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 1-21 are pending and under examination.
WITHDRAWN REJECTIONS
Claim Rejections - 35 USC § 101
Claims 1-4 were rejected under 35 U.S.C. 101 because they are directed to product of nature.
The rejection is withdrawn in view of Applicant’s amendments to clarify that the organoid comprises a spherical structure. It is known in the art that GI organs arise from gut-tubes or buds in vivo and do not pass through a spherical stage. (See Bhatia p. 1, 2nd para).
Claim Rejections - 35 USC § 112
Claims 5-21 were 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The rejections are withdrawn in view of amendments and arguments.
Claim Rejections - 35 USC § 103
Claim 6 was rejected under 35 U.S.C. 103 as being unpatentable over Talchai et al (US20130216554; Published Oct 4, 2016; hereinafter Talchai; See PTO-892), in view of Karp et al (WO2017120543A1; Published July 13 2017; hereinafter "Karp;" See IDS filed 12/16/2022) and Christensen et al (Mol Med. 2011 May-Jun; hereinafter “Christensen;” See PTO-892).
Claim 8 was rejected under 35 U.S.C. 103 as being unpatentable over Talchai et al (US20130216554; Published Oct 4, 2016; hereinafter Talchai; See PTO-892) in view of Karp et al (WO2017120543A1; Published July 13 2017; hereinafter "Karp;" See IDS filed 12/16/2022).
The rejections are withdrawn in view of amendments and arguments. New rejections are set forth below.
Claim Rejections - 35 USC § 102
Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Karp et al (WO2017120543A1; Published July 13 2017; hereinafter "Karp;" See IDS filed 12/16/2022).
The rejection is withdrawn in view of the amendments. New rejections are set forth below.
Claims 5, 7 and 11-21 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Talchai et al (US20130216554; Published Oct 4, 2016; hereinafter Talchai; See PTO-892).
The rejection is withdrawn in view of the amendments.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sinagoga et al (Development. 2018 Oct 1; hereinafter "Sinagoga;" See PTO-892).
Regarding claims 1-3: Sinagoga cultured intestinal spheroids on 3D matrix of Matrigel. (See Sinagoga Fig. 1). Sinagoga pulsed the human intestinal organoid with doxycycline to generate functional, CHGA+ and SNYAP+ enteroendocrine cells secreting hormone markers GHRL and GIP. (See Sinagoga Fig. 1 and Fig. 2 B). Sinagoga demonstrated production of GIP as required by claim 3. Sinagoga also demonstrated organoids comprising CHGA+ cells, which is a marker of enteroendocrine lineage, as required by claim 4. As such Sinagoga disclosed a human intestinal organoid comprising a spherical structure and functional differentiated enteroendocrine cells. It is noted that Sinagoga does not explicitly disclose that the enteroendocrine cells are derived from GISCs. However, absent any claimed structural or functional distinction resulting from the source of the stem cells, the source of the EECs constitutes a process of manufacture limitation that does not impart patentable distinction to the composition.
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 5, 7-8 and 11-21 are rejected under 35 U.S.C. 103 as being unpatentable over Talchai et al (US20130216554; Published Oct 4, 2016; hereinafter Talchai; See PTO-892 of 07/23/2025), in view of Chen et al (J Mol Endocrinol. 2019 Apr 1; hereinafter “Chen;” See PTO-892).
Regarding claims 5 and 7: Talchai taught [a] method for making insulin producing enteroendocrine cells comprising:
a. obtaining a population of non-insulin producing enteroendocrine progenitor cells from the mammal,
b. contacting the population with an agent that reduces the expression or biological activity of Foxo1 (See Talchai claim 51)
Talchai did not teach or suggest AS1842856 as a FOXO1 inhibitor. However, at the time of the invention, AS1842856 was a well-known FOXO1 inhibitor and was used for the purpose of differentiation. For example, Chen taught that 5-amino-7-cyclohexylaminoacyl-1-ethyl-6-fluoro-4-oxo-1-dihydroquinoline-3- carboxylic acid (AS1842856) is a FOXO1 inhibitor that inhibits the transcriptional activity of FOXO1 by blocking the phosphorylation of FOXO1 and repressing interaction with DNA-binding sites. By means of such a mechanism, AS1842856 can further restrain autophagy, lipid accumulation and adipocyte differentiation. (See Chen p. R241, col. 1, para 1). It would have been obvious for a person of ordinary skill in the art to substitute AS1842856 as the FOXO1 inhibitor in the methods taught by Talchai to promote the differentiation of enteroendocrine cells. The skilled artisan would have expected that using a known FOXO1 inhibitor such as AS1842856 in the Talchai methods would result in the same or similar differentiation outcome as the mechanism of action of the small molecule or the siRNA based FOXO1 inhibitor of Talchai are the same.
Regarding claim 8: As indicated above, Talchai taught that FOXO1 ablation increased Neurog3+ cells and “[t]he increase of Neurog3+ cells was associated with a similar increase of cells expressing Chromagranin A, a marker of enteroendocrine cell differentiation that is expressed after Neurog3 activation, indicating that Foxo1 ablation expands gut Neurog3+ progenitors and their daughter cells”. (See Talchai [0240]).
Talchai did not teach or suggest AS1842856 as a FOXO1 inhibitor. However at the time of the invention, as pointed out above, AS1842856 was a well-known FOXO1 inhibitor and was used for the purpose of differentiation. It would have been obvious for a person of ordinary skill in the art to substitute AS1842856 as the FOXO1 inhibitor in the methods taught by Talchai to promote the differentiation of enteroendocrine cells. Further, it would have been obvious for a person of ordinary skill in the art to treat enteroendocrine progenitors with Foxo1 inhibitor for at least 1 day. It is also noted that “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In reAller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Thus a person of ordinary skill in the art would have expected to treat the stem cells with FOXO inhibitor for at least 24 hrs as required by the claim. In the instant case, Talchai and Karp taught that ChgA was expressed in 5 days and that Ngn3 was expressed in 24 hrs. It would have been obvious for a skilled person to determine a time period for FOXO1 inhibitor treatment by routine optimization.
Regarding claim 11 and 13: Talchai taught culture and differentiation of EEC progenitors and EEC in a medium comprising Wnt3a and insulin (hormone). (See Talchai [0222]-[0228])
Regarding claim 12 and 14: Talchai disclosed that the cells are incubated in a media with FOXO1 siRNA for days 4-6, which is greater than 1 day and cultured for 4 days. (See Talchai [0227]-[0228])
Regarding claim 15: Talchai disclosed culturing crypts for 3 days in a medium with no differentiating agent and then incubating the cells with differentiating agents for 2 days. (See Talchai [0222]-[0228])
Regarding claim 16: Talchai disclosed that the FOXO1 siRNA composition can be in a pharmaceutically acceptable carrier. “The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of an antisense compound to a suitable pharmaceutically acceptable diluent or carrier. “ (See Talchai [0125]). It is noted that Talchai did not teach or suggest AS1842856 as a FOXO1 inhibitor. However, as noted above, at the time of the invention, AS1842856 was a well-known FOXO1 inhibitor and was used for the purpose of differentiation. It would have been obvious for a person of ordinary skill in the art to substitute AS1842856 as the FOXO1 inhibitor in the methods taught by Talchai to promote the differentiation of enteroendocrine cells and use it in a pharmaceutical composition. The skilled artisan would have expected that using a known FOXO1 inhibitor such as AS1842856 in the Talchai methods would result in the same or similar differentiation outcome as the mechanism of action of the small molecule or the siRNA based FOXO1 inhibitor of Talchai are the same.
Regarding claims 17 and 20-21: Talchai enumerated among other diseases diabetes, as a target condition for treatment using their FOXO1 inhibitor. (See Talchai [0190]-[0192]).
Regarding claims 18-19: Talchai disclosed that it is known to administer Gut Ins+ cells as a therapeutic method for treating a disease associated with low insulin production or impaired pancreatic function. Talchai disclosed that it is possible to promote Gut Ins− Prog can be induced to differentiate into Gut Ins+ cells that secrete biologically active insulin using FOXO1 inhibitory agents. (See Talchai [0077]-[0078])
Regarding claims 6, 9 and 10:
Claims 6, 9 and 10 appear free of prior art.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 5-21 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 claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 5 requires any combination of a GATA4 activator, a cannabinoid type 1 receptor (CB1) inverse agonist, a direct or indirect PDX1 activator, a JNK inhibitor, a FOXO1 inhibitor, wherein the GATA4 activator or CB1 inverse agonist comprises rimonabant, the JNK inhibitor or PDX1 activator comprises SP600125, and the FOXO1 inhibitor comprises AS1842856. Working examples of the instant specification are directed to first, rimonabant (Rim), a highly selective cannabinoid receptor type I (CB1) antagonist that has been shown to increase human serum GIP level. (See instant specification at [0224]). Separately, instant application showed that inhibition of FOXO1 could facilitate the differentiation of EE cells in enteroids. (See instant specification at [0266]). Additionally, instant specification demonstrated that treatment with AS1842856 Followed by Rimonabant and SP600215 can produce EE cells. As such instant specification only demonstrated specific combinations of arriving at the differentiated product using the listed differentiating agents. It is submitted that the claim as recited covers
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different combinations of agents. It is submitted that absent support in the specification that any and all combination of the recited differentiating agents results in the production of enteroendocrine cells, the specification lacks sufficient description for claimed composition.
Claims 5-21 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 rimonabant as a GATA4 activator or CB1 inverse agonist, SP600125 as JNK inhibitor or PDX1 activator and AS1842856 as FXO1 inhibitor.
Applicant's specification is not found to be enabling for a GATA4 activator or CB1 inverse agonist comprising rimonabant, the JNK inhibitor or PDX1 activator comprising SP600125, and the FOXO1 inhibitor comprising AS1842856. 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 a GATA4 activator or CB1 inverse agonist comprising rimonabant, the JNK inhibitor or PDX1 activator comprising SP600125, and the FOXO1 inhibitor comprising AS1842856. The breadth of the claims includes GATA4 activator, CB1 inverse agonist, JNK inhibitor PDX1 activator or FOXO1 inhibitors that are not limited to rimonabant, SP600125 or AS1842856 respectively. In fact the breadth of the claim can encompass agents that have the claimed inhibitory or activator activity that are not exemplified in the specification or even not yet discovered.
Working examples of the instant specification are directed to first, rimonabant (Rim), a highly selective cannabinoid receptor type I (CB1) antagonist that has been shown to increase human serum GIP level. (See instant specification at [0224]). Separately, instant application showed that inhibition of FOXO1 could facilitate the differentiation of EE cells in enteroids. (See instant specification at [0266]). Additionally, instant specification demonstrated that treatment with AS1842856 Followed by Rimonabant and SP600215 can produce EE cells.
At the time the invention was made the prior art did not teach that any combination of FOXO1 inhibitors or GATA4 activator or CB1 inverse agonist, JNK inhibitor or PDX1 activator can be used interchangeably. For example, Sinagoga disclosed generation of functional enteroendocrine cells in HIO through forced expression of NEUROG3 (FOXO1 inhibitor). There has not been teachings or suggestion that EEC differentiation can be achieved using arbitrary FOXO1 inhibitors or combination of FOXO1 inhibitors or any other signaling modulators. Therefore, there was a recognized level of unpredictability with regards to the claimed modulators.
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 rimonabant (Rim), a highly selective cannabinoid receptor type I (CB1) antagonist that has been shown to increase human serum GIP level. (See instant specification at [0224]). Separately, instant application showed that inhibition of FOXO1 could facilitate the differentiation of EE cells in enteroids. (See instant specification at [0266]). Additionally, instant specification demonstrated that treatment with AS1842856 Followed by Rimonabant and SP600215 can produce EE cells. 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 EEC differentiation, and limited teachings with regards to the available number of modulators that promote enteroendocrine cell differentiation, the Office would require appropriate disclosure to support the contention that multiple modulators of the claimed functions can be successfully employed in the methods of claims 5-21. 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 claim 5. 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 any species of stem cell. Accordingly, claims 5-21are deemed properly rejected.
MAINTAINED REJECTION
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 17 is 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 claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Regarding claim 17: The claim requires treatment of a subject suffering from a disease having enteroendocrine cell dysfunction, by administering functional enteroendocrine cells. It is noted that the specification does not teach any specific way of administering the cells of the claim to the subject suffering from the enteroendocrine cell dysfunction. It is also noted that the specification taught pharmaceutical compositions can be formulated, for example, for oral administration, topical, intravenous and other forms. However, the specification did not explicitly teach treatment of any enteroendocrine dysfunction by administration of the pharmaceutical composition comprising the enteroendocrine cells. At most the specification has support for generation of the enteroendocrine cells and their pharmaceutical compositions. As such, it is determined that the specification lacks sufficient description for claim 17.
Response to Applicant’s Arguments: Applicants argued that the specification describes, in detail, the generation, characterization, and therapeutic use of functional enteroendocrine cells, as well as their formulation into pharmaceutical compositions and administration to subjects in need thereof See, e.g., Specification at p5,lns 28-35; p8, lns 29-33; p9, In 3-10 , ln18. It is noted that the indicated lines in the specification do not teach treatment of any disease by administration of the enteroendocrine cells arrived at, by performing the various methods in the invention. The specification does not describe treatment of any disease associated with enteroendocrine cell dysfunction through administration of enteroendocrine cells. The specification does not describe disease models, therapeutic outcomes or functional restoration in vivo. It is therefore pointed out that there is no possession of the claimed method in the specification. Merely listing the conventional routes of administration does not demonstrate method of treating the claimed disease. As such it is determined that the claim lacks sufficient description in the specification.
Conclusion
Claims 6, 9-10 appear free of art, however do not have sufficient description or enablement in the specification.
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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/JAGAMYA NMN VIJAYARAGHAVAN/ Examiner, Art Unit 1633
/EVELYN Y PYLA/ Primary Examiner, Art Unit 1633