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 .
Status of Claims
Claims 1-6, and 9-21 are pending and under examination.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 103
Claims 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Karp et al (WO2017120543A1; Published July 13 2017; hereinafter "Karp;" See IDS filed 12/16/2022).
The rejection is withdrawn following claim amendments. New rejections are set forth below.
Claim Rejections - 35 USC § 112
Claims 5-6 and 9-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.
The rejection is withdrawn following claim amendments.
Claims 2-3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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The rejection is withdrawn following claim amendments.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 103
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.
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 1-4 are rejected under 35 U.S.C. 103 as being unpatentable over Karp et al (WO2017120543A1; Published July 13 2017; hereinafter "Karp;" See IDS filed 12/16/2022) in view of Sinagoga et al (Development. 2018 Oct 1; See IDS 07/23/2025).
Regarding claims 1-3: Karp disclosed [a] cell population having enteroendocrine cells derived from post-natal stem cells by treating with a plurality of small molecules, wherein a fraction of the enteroendocrine cells is at least about 1% of the total cell population. (See Karp claim 58). The cell population, as disclosed in Karp is interpreted to read on an organoid. In fact, claim 99 indicated that the in vitro population comprises organoids. It is also noted that Karp defines “enteroendocrine cells” as comprising cells expressing CCK and GIP among other markers. (See [0085]). Further the specification defined enteroendocrine cells as cells that can secrete hormones such as GLP-1, 5HT among others – alluding to the functional enteroendocrine cells as required by the claim. For example, Karp taught that “[t]he enteroendocrine cells form the largest endocrine system in the body, and can sense luminal contents, particularly nutrients, and respond by the secretion of a diversity of hormones (e.g. GLP-1) which modulate food intake, energy homeostasis and glucose tolerance.” (See Karp [0085]). Additionally, "post-natal stem cell" of Karp is defined in [00118] as "non-embryonic stem cells that have the capacity to self-renew and to differentiate into multiple cell lineages. Post-natal stem cells may also be referred to as adult stem cells or somatic stem cells. Post-natal stem cells can include intestinal stem cells." As such “intestinal stem cells” read on gastrointestinal stem cells. Further Fig. 19 of Karp showed spherical structure of EEC differentiated from intestinal stem cells (See Karp [0028], [00242]) and that most of the EECs secrete 5-HT as well as GLP1. It is noted that Karp did not explicitly teach that the organoid secretes GIP as required by the claim. It is initially, pointed out that Karp taught the existence of GIP positive EEC in their organoids. Further, Sinagoga pointed taught EEC cells expressing GIP using qPCR data (See Sinagoga Fig, 4). Additionally, Sinagoga taught expression of GIP in these GIP positive cells of the intestinal organoids comprising EEC. (See Sinagoga Figure 4). Sinagoga as such demonstrated that human intestinal organoids containing GIP positive cells exhibit GIP secretion. Moreover, Figure 5 of Sinagoga exhibited that luminal glucose increased bothe GIP and GIP positive cells. Thus Sinagoga provided direct evidence that GIP-positive EEC in human intestinal organoids are associated with and functionally capable of GIP secretion.
It would have been obvious to arrive at the claimed composition of enteroendocrine cells that are spherical organoids, and expressing CCK, and GIP from gastrointestinal stem cells as required by claims 1-3 in view of teachings of Karp wherein the cell secrete GIP and 5HT. A person of ordinary skill in the art in view of Karp would have recognized that the differentiation and functional maturation of enteroendocrine cells is governed by network of signaling pathways. It would therefore have been obvious to combine or substitute known pathway modulators as taught by Karp to arrive at the claimed composition from stem cells. Karp disclosed the same or substantially the same enteroendocrine cell population as recited in claim 1, including cells exhibiting the same differentiated endocrine markers. As such Karp renders obvious the claimed composition.
Regarding claim 4: Instant specification indicated that enteroendocrine lineage markers can be “ALP1, ATOH1, CCK, CHGA, GCG, GIP, LGR5, MUC2, NEUROD1, NEUROG3, PAX4, PYY, and SST, or combinations thereof.” (See instant specification [0008]). Karp taught that “Enteroendocrine cells can be identified by expression of ChgA marker, which can be detected by assays such as the mRNA ChgA Expression Assay and ChgA Immunostaining Assay described herein.” As such Karp taught the claimed compositions.
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 1-4 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as failing to set forth 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 terms GIP, and 5HT need to be expanded at the first instance of their use for greater clarity.
MAINTAINED REJECTIONS
Claims 17-21 are rejected under 35 USC 112(a) as failing to comply with the enablement requirement.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Applicant's specification is found enabling for differentiation of gastrointestinal stem cells into enteroendocrine cells using certain differentiation agents administered at specific intervals.
Applicant's specification is not found to be enabling for treatment of enteroendocrine dysfunction, metabolic diseases, Crohn’s disease, IBD or IBS or Colitis using the enteroendocrine cells produced by the claimed methods. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to carry out the method of the invention commensurate in scope with the current claims.
Analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention without undue or unreasonable experimentation. See Mineral Separation v. Hyde, 242 U.S. 261, 270 (1916). The key word is 'undue,' not experimentation.' " (Wands, 8 USPQ2d 1404). The factors to be considered in determining whether undue experimentation is required are summarized In re Wands 858 F.2d 731, 8 USPQ2nd 1400 (Fed. Cir, 1988). The factors to be considered in determining whether undue experimentation is required include: (1) the quantity of experimentation necessary, (2) the amount or direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims. While all these factors are considered, a sufficient number are discussed below so as to create a prima facie case.
Applicants' claims are directed to treatment of enteroendocrine dysfunction, metabolic diseases, Crohn’s disease, IBD or IBS or Colitis using the enteroendocrine cells produced by the claimed methods. The breadth of the claims include fatty liver disease, types 1 and 2 diabetes, polycystic ovary syndrome, obesity among many others.
Working examples of the instant specification are directed to production of enteroendocrine cells using differentiation agents like, rimonabant (Rim), a highly selective cannabinoid receptor type I (CB1) antagonist and FOXO1 inhibitors in specific treatment regimen.
At the time the invention was made the prior art taught that metabolic diseases like obesity or irritable bowel diseases are highly complex diseases. For example, Khanna taught that “[o]besity has a multifactorial etiology that includes genetic, environmental, socioeconomic, and behavioral or psychological influences.” (See Khanna p. 1, para 1). Khanna et al taught that “Obesity is also referred to as chronic-low-grade inflammation or “metabolic inflammation, ”which is often the focus in the pathogenesis of several diseases such as coronary artery disease, atherosclerosis, and insulin resistance.” (See Khanna et al, p. 2, para 3). Next, Nathani et al taught that “[i]rritable bowel syndrome (IBS) is a complex and highly prevalent disorder of gut-brain interaction (DGBI), characterized by recurrent abdominal pain and altered bowel habits, including constipation, diarrhea, or a combination of both.” (See Nathani et al p. 1, para 1). Nathani et al further taught that “visceral hypersensitivity, dysmotility, microbiota alterations, psychosocial influences, and gut-brain axis dysfunction” also play a role in IBS pathogenesis (See Nathani et al, p. 1, 1st para). A person of ordinary skill in the art would readily recognize that metabolic diseases including obesity, IBS are not simple diseases or can be cured using a single approach. There is no teaching in the prior art that transplanting enteroendocrine cells can treat all metabolic diseases, Crohn’s, enteroendocrine dysfunctions or any of the diseases encompassed by the subject claims. Neither does the specification specifically demonstrate treatment of the claimed diseases.
Due to the recognized unpredictability in the area of differentiation of EEC, a large amount of guidance and teachings would be necessary in order to be enabling for methods of such.
Guidance and teachings provided by Applicants in the instant specification is limited to disclosure that enteroendocrine cells can be differentiated by gastrointestinal stem cells using specific differentiation agents. The Examiner acknowledges that the Office does not require the presence of working examples to be present in the disclosure of the invention (see MPEP §2164.02). However, in light of the state of the art, discussed above, which recognizes a high level of unpredictability in the field of treatment of any and all metabolic diseases, enteroendocrine diseases, irritable bowel syndrome, Crohn’s disease among many others, the Office would require appropriate disclosure to support the contention that the claimed enteroendocrine cells can be employed for the treatment of diseases claimed in the methods of claims 17-21. The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). Thus, due to the high level of unpredictability in the art, the current specification would have to provide greater amounts of teachings and guidance directed to methods of carrying out the claimed invention.
Therefore, due to the sum of all the aforementioned factors, one of ordinary skill in the art, at the time the invention was made, would not expect success carrying out the claimed method of claims 17-21. Given that the art fails to recognize, and Applicant has failed to demonstrate, use of combinations of the claimed modulators, the skilled artisan would be faced with the impermissible burden of undue experimentation in order to practice the claimed invention using enteroendocrine cells. Accordingly, claims 17-21 are deemed properly rejected.
Response to Applicant’s arguments: Applicant argued that the specification teaches methods for differentiating gastrointestinal stem cells into functional enteroendocrine cells, provides examples demonstrating hormone expression and secretion and describes administration or transplantation of the resulting cells. However, these disclosures do not adequately address the full scope of the claimed therapeutic method.
Claims 17-21 require administering a pharmaceutical composition comprising functional EECs in an effective amount to treat a subject suffering from a disease having EEC dysfunction. Accordingly, the claimed invention is not limited to methods of producing EECs or demonstrating their hormone-secretion capabilities. Rather, the claim requires that administration of the cells achieve a therapeutic result.
The examples cited by the Applicant demonstrate differentiation of GSIC cells and expression or secretion of EEC-associated hormones including serotonin, GIP somatostatin among others. However, demonstrating that differentiated cells possess certain EEC-associated characteristics does not by itself establish that administering those cells will effectively treat the diseases encompassed by the claims.
Moreover the claims encompass a broad range of metabolic and gastrointestinal conditions, including obesity, TIID Crohn’s and ulcerative colitis. The fact that EEC hormones may participate in physiological processes relevant to these conditions does not establish that administration of the disclosed EECs will produce therapeutic benefit across the claimed scope. As such, it is submitted that the diversity of the claimed conditions considered together with the breadth of the therapeutic method and the limited guidance in the specification as well as prior art to determine whether and under what conditions, administration of the claimed composition would achieve the therapeutic result, all establish the deficiency of enablement in the instant claims.
It is also submitted that routine optimization techniques do not establish enablement. It is noted that the specification does not provide guidance to practice the claimed therapeutic method across it’s full scope. As such, Applicant’s disclosures concerning the production and characterization of functional EEC do not resolve the indicated deficiency of enablement. The rejection is maintained.
Allowable subject matter
Claims 5-6, and 9-16 appear free of art. There is no disclosure in the prior art to arrive at the claimed EEC using the claimed method.
Conclusion
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 JAGAMYA VIJAYARAGHAVAN whose telephone number is (703)756-5934. The examiner can normally be reached 9:00a-5:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher M. Babic can be reached at 571-272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/Primary Examiner, Art Unit 1633
