DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
As of the Non-Final Office Action mailed 5/23/2025, claims 32-37 and 39-54 were pending and claims 32, 34-35, and 52-53 were withdrawn from consideration for being drawn to non-elected invention(s).
In Applicant's Response filed on 8/25/2025, claims 33, 39-41, 43-44, and 50 were amended.
As such, claims 32-37 and 39-54 are pending and claims 33, 36-37, 39-51, and 54 have been examined herein.
Withdrawn Objections/Rejections
The objection of record to claims 33 and 40 for minor informalities has been withdrawn in view of Applicant’s amendment to claims 33 and 40.
The rejection of record of claim 41-42 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 41.
The rejection of record of claim 43 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 43.
The rejection of record of claim 44 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 44.
The rejection of record of claim 50 under 35 USC § 112(b) have been withdrawn in view of Applicant’s amendment to claim 50.
The rejection of record of claims 33, 36-37, 39-51, and 54 under 35 USC 101 for being directed to a judicial exception (natural correlation and abstract idea) without significantly more have been withdrawn in view of Applicant’s amendment.
The rejection of record of claims 33, 36-37, 39-51, and 54 under 35 USC 112(a) enablement have been withdrawn in view of Applicant’s amendment.
Maintained Rejections
The rejection of record of claims 33, 39-40, 43, and 54 under 35 USC § 103 as being unpatentable over Matsunaga et al (WO 2018207714 A1, 2 May 2018; Published 15 Nov 2018) in view of Spence et al (Nature, 12 Dec 2010; 470(7332):105-109; Ref. 592 of Non-Patent Literature Documents in IDS filed 2 Nov 2021; previously cited), McGrath et al (Diabetes, 29 Jan 2015; 64(7):2497-2505; Ref. 8 of Non-Patent Literature Documents in IDS filed 27 Oct 2021; previously cited), and Huch Ortega et al (US 10597633 B2, 16 May 2014; published 6 July 2017) as evidenced by Raouf et al (Cell Mol Gastroenterol Hepatol. 2 Mar 2024;18(1):53-70; previously cited) have been fully considered but are not persuasive. Thus, the rejection has been maintained. Response to arguments will follow the recast rejection.
The rejection of record of claims 36-37 under 35 USC § 103 as being unpatentable over Matsunaga et al in view of Spence et al, McGrath et al, and Huch Ortega et al as applied to claims 33, 39-40, 43, and 54 above, and further in view of Clark et al (Am J Physiol Gastrointest Liver Physiol. 2 Apr 2009; 296(6):G1151-66.; Ref. 112 of Non-Patent Literature in IDS filled 2 Nov 2021) have been fully considered but are not persuasive. Thus, the rejection has been maintained. Response to arguments will follow the recast rejection.
The rejection of record of claims 41-42, 44, 47-49, and 51 under 35 USC § 103 as being unpatentable over Matsunaga et al in view of Spence et al, McGrath et al, and Huch Ortega et al as applied to claims 33, 39-40, 43, and 54 above, and further in view of Levy et al (US 20130281374 A1, 17 Aug 2007; Ref. 5 of US Patent Documents in IDS filed 27 Oct 2021; previously cited) have been fully considered but are not persuasive. Thus, the rejection has been maintained. Response to arguments will follow the recast rejection.
The rejection of record of claims 45-46 and 50 under 35 USC § 103 as being unpatentable over Matsunaga et al in view of Spence et al, McGrath et al, and Huch Ortega et al as applied to claims 33, 39-40, 43, and 54 above, and further in view of Cho et al (US 20100048871 A1, 4 Nov 2009; Ref. 3 of US Patent Documents in IDS filed 27 Oct 2021; previously cited) have been fully considered but are not persuasive. Thus, the rejection has been maintained. Response to arguments will follow the recast rejection.
New Grounds of Rejections Necessitated by Amendments
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 33, 36-37, 39-51, and 54 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 33 recites “a subject” in the preamble and in step (c). It is unclear whether the subject in step (c) is the same as the subject recited in the preamble. Thus, the claim is indefinite. For the purpose of compact prosecution, the examiner is interpreting that the subject receiving the treatment is the same.
Claim 33 further recites “a malabsorptive disorder” in step (c) and the administration step. It is unclear if the malabsorptive disorder recited in step (c) and the administration step is the same as the “malabsorptive diarrhea due to EEC dysgenesis” as recited in the preamble. Thus, the claim is indefinite. For the purpose of compact prosecution, the examiner is interpreting that the disorders are the same.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 33 recites the broad recitation of “malabsorptive disorder,” and the claim also recites “malabsorptive diarrhea due to EEC dysgenesis” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 39 recites, inter alia, “wherein the malabsorptive diarrhea further comprises metabolic acidosis . . . malnutrition.” Metabolic acidosis and malnutrition are not a “malabsorptive diarrhea” and there is no nexus between these two diseases and EEC dysgenesis as instantly claimed. Thus, the claim is indefinite. Claim 40 is included in this rejection for being dependent on indefinite claim 39.
Please note that claims 36-37, 39-51, and 54 are included in this rejection for being dependent on indefinite claim 33.
It is noted that any interpretation of the claims set forth above does not relieve Applicant of the responsibility of responding to rejections made based on said interpretations. If the actual interpretation of the claims is different than that posited by the Examiner, additional rejections and art may be readily applied in a subsequent final Office action.
Claim Rejections - 35 USC § 103 - Maintained
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 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.
Claim(s) 33, 39-40, 43, and 54 remain rejected under 35 U.S.C. 103 as being unpatentable over Matsunaga et al (WO 2018207714 A1, 2 May 2018; Published 15 Nov 2018; previously cited) in view of Spence et al (Nature, 12 Dec 2010; 470(7332):105-109; Ref. 592 of Non-Patent Literature Documents in IDS filed 2 Nov 2021; previously cited), McGrath et al (Diabetes, 29 Jan 2015; 64(7):2497-2505; Ref. 8 of Non-Patent Literature Documents in IDS filed 27 Oct 2021; previously cited), and Huch Ortega et al (US 10597633 B2, 16 May 2014; published 6 July 2017; previously cited) as evidenced by Raouf et al (Cell Mol Gastroenterol Hepatol. 2 Mar 2024;18(1):53-70; previously cited).
Matsunaga teaches a method for producing an intestinal organoid from pluripotent stem cells, where the pluripotent stem cells are induced pluripotent stem cells or embryonic stem cells from a human and the pluripotent stem cells are derived from a patient with intestinal disease (see claims 1-2, and 5 of Matsunaga) (“wherein the pluripotent stem cells are derived from the subject” as in instant claim 54). Disease-specific intestinal organoids can be produced from patients having intestinal diseases such as inflammatory bowel disease (Crohn’s disease, ulcerative colitis) and can be used to as drug evaluation systems (“Technical field” para 8) (“wherein the malabsorptive disorder comprises . . . inflammatory bowel disease” as in instant claim 39; “wherein the inflammatory bowel disease comprises Crohn’s and/or colitis” as in instant claim 40). The reference also teaches a method for evaluating the pharmacokinetics of a test substance using the created organoid, where the test substance is brought into contact with the organoid and the metabolism, absorbability, membrane permeability, drug interaction, drug metabolizing enzyme induction, drug transporter induction, or toxicity of the test substance is evaluated or measured (see claims 17 and 19 of Matsunaga). The reference also teaches metabolism, absorption, drug interaction, etc., can be measured and evaluated using, for example, fluorescence immunoassay (FIA) (p. 7 of Translation, para 10). This reads on “screening a compound in vitro . . . comprising a) contacting an intestinal organoid with a compound in vitro wherein the intestinal organoid . . . is differentiated from pluripotent stem cells . . . (b) assessing one or more effect of the compound . . . in the intestinal organoid by immunofluorescence” as in instant claim 33 in-part.
Matsunaga differs from the instant invention in that it does not teach that the organoid comprises a null mutation in Neurog3, lacks EECs, does not express CHGA, and that the tested compound is administered to the subject after determination of effectiveness.
Spence teaches the directed differentiation of human pluripotent stem cells into intestinal tissue to create three-dimensional intestinal organoids (abstract and p. 6, “Generation of human intestinal organoids”). 28-day intestinal organoids generated using shRNA-expressing lentiviral vectors for NEUROG3 knockdown results in 63% reduction in NEUROG3 mRNA (p. 15 of Supplementary Information, Fig. 15f) and 90% reduction in enteroendocrine cells in the organoid (“intestinal organoid comprises a null mutation in NEUROG3, lacks enteroendocrine cells” as in instant claim 33 in-part). The reference also teaches PSC-derived human intestinal tissue allows for functional studies to investigate the molecular basis of human congenital gut defects in vitro and to generate intestinal tissue for eventual transplantation-based therapy for diseases such as necrotizing enterocolitis, inflammatory bowel diseases and short gut syndromes as well as facilitate future studies of drug design to enhance absorption and bioavailability (p. 5, para 3).
McGrath teaches that NEUROG3 knockdown (NEUROG3-/-) (i.e., null mutation) is sufficient to cause a complete absence of CHGA protein and mRNA, leading to lack of enteroendocrine cell development (p. 2499, Results; p.2503, Discussion, para 1) (“null mutation in NEUROG3, lacks enteroendocrine cells, and does not express Chromogranin A (CHGA)” as in instant claim 33 in-part). The teachings of McGrath show that NEUROG3 null mutation causes both loss of CHGA expression and lack of enteroendocrine cell development.
Huch Ortega teaches uses of organoids (abstract). The reference teaches that an intestinal organoid can be used to study diseases such as cystic fibrosis, inflammatory bowel disease (such as Crohn's disease) and in drug discovery screening, toxicity assay, or regenerative medicine (“Uses of Organoids” para 1 and 10-11). The reference also teaches that the organoid can be used for testing individual patient responses to specific drugs and tailoring the treatment based on responsiveness (“Drug Screening” para 2). The reference further teaches a method of treating a patient comprising obtaining a biopsy from the diseased tissue of interest, culturing the cells obtained from the biopsy to obtain an organoid, screening a suitable drug using a screening method and treating said patient with the screened drug (Drug screening, para 11). The drug is used for treating or ameliorating symptoms of metabolic diseases such as inflammatory bowel disease such as Crohn’s disease (Drug screening, para 12). This reads on “determining whether the compound will be effective in treating a malabsorptive disorder in a subject based on the assessed effect of the compound on the intestinal organoid or enteroid; and administering the compound to the subject when the compound is determined in step c) as being effective in treating a malabsorptive disorder” as in instant claim 33 in-part.
Finally, evidentiary reference Raouf teaches that mouse models with reduced EECs had severe
colitis, indicated by colon histology, significantly more body weight loss, colon shortening, and increased TNF expression compared to wild type strains (“Mouse models with reduced EECs” para 1; Fig. 12A-C).
This shows that reduced/lack of enteroendocrine cells is present in colitis, and thus, the subject with colitis would be EEC-deficient/have a decreased EEC population as claim in instant claim 43.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to use an intestinal organoid created with pluripotent stem cells to screen drugs as taught by Matsunaga, where the organoid has Neurog3 knockdown as taught by Spence, where NEUROG3 null mutation causes lack of Chromogranin A expression and loss of EEC cell development as taught by McGrath, to arrive at the instantly claimed invention. Spence shows that knockdown of NEUROG3 is sufficient to induce 90% reduction in enteroendocrine cells in the organoid. McGrath shows enteroendocrine cells cannot develop when NEUROG3-/- mutation (i.e., null mutation) is present due to lack of CHGA expression. One of ordinary skill would have been motivated to modify the intestinal organoid of Matsunaga to contain NEUROG3 null mutation as taught by Spence and McGrath with the reasonable expectation of advantageously causing no CHGA expression. One of ordinary skill would have been motivated because lack of CHGA expression results in no enteroendocrine cell development and results in recapitulation of inflammatory diseases like colitis in the organoid as evidenced by Raouf.
Finally, it would have been obvious prior to the effective filing date of the instantly claimed invention to create an intestinal organoid as taught by Matsunaga, Spence, and McGrath where the organoid is used to screen drugs and the screened drug is used to treat a subject as taught by Huch-Ortega, to arrive at the instantly claimed invention. As Huch-Ortega shows that an organoid derived from patient cells can be used to screen drugs, one of ordinary skill would have been motivated to use the organoid of Matsunaga, Spence, and McGrath in combination in a similar manner with a reasonable expectation of advantageously testing individual patient responses to specific drugs and tailoring the treatment based on responsiveness as taught by the prior art.
Response to Arguments
Applicant’s arguments have been fully considered but have not been found persuasive.
On p. 13of Remarks, Applicant argues that none of the cited references teaches treating malabsorptive diarrhea due to EEC dysgenesis. Applicant also argues that Huch Ortega has no teachings regarding the use of pluripotent stem cell-derived organoids and states that “”. Thus, Applicant argues that Huch-Ortega teaches away from using pluripotent stem cell-derived organoids as a model system. Finally, Applicant argues that none of the references teach using an intestinal organoid containing a null mutation in NEUROG3 as a model system to screen compounds.
In response, the examiner disagrees. First, as detailed in the above Office action, Matsunaga teaches an intestinal organoid derived from pluripotent stem cells containing a knockdown of NEUROG3 that can be used as drug evaluation systems (“Technical field” para 8) particularly in recapitulated diseases such as inflammatory bowel disease (Crohn’s disease, ulcerative colitis). There is no explicit teaching in Matsunaga that describes the effect of NEUROG3 mutation on expression of CHGA, however, previously cited reference Spence and McGrath each show that (1) knocking down NEUROG3 results in loss of CHGA expression and (2) the loss of CHGA expression results in loss of EEC cells in organoids (see McGrath, p. 2499, Results; p.2503, Discussion, para 1; see Spence, p. 15 of Supplementary Information, Fig. 15f). Thus, the organoid of Matsunaga would have the same lack of CHGA expression and lack of EECs as required by the instant claims. Huch-Ortega teaches that an intestinal organoid can be used to screen a suitable drug using a screening method and treating said patient with the screened drug (Drug screening, para 11). The drug is used for treating or ameliorating symptoms of metabolic diseases such as inflammatory bowel disease such as Crohn’s disease (Drug screening, para 12). Finally, evidentiary reference Raouf illustrates that colitis (as taught by the Matsunaga reference) is a disease due to lack of EECs (i.e., EEC dysgenesis as newly amended). Thus, the references in combination render the instant claims for screening and treating diseases using a model intestinal organoid containing Neurog3 mutation prima facie obvious.
Finally, Applicant is misconstruing the Huch-Ortega reference with respect to the use of PSC-derived organoids. Applicant's assertion needs to be read in context of the reference as a whole. The reference states “Liver cultures derived from hepatocytes, or by differentiation of embryonic stem cells (ES) or induced pluripotent stem cells, are known but these do not expand and self-renew for long periods.” The reference’s disclosure regarding liver cultures derived from hepatocyte or liver cultures derived by differentiation of ESCs or IPSCs cannot be readily extrapolated to include intestinal cultures. When read in context, one of ordinary skill in the art would have readily understood that teaching to be applicable to liver cells cultures and not intestinal organoids. Thus, Applicant’s arguments are not persuasive.
Claim(s) 36-37 remain rejected under 35 U.S.C. 103 as being unpatentable over Matsunaga et al in view of Spence et al, McGrath et al, and Huch Ortega et al as applied to claims 33, 39-40, 43, and 54 above, and further in view of Clark et al (Am J Physiol Gastrointest Liver Physiol. 2 Apr 2009; 296(6):G1151-66.; Ref. 112 of Non-Patent Literature in IDS filled 2 Nov 2021; previously cited).
The teachings of Matsunaga, Spence, McGrath, and Huch Ortega in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 33 of which claims 36-37 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that assessing the effect of the compound on the intestinal organoid or enteroid comprises determining ion transport and/or response to luminal glucose (claim 36) or that ion transport in the organoid or enteroid is determined by measuring basal short-circuit current and/or wherein response to luminal glucose is determined by measuring electrochemical gradients in the Ussing chamber (claim 37).
Clarke teaches a guide to using Ussing chamber (title). The reference teaches that the Ussing chamber provides a physiological system to measure the transport of ions, nutrients, and drugs across various epithelial tissues (abstract, para 1). The passive transepithelial driving force created by the spontaneous electrical potential across the epithelium was eliminated by clamping the potential to zero with an external current passed across the epithelium (Introduction para 1). This current, known as the short-circuit current (Isc), allows the movement of ions as measured by isotopic tracers or the Isc in the Ussing chamber resulted from active transport to be measured (same para). This reads on “assessing the effect of the compound on the intestinal organoid or enteroid comprises determining ion transport” as in instant claim 36 and “that ion transport in the organoid or enteroid is determined by measuring basal short-circuit current . . . in the Ussing chamber” as in instant claim 37.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to use an intestinal organoid to screen drugs and administer the screened drug to a patient as taught by Matsunaga, Spence, McGrath, and Huch Ortega in combination, where the Ussing chamber is used to assess the compound as taught by Clarke, to arrive at the instantly claimed invention. As Clarke shows that Ussing chamber can be used to measure active transport using short-circuit current, one of ordinary skill would have been motivated to simply substitute one known drug screening element [immunofluorescence assay of Matsunaga, Spence, McGrath, and Huch Ortega in combination] for another [Ussing chamber of Clark] to obtain the predictable result of advantageously measuring the transport of ions, nutrients, and drugs across intestinal epithelium as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments challenging the teachings of cited reference Clark nor has Applicant attempted to distinguish the teachings of Clark and the instantly claimed invention.
Claim(s) 41-42, 44, 47-49, and 51 remain rejected under 35 U.S.C. 103 as being unpatentable over Matsunaga et al in view of Spence et al, McGrath et al, and Huch Ortega et al as applied to claims 33, 39-40, 43, and 54 above, and further in view of Levy et al (US 20130281374 A1, 17 Aug 2007; Ref. 5 of US Patent Documents in IDS filed 27 Oct 2021; previously cited).
The teachings of Matsunaga, Spence, McGrath, Huch Ortega in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 33 of which claim 41-42, 44, 47-49, and 51 depend. The teachings will not be repeated here.
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that treating a malabsorptive disorder comprises improving carbohydrate, protein, and/or amino acid absorption, restoring normal electrophysiology, diminishing diarrhea, and/or rescuing postnatal survival (claim 41), improving carbohydrate, protein and/or amino acid absorption comprises improving glucose and/or dipeptide absorption (claim 42), the subject is dependent on parenteral nutrition (claim 44), that the compound is administered with a type of nutrition (claim 47), that the compound and the nutrition is administered in a single composition (claim 48), that the compound is PYY (claim 49), or that the compound is administered for at least one day (claim 51).
Levy teaches a method for non-alimentary nutrition comprising administering parenteral nutrition (i.e., “a type of nutrition” as instantly claimed), a nutritively effective amount of one or more nutrients selected from the group consisting of carbohydrates, ammo acids, lipids, free fatty acids, mono- or diglycerides, glycerol and any combination thereof; and a GIP compound (para 0574) (“wherein the compound is administered with a type nutrition” as in instant claim 47). The reference teaches that GIP compounds reduces the problems associated with parenteral nourishment (same para). The reference also teaches that the GIP compound includes peptide YY (para 0019). Finally, the reference teaches administration infusion treatment of PYY (“wherein the compound is PYY” as in instant claim 49) via infusion for 14 days (para 0530) (“wherein the compound is administered . . . from about one day to about 30 days” as in instant claim 51). The reference also teaches that insulin secretion during parenteral nourishment in the presence of a GIP compound can be controlled such that the plasma glucose increase will be less than without the GIP compound (para 0574) (“wherein improving carbohydrate absorption comprises improving glucose absorption” as in instant claim 42). Administering a GIP compound reduces problems associated with parenteral nourishment to a patient in need of parenteral nutrition (i.e., dependent on parenteral nourishment), where the nourishment is carbohydrate and enhances nutrient metabolism can be achieved in patients with gastrointestinal diseases (para 0574) (“wherein treating malabsorptive disorder comprises improving carbohydrate absorption” as in instant claim 41; “wherein the subject is dependent on parenteral nutrition” as in instant claim 44). While the reference does not explicitly teach a single composition of GIP compound with parenteral nutrition, one of ordinary skill would have reasonably combined PYY with parenteral nutrition into a single composition as the reference teaches that GIP compounds such as PYY reduces parenteral nourishment problems when given in combination as in instant claim 48.
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to use an intestinal organoid to screen drugs and administer the screened drug to a patient as taught by Matsunaga, Spence, McGrath, and Huch Ortega in combination, where the drug is PYY and it is administered with parenteral nutrition as taught by Levy, to arrive at the instantly claimed invention. As Levy shows PYY can be administered with parenteral nutrition, one of ordinary skill would have been motivated to simply substitute the drug to be screened as taught by Matsunaga, Spence, McGrath, and Huch Ortega with PYY as taught by Levy with a reasonable expectation of advantageously screening a drug known to reduces the problems associated with parenteral nourishment as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments challenging the teachings of cited reference Levy nor has Applicant attempted to distinguish the teachings of Levy and the instantly claimed invention.
Claim(s) 45-46 and 50 remain rejected under 35 U.S.C. 103 as being unpatentable over Matsunaga et al in view of Spence et al, McGrath et al, and Huch Ortega et al as applied to claims 33, 39-40, 43, and 54 above, and further in view of Cho et al (US 20100048871 A1, 4 Nov 2009; Ref. 3 of US Patent Documents in IDS filed 27 Oct 2021; previously cited).
The teachings of Matsunaga, Spence, McGrath, and Huch Ortega in combination were recited in the above 35 U.S.C. 103 rejection as applied to claim 33 of which claim 45-46 and 50 depend.
Regarding claim 50, Huch Ortega teaches screening a suitable drug using a screening method and treating said patient with the screened drug where the drug is used for treating or ameliorating symptoms of metabolic diseases such as inflammatory bowel disease such as Crohn’s disease, which reads on “further comprising identifying a compound effective in treating a malabsorptive disorder” as in instant claim 50 in-part (see first 103 rejection above).
The difference between the combined teachings and the invention as instantly claimed is that they do not teach that the compound is administered with one or more additional active component (claim 45), wherein the one or more additional active component comprises a dipeptidyl peptidase-4 ("DPP4") inhibitor and/or a vasoactive intestinal peptide (VIP) inhibitor, administered before, after, or concurrently with administration of the compound (claim 46), or wherein the compound improves nutrient absorption, restores normal electrophysiology, restores intracellular pH, diminishes diarrhea, and/or rescues postnatal survival (claim 50 in-part).
Cho teaches that when administered intravenously, PYY suppresses appetite and food intake in both lean and obese subjects however its oral activity is negligible due to its low absorption and rapid degradation in the gastrointestinal tract (para 0205). The reference also teaches that treatment with DPP-IV inhibitors prevents degradation of Peptide YY (PYY as in instant specification) which has been linked to gastrointestinal conditions such as ulcers, irritable bowel disease and inflammatory bowel disease (para 0210) (“ wherein the compound is administered with one or more additional active component” as in instant claim 45; “wherein the one or more additional active component comprises a dipeptidyl peptidase-4 inhibitor” as in instant claim 46). Peptide YY and its analogs or agonists have been used to manipulate endocrine regulation of cell proliferation, nutrient transport, and intestinal water and electrolyte secretion (i.e., diarrhea) (same para) ( “wherein the compound improves nutrient absorption . . . diminishes diarrhea” as in instant claim 50 in-part). The reference also teaches that conditions or disorders can be alleviated by reducing nutrient availability in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of PYY, a PYY agonist, or a mixture thereof with at least one delivery agent compound (para 0213). Finally, the reference teaches PYY and PYY agonists with the delivery agent compound may be administered separately or together (i.e., concurrently) with one or more other compounds and compositions that exhibit a long term or short-term action to reduce nutrient availability (para 0214) (“administered . . . concurrently with administration of the compound” as in instant claim 46).
Therefore, it would have been obvious prior to the effective filing date of the instantly claimed invention to create an intestinal organoid with NEUROG3 null mutation and assess the effect of compounds on the organoid and administering the assessed compound to the patient as taught by Matsunaga, Spence, McGrath, and Huch Ortega in combination, where PYY is delivered with a DPP4 inhibitor as taught by Cho, to arrive at the instantly claimed invention. As Cho shows that PYY and DPP4 inhibitor can be co-administered, one of ordinary skill would have been motivated to administer PYY with DPP4 inhibitor together with a reasonable expectation of advantageously preventing degradation of PYY, manipulate endocrine regulation of cell proliferation, nutrient transport, and intestinal water and electrolyte secretion, and alleviate conditions and disorders as taught by the prior art.
Response to Arguments
Applicant has not provided any arguments challenging the teachings of cited reference Cho nor has Applicant attempted to distinguish the teachings of Cho and the instantly claimed invention.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 GILLIAN C REGLAS whose telephone number is (571)270-0320. The examiner can normally be reached M-F 7-3.
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/G.R./Examiner, Art Unit 1632
/KARA D JOHNSON/Primary Examiner, Art Unit 1632