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
Claim 1 is currently pending in this application.
Status of Rejections
The previous claim rejections under sections 112(a), 112(b) and 103 are withdrawn in view of applicant’s claim amendments.
Claim Interpretation
In claim 1, the term “definitive endoderm” is interpreted as meaning an in vitro cellular aggregate, typically a monolayer, comprising mostly or entirely definitive endoderm cells, but often comprising iPSCs as well.
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.
Claim 1 is 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 pre-AIA the applicant regards as the invention.
Claim 1 recites the term “Oct3/4,” which is ambiguous and unclear as this term is not defined by the claim or the specification and it is not clear if what is before and after the slash forms a single limitation, recites an optional feature or alternative combinations.
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.
Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Munera (WO 2018/106628 A1) in view of Andrews (WO 2009/093022 A2), McGovern (McGovern et al., Nat Genet 42: 332-7 (2010)), and Fair (Fair et al., Philos Trans R Soc Lond B Biol Sci 373: 20170217 (2018)).
Munera teaches a method of generating induced human colonic organoids (HCOs) from iPSCs (Abstract; [0032]-[0033], [0039]; [0049], [0051]) derived from adult fibroblasts of a human subject to study inflammatory bowel diseases like ulcerative colitis (UC) and potential therapies thereof ([0041]; [00121]; [0081]-[0082]), the method comprising (a) isolating and propagating human fibroblasts from a human subject; (b) contacting human fibroblasts with an expression vector encoding induced pluripotent stem cell (IPSC) reprogramming factors to generate IPSCs ([0049], [0027]); (c) then contacting the IPSCs with the TGF-beta growth factor Activin A to generate definitive endoderm ([0058]); (d) then contacting the definitive endoderm with WNT3a ([0067]) and FGF4 ([0067], [0126], [0036]; [0058] [0062], [0064]-[0066], [0071], claims 3-4) while generating spheroids of human cells; and (e) then culturing the spheroids in culture medium with EGF and the BMP inhibitor Noggin ([0034]; [00127]; [0076]) to form induced colonic organoids having intestinal tissue comprising all the major intestinal cell types ([0063]-[0064]). Munera teaches the method produces organoids (e.g., hindgut spheroids and colonic organoids) comprising epithelium and mesenchyme compartments ([0063]; [0074]; [0096]).
While Munera teaches making iPSC using reprogramming factors like Oct-3/4 and Sox2, Munera does not teach the reprogramming factors specifically comprises c-Myc and KLF4. Munera also does not teach wherein the spheroids are specifically cultured in a media comprising Rspondin1 or that the resulting human colonic organoids comprise a leaky epithelial barrier.
However Andrews teaches reprogramming adult intestinal fibroblasts (pg. 8, lines 24-29; claims 5 and 7) into iPSCs using the four factor combination of Oct4, Sox2, Klf4 and c-myc (pg. 7, lines 31-32) or expanded upon with additional factor(s), such as via transfection with mRNAs encoding the factors (pg. 8, lines 1-3 and 30-31; pg. 9, lines 1-2). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to select for use in the method of Munera the specific type of fibroblast that is a colonic fibroblast (e.g., intestinal mucosa fibroblast) as taught by Andrews wherein the fibroblast is obtained from inflamed tissue from a human subject with ulcerative colitis (e.g., inherently having the genetic background and/or epigenetic state required for disease, such as one or more locus or SNP identified by GWA as taught by McGovern (Abstract; Tables 1-2; Suppl. Table 4, pg. 335, left col., last para.) for isolation and propagation in view of McGovern teaching genetic components to ulcerative colitis (id.). One of ordinary skill in the art would be motivated to introduce genetic determinants and susceptibility loci of ulcerative colitis (complete genetic background) from a validated source (inflamed colonic tissue of an ulcerative colitis patient) as opposed to using more normal or healthy fibroblasts as the source with the goal of replicating pathological phenotypes in vitro in colonic organoids. Because McGovern teaches genetic backgrounds associated with ulcerative colitis, using a confirmed ulcerative colitis patient’s cells with the inflamed phenotype ensures a complete repertoire of requisite genetic components (and perhaps epigenetic states) are present to produce ulcerative colitis pathology, at least in some circumstances/environments.
As Fair teaches culture conditions for stem-cell derived intestinal organoids typically include EGF and the BMP inhibitor Noggin as well as some form of Wnt signaling stimulation, such via R-Spondin-1, (to replicate Wnt3a signaling in vivo) essential for cell/organoid proliferation and differentiation and gut mucosal formation (pg. 4; Fig. 2b). Thus, it would have been prima facie obvious to one of ordinary skill in the art before the effective time of filing to culture the developing organoids in a medium comprising Rspondin1, EGF and a BMP inhibitor (Noggin).
Although the combination of Munera, Andrews, McGovern, and Fair does not expressly teach the resulting organoids would comprise a leaky epithelial barrier, one of ordinary skill in the art with the goal of modeling ulcerative colitis in vitro would be motivated to perform the culturing step in culture medium with EGF or EGF and the BMP inhibitor Noggin for a sufficient duration, e.g., 28 days or longer as already taught by Munera ([0074]; [0097]-[0098]), to generate human colonic organoids comprising a leaky epithelial barrier. As the prior art combination teaches the same active method steps claimed, thus the claim recited effects of producing induced human colonic organoids (iHCOS) comprising epithelial and mesenchymal compartments and a leaky epithelial barrier are inherently produced by performing the method, when performed to make UC in vitro models and maintain genetic contributing factors in view of McGovern.
Thus, the claimed invention as a whole is prima facie obvious before the effective filing date in the absence of evidence to the contrary.
Response to Arguments
Applicant’s arguments regarding the previous 103 rejection in view of the claim amendments has been found persuasive; however, new grounds of nonobviousness are presented above.
Applicant traverses the rejection by arguing a lack of a reasonable expectation of success (pg. 8-11), especially in view of Fari and Andrews, to produce a colonic organoid having the characteristics recited in the claims which can be referred to as an “inflammatory” phenotype. However as detailed above, the prior art does not need to expect this specific result, but rather merely the expectation the prior art method steps will reasonably produce a colonic organoid (i.e., iHCOS), such as surviving for 28 days or longer for patient-derived phenotypes to develop. The inherent characteristics of the organoid, such as of comprising epithelial and mesenchymal compartments and a leaky epithelial barrier are considered inherent due to the laws of nature and logic of claim as drafted.
A chemical composition and its properties are inseparable (see MPEP 2112.01). Further, when the Office shows a sound basis for believing that the products of the applicant and the prior art are not distinguishable, “the applicant has the burden of showing that they are not.” See In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990) (MPEP 2112(V)).
The present 103 rejection is not based on whether the resulting organoids would be expected to comprise a leaky epithelial barrier based on the prior art but rather that one of ordinary skill in the art would be motivated to perform the active method steps to generate human colonic organoids as the claim recited effects of producing induced human colonic organoids (iHCOS) comprising epithelial and mesenchymal compartments with a "leaky epithelial barrier" inherently result from performing the method steps positively recited in claim 1 and rendered obvious by the prior art. The relied upon prior art teachings need not expressly teach any expectation of a leaky epithelium because as noted in the rejection above, the recited characteristics of the resulting iHOC from performing the method steps positively recited are inherent or the claims are lacking essential details in view of section 112(a). The prior art of record establishes a reasonable expectation of being able to perform all the active steps of the claimed method.
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
/JAMES D SCHULTZ/Supervisory Patent Examiner, Art Unit 1631
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