaki et al., F1000Res 8: F1000 Faculty Rev-1629 (2019)).
The claims are interpreted as set forth in a previous section.
Regarding claim 1, Boccellato teaches methods of long-term culturing live cell constructs comprising epithelial cells (mucosoid culture) (pg. 1, 1st para.; pg. 8; pg. 20, lines 1-6) formed by (a) culturing stem cells (pg. 10, lines 6-15 (e.g., epithelial stem cells from gastric or colon mucosa) pg. 59, lines 5-12, pg. 60, lines 1-7 and 22-28) that are capable of differentiating into enteroendocrine cells (EECs) on a cell support structure (thin matrix-coated solid semi-permeable filter) comprising both a first surface configured to be in contact with a liquid or an air-liquid interface and a second surface configured to be in contact with a liquid interface (pg. 10, last para., to pg. 11, 1st para.; FIG. 1; pg. 4, 1st para.), until at least a portion of the first surface of the cell support structure is substantially covered by cells (pg. 10, lines 18-20); and (b) differentiating the stem cells into EECs cells by exposing the stem cells to one or more chemicals/hormones that induces secretion (pg. 15, line 18-22; pg. 2, line 4, e.g., gastrin), and by maintaining a thin layer of fluid at the first surface of the cell support structure (FIG. 1), thereby generating an EEC-comprising (“enriched”) live cell monolayer construct (polarized, mucus-secreting epithelial layer) comprising CHGA positive EECs, mucus-secreting EEC subtypes (e.g., MUC5+, MUC6+, and/or MUC2+) and EEC stem cells (LGR5+, β-catenin+, and CD44+) (Examples 1-2; FIG. 2, 8-10; pg. 19, lines 11-16, 18-23).
Although Boccellato does not disclose wherein the hormones or agents expressly includes vasoactive intestinal peptide (VIP) and VIP is added to differentiating stem cells in a specific amount to induce luminal secretion, VIP was already known in the prior art as having luminal fluid secretion inducing properties, e.g., via CFTR activation and anion secretion, as well as mucosa impermeability enhancing properties, e.g., via tight junction upregulation (Iwasaki at pg. 5, left col., 3rd para., to pg. 6, left col., 3rd para.).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to perform a method of Boccellato wherein once a mucus layer is begun to be produced to add VIP to the medium with the goal of stimulating more mucus production and mucosa structural integrity. One of ordinary skill in the art would be motivated by Iwasaki teaching, via CFTR activation and anion secretion, as well as mucosa impermeability enhancing properties, e.g., via tight junction upregulation (Iwasaki at pg. 5, left col., 3rd para., to pg. 6, left col., 3rd para.).
Regarding claim 2, Boccellato teaches wherein the fluid layer comprises a liquid, e.g., fluid materials or mucus released by the mucosoid (FIG. 1; pg. 5, lines 23-25).
Regarding claim 5, Boccellato teaches adding to the medium IL-1β or TNF-α (FIG. 16, pg. 53, last para.; Example 9).
Regarding claims 8-12 and 14-16, as none these claims recites any active process step or implied limitation to the method of claim 1, these claims are obvious over Boccellato in view of Iwasaki teaching methods comprising the same active steps as claim 1 as set forth above.
Regarding claims 17-19, Boccellato teaches wherein the stem cells are derived human gastrointestinal epithelia from gastric or colon tissues (Examples 1-2).
Regarding claims 21 and 40, Boccellato discloses wherein the culturing medium comprises the Wnt signaling activator CHIR99021 and the Wnt signaling enhancers WNT3A and R-spondin1 (Example 2).
Regarding claim 37, Boccellato teaches wherein gastrin is added to the culture medium (Table 1, pg. 33, line 16, Example 2).
Claims 1-3, 5, 7-12, 14-19, 21, 37 and 40 are rejected under 35 U.S.C. 103 as being unpatentable over Boccellato in view of Iwasaki as applied above, and further in view of Sontheimer (Sontheimer-Phelps, A., et al., Cell Mol Gastroenterol Hepatol 9: 507-26 (2020)).
Regarding claims 3 and 7, Boccellato and Iwasaki does not teach maintaining the fluid layer at the first surface in a range of about 0.001 mm to about 10 mm above the cell monolayer or maintaining the fluid layer at the first surface using a microfluidic flow step.
However Sontheimer teaches microfluidic setups for intestine or colon tissue polarized epithelial monolayer culture “on-a-chip” that resembles in vivo tissues made from differentiating primary epithelial stem cells (Abstract, pg. 508, right col., last para.; Fig. 2-3; pg. 518, right col., 1st para.). Sontheimer teaches the microfluidic colonic monolayer setup maintains epithelial stem cell proliferation while providing differentiated cells that reconstitutes a mucus bilayer and can be used to assay changes in mucus physiology in response to stimuli (pg. 513, right col., 2nd para.; Fig. 7, 9-10). Sontheimer teaches wherein the fluid layer on the first surface is constrained to 1 mm (1000 µm) (pg. 2020, left col., 2nd para.) and the total height of the mucus layer is measured to be at least 300-600 µm (Fig. 8, Fig. 9E).
It would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to use a microfluidic setup taught by Sontheimer to perform a method of Boccellato wherein the fluid layer above the first surface is 1 mm or less as in Sontheimer. One of ordinary skill in the art without the goal of replicating natural gut epithelia and its mucus layer would be motivated by Sontheimer showing microfluidic culture achieves such close resemblance to human colonic epithelia and mucus layers and associated apparatus for assaying changes in mucus physiology (Fig. 7A). Furthermore Boccellato teaches using its methods for human medical applications, growing human cells and tissues recapitulating natural ones, investigating responses to stimuli and mimicking pathological conditions, e.g., for screening diagnostic or therapeutic agents (pg. 3, lines 1-11; pg. 21, line 20, to pg. 22, line 4; pg. 26, line 25, to pg. 30 line 2; pg. 1, lines 28-29).
Thus, the claimed invention as a whole is prima facie obvious prior to the earliest effective filing date in the absence of evidence to the contrary.
Response to arguments
Applicant’s arguments filed 5/19/26 regarding the 103 rejections (pg. 11-12) have been fully considered and found persuasive regarding the previous rejections.
In the new prima facie rejection laid out above, the prior art teaches methods encompassing performing submerged and/or ALI culture with exogenous VIP added, regardless of whether before the earliest effective filing date one of ordinary skill in the art would appreciate the effect of VIP on goblet cell, EEC, and/or EC formation rates. The motivation is to increase mucus production and/or mucosa structural integrity of the in vitro EEC construct as taught by Iwasaki. Thus, there is sufficient motivation to perform all the active method steps in the prior art regardless of whether any specific advantageous characteristics were appreciated or expected prior to the instant filing date and by the logic of the claims as drafted, all these advantageous characteristics would be inherently present merely by performing such active method steps absent evidence to the contrary.
Applicant traverses prima facie obviousness (pg. 12-13) by pointing to unexpected results, including barrier integrity properties (e.g., Papp), increased goblet cell formation, increased mucus secretion/accumulation, and synergy of combining an air-liquid interface (ALI) format with adding effective amount of VIP to cause a greater number of enteroendocrine (EEC) (377%) and enterochromaffin cells (EC) (430%) formed compared to traditional submerged culture without exogenous VIP (termed “VIP-assisted ALI culture”) (see instant Examples 2-3, [0113], FIG. 3-4). This is misleadingly presented, as there is merely an increased in formation of EECs by 118% (377-259%) and ECs by 180%) (430-260%) over the prior art at best by the instant data presented in view of the alternative comparator of prior art ALI culture without exogenous VIP. Regardless, there this is evidence of both an improvement and the purported synergy.
From the instant specification the prior art ALI format is understood to require an “air” interface at the apical side that is completely dry (at least at some point before and/or during differentiating); however, the instant claims encompass wherein this interface is either dry prior to the differentiating step or in contact with a liquid during the entire method as the claims expressly require an apical fluid layer of about 0.1-1.0 mm be present during the entire differentiating step FIG. 1, 3, [0021], [0023]; Wang et al., Cell 179: 1144-59 (2019) at e4 (ALI culture), pg. 1147, right col., Fig. 2 and 4, Graphical abstract).
Thus, it is noted that not all the features upon which applicant relies for unexpected results are required in the rejected claims (i.e., avoiding prior art ALI culture formats and any specific level of goblet cell, EEC and EC cell formation). Instead, the claims recite exposing the cells to sufficient VIP to “induce luminal fluid secretion” and a first surface configured to be in contact with a liquid (e.g., submerged) or an air-liquid interface. Thus, the only unexpected result possibly ensured to be present concerns increased mucus secretion/accumulation compared to prior art methods due to the VIP limitation, which is functional tied in amounts only requiring a de minimums level of luminal fluid secretion but not to any level for goblet, EEC and/or EC cell formation or barrier integrity property. In other words, the purported unexpected results are not commensurate in scope with the claimed method that is not limited to exclude either (1) a submerged format or (2) an ineffective amount of VIP to ensure the purported synergy resulting in an unexpected increase(s) in barrier integrity and/or goblet, EEC, and/or EC cell formation over what is expected from the teachings of the prior art.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERIC J ROGERS whose telephone number is (571)272-8338. The examiner can normally be reached Monday - Friday 9:00-6:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached on (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ERIC J ROGERS/Examiner, Art Unit 1638
/Tracy Vivlemore/Supervisory Primary Examiner, Art Unit 1638
Prosecution Insights